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Sample records for mir-17-5p promotes migration

  1. MicroRNA-17-5p promotes gastric cancer proliferation, migration and invasion by directly targeting early growth response 2

    PubMed Central

    Chen, Peng; Zhao, Huasi; Huang, Jingjing; Yan, Xizhong; Zhang, Yunfei; Gao, Yongshun

    2016-01-01

    MicroRNA-17-5p (miR-17-5p) has previously been reported to play an important role in tumor development and progression. However, it functions differently regarding different kinds of malignant tumor, and its role and mechanism in gastric cancer (GC) still lacks investigation. In this study, we detected the relationship between miR-17-5p and the development of GC by qRT-PCR, and it turned out that the level of miR-17-5p was significantly higher in GC patients than that in normal controls, and the aberrant expression of miR-17-5p was correlated with lymph node metastasis. After that, we examined the effect of miR-17-5p taking on the proliferation, apoptosis, migration and invasion of GC cells and the underlying mechanism. Experiments indicated that knockdown of miR-17-5p inhibited the proliferation, invasion and migration, while promoting apoptosis of SGC7901 cells. Early Growth Response 2 (EGR2) protein or mRNA levels were downregulated or upregulated after overexpression or knockdown of miR-17-5p, respectively. By using dual luciferase assay and Western blot, we identified EGR2 as a functional target of miR-17-5p. As far as we know, this could be the first study to demonstrate that miR-17-5p is associated with tumor stage of GC and that it could possibly become a new therapeutic method for the treatment of GC. PMID:27725906

  2. Repression of miR-17-5p with elevated expression of E2F-1 and c-MYC in non-metastatic hepatocellular carcinoma and enhancement of cell growth upon reversing this expression pattern

    SciTech Connect

    El Tayebi, H.M.; Omar, K.; Hegy, S.; El Maghrabi, M.; El Brolosy, M.; Hosny, K.A.; Esmat, G.; Abdelaziz, A.I.

    2013-05-10

    Highlights: •The oncogenic miR-17-5p is downregulated in non-metastatic hepatocellular carcinoma patients. •E2F-1 and c-MYC transcripts are upregulated in non-metastatic HCC patients. •miR-17-5p forced overexpression inhibited E2F-1 and c-MYC expression in HuH-7 cells. •miR-17-5p mimicking increased HuH-7 cell growth, proliferation, migration and colony formation. •miR-17-5p is responsible for HCC progression among the c-MYC/E2F-1/miR-17-5p triad members. -- Abstract: E2F-1, c-MYC, and miR-17-5p is a triad of two regulatory loops: a negative and a positive loop, where c-MYC induces the expression of E2F-1 that induces the expression of miR-17-5p which in turn reverses the expression of E2F-1 to close the loop. In this study, we investigated this triad for the first time in hepatocellular carcinoma (HCC), where miR-17-5p showed a significant down-regulation in 23 non-metastatic HCC biopsies compared to 10 healthy tissues; however, E2F-1 and c-MYC transcripts were markedly elevated. Forced over-expression of miR-17-5p in HuH-7 cells resulted in enhanced cell proliferation, growth, migration and clonogenicity with concomitant inhibition of E2F-1 and c-MYC transcripts expressions, while antagomirs of miR-17-5p reversed these events. In conclusion, this study revealed a unique pattern of expression for miR-17-5p in non-metastatic HCC patients in contrast to metastatic HCC patients. In addition we show that miR-17-5p is the key player among the triad that tumor growth and spread.

  3. miR-31 and miR-17-5p levels change during transformation of follicular lymphoma.

    PubMed

    Thompson, Mary Ann; Edmonds, Mick D; Liang, Shan; McClintock-Treep, Sara; Wang, Xuan; Li, Shaoying; Eischen, Christine M

    2016-04-01

    The 30% of patients whose indolent follicular lymphoma transforms to aggressive diffuse large B-cell lymphoma (DLBCL) have poor survival. Reliable predictors of follicular B-cell lymphoma transformation to DLBCL are lacking, and diagnosis of those that will progress is challenging. MicroRNA, which regulates gene expression, has critical functions in the growth and progression of many cancers and contributes to the pathogenesis of lymphoma. Using 5 paired samples from patients who presented with follicular lymphoma and progressed to DLBCL, we identified specific microRNA differentially expressed between the two. Specifically, miR-17-5p levels were low in follicular lymphoma and increased as the disease transformed. In contrast, miR-31 expression was high in follicular lymphoma and decreased as the lymphoma progressed. These results were confirmed in additional unpaired cases of low-grade follicular lymphoma (n = 13) and high-grade follicular lymphoma grade 3 or DLBCL (n = 17). Loss of miR-31 expression in DLBCL was not due to deletion of the locus. Changes in miR-17-5p and miR-31 were not correlated with immunophenotype, genetics, or status of the MYC oncogene. However, increased miR-17-5p expression did significantly correlate with increased expression of p53 protein, which is indicative of mutant TP53. Two pro-proliferative genes, E2F2 and PI3KC2A, were identified as direct messenger RNA targets of miR-31, suggesting that these may contribute to follicular lymphoma transformation. Our results indicate that changes in miR-31 and miR-17-5p reflect the transformation of follicular lymphoma to an aggressive large B-cell lymphoma and may, along with their targets, be viable markers for this process.

  4. Non-Specific Blocking of miR-17-5p Guide Strand in Triple Negative Breast Cancer Cells by Amplifying Passenger Strand Activity

    PubMed Central

    Jin, Yuan-Yuan; Andrade, Jade; Wickstrom, Eric

    2015-01-01

    Conventional wisdom holds that only one of the two strands in a micro ribonucleic acid (miRNA) precursor duplex is selected as the active miRNA guide strand. The complementary miRNA passenger strand, however, is thought to be inactive. High levels of the oncogenic miRNA (oncomiR) guide strand called miR-17-5p is overexpressed in triple negative breast cancer (TNBC) and can inhibit ribosomal translation of tumor suppressor gene mRNAs, such as programmed cell death 4 (PDCD4) or phosphatase and tensin homolog (PTEN). We hypothesized that knocking down the oncogenic microRNA (oncomiR) miR-17-5p might restore the expression levels of PDCD4 and PTEN tumor suppressor proteins, illustrating a route to oligonucleotide therapy of TNBC. Contrary to conventional wisdom, antisense knockdown of oncomiR miR-17-5p guide strand reduced PDCD4 and PTEN proteins by 1.8±0.3 fold in human TNBC cells instead of raising them. Bioinformatics analysis and folding energy calculations revealed that mRNA targets of miR-17-5p guide strand, such as PDCD4 and PTEN, could also be regulated by miR-17-3p passenger strand. Due to high sequence homology between the antisense molecules and miR-17-3p passenger strand, as well as the excess binding sites for the passenger strand on the 3’UTR of PDCD4 and PTEN mRNAs, introducing a miR-17-3p DNA-LNA mimic to knock down miR-17-5p reduced PDCD4 and PTEN protein expression instead of raising them. Our results imply that therapeutic antisense sequences against miRNAs should be designed to target the miRNA strand with the greatest number of putative binding sites in the target mRNAs, while minimizing affinity for the minor strand. PMID:26629823

  5. Involvement of MAP3K8 and miR-17-5p in Poor Virologic Response to Interferon-Based Combination Therapy for Chronic Hepatitis C

    PubMed Central

    Tsubota, Akihito; Mogushi, Kaoru; Aizaki, Hideki; Miyaguchi, Ken; Nagatsuma, Keisuke; Matsudaira, Hiroshi; Kushida, Tatsuya; Furihata, Tomomi; Tanaka, Hiroshi; Matsuura, Tomokazu

    2014-01-01

    Despite advances in chronic hepatitis C treatment, a proportion of patients respond poorly to treatment. This study aimed to explore hepatic mRNA and microRNA signatures involved in hepatitis C treatment resistance. Global hepatic mRNA and microRNA expression profiles were compared using microarray data between treatment responses. Quantitative real-time polymerase chain reaction validated the gene signatures from 130 patients who were infected with hepatitis C virus genotype 1b and treated with pegylated interferon-alpha and ribavirin combination therapy. The correlation between mRNA and microRNA was evaluated using in silico analysis and in vitro siRNA and microRNA inhibition/overexpression experiments. Multivariate regression analysis identified that the independent variables IL28B SNP rs8099917, hsa-miR-122-5p, hsa-miR-17-5p, and MAP3K8 were significantly associated with a poor virologic response. MAP3K8 and miR-17-5p expression were inversely correlated with treatment response. Furthermore, miR-17-5p repressed HCV production by targeting MAP3K8. Collectively, the data suggest that several molecules and the inverse correlation between mRNA and microRNA contributed to a host genetic refractory hepatitis C treatment response. PMID:24819603

  6. Stress response of glioblastoma cells mediated by miR-17-5p targeting PTEN and the passenger strand miR-17-3p targeting MDM2.

    PubMed

    Li, Haoran; Yang, Burton B

    2012-12-01

    Tumor development not only destroys the homeostasis of local tissues but also the whole body, and thus the tumor cells have to face the body's defense system, a shortage of nutrition and oxygen, and chemotherapeutic drug treatment. In response to these stresses, tumor cells often alter gene expression and microRNA levels to facilitate survival. We have demonstrated that glioblastoma cells deprived of nutrition or treated with chemotherapeutics drugs expressed increased levels of miR-17. Ectopic transfection of miR-17 prolonged glioblastoma cell survival when the cells were deprived with nutrition or treated with chemotherapeutic drugs. Expression of miR-17 also promoted cell motility, invasion, and tube-like structure formation. We found that these phenotypes were the results of miR-17 targeting PTEN. As a consequence, HIF1α and VEGF were up-regulated. Ectopic expression of miR-17 was found to facilitate enrichment of stem-like tumor cells, since the cells became drug-resistant, showed increased capacity to form colonies and neurospheres, and expressed higher levels of CD133, a phenotype similar to ectopic expression of HIF1α. To further confirm the phenotypic property of stem cells, we demonstrated that glioblastoma cells transfected with miR-17 proliferated slower in different nutritional conditions by facilitating more cells staying in the G1 phase than the control cells. Finally, we demonstrated that miR-17 could repress MDM2 levels, resulting in decreased cell proliferation and drug-resistance. Our results added a new layer of functional mechanism for the well-studied miRNA miR-17.

  7. Neuritin 1 promotes neuronal migration.

    PubMed

    Zito, Arianna; Cartelli, Daniele; Cappelletti, Graziella; Cariboni, Anna; Andrews, William; Parnavelas, John; Poletti, Angelo; Galbiati, Mariarita

    2014-01-01

    Neuritin 1 (Nrn1 or cpg15-1) is an activity-dependent protein involved in synaptic plasticity during brain development, a process that relies upon neuronal migration. By analyzing Nrn1 expression, we found that it is highly expressed in a mouse model of migrating immortalized neurons (GN11 cells), but not in a mouse model of non-migrating neurons (GT1-7 cells). We thus hypothesized that Nrn1 might control neuronal migration. By using complementary assays, as Boyden's microchemotaxis, scratch-wounding and live cell imaging, we found that GN11 cell migration is enhanced when Nrn1 is overexpressed and decreased when Nrn1 is silenced. The effects of Nrn1 in promoting neuronal migration have been then confirmed ex vivo, on rat cortical interneurons, by Boyden chamber assays and focal electroporation of acute embryonic brain slices. Furthermore, we found that Nrn1 level modulation affects GN11 cell morphology. The process is also paralleled by Nrn1-induced α-tubulin post-translational modifications, a well-recognized marker of microtubule stability. Altogether, the data demonstrate a novel function of Nrn1 in promoting migration of neuronal cells and indicate that Nrn1 levels impact on microtubule stability. PMID:23212301

  8. Schwann cells promote endothelial cell migration

    PubMed Central

    Ramos, Tiago; Ahmed, Maqsood; Wieringa, Paul; Moroni, Lorenzo

    2015-01-01

    Directed cell migration is a crucial orchestrated process in embryonic development, wound healing, and immune response. The underlying substrate can provide physical and/or chemical cues that promote directed cell migration. Here, using electrospinning we developed substrates of aligned poly(lactic-co-glycolic acid) nanofibres to study the influence of glial cells on endothelial cells (ECs) in a 3-dimensional (3D) co-culture model. ECs build blood vessels and regulate their plasticity in coordination with neurons. Likewise, neurons construct nerves and regulate their circuits in coordination with ECs. In our model, the neuro-vascular cross-talk was assessed using a direct co-culture model of human umbilical vein endothelial cells (HUVECs) and rat Schwann cells (rSCs). The effect of rSCs on ECs behavior was demonstrated by earlier and higher velocity values and genetic expression profiles different of those of HUVECs when seeded alone. We observed 2 different gene expression trends in the co-culture models: (i) a later gene expression of angiogenic factors, such as interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF), and (ii) an higher gene expression of genes involved in actin filaments rearrangement, such as focal adhesion kinase (FAK), Mitogen-activated protein kinase-activated protein kinase 13 (MAPKAPK13), Vinculin (VCL), and Profilin (PROF). These results suggested that the higher ECs migration is mainly due to proteins involved in the actin filaments rearrangement and in the directed cell migration rather than the effect of angiogenic factors. This co-culture model provides an approach to enlighten the neurovascular interactions, with particular focus on endothelial cell migration. PMID:26491999

  9. HIF-1α Promotes A Hypoxia-Independent Cell Migration.

    PubMed

    Li, Liyuan; Madu, Chikezie O; Lu, Andrew; Lu, Yi

    2010-01-01

    Hypoxia-inducible factor-1α (HIF-1α) is known as a transactivator for VEGF gene promoter. It can be induced by hypoxia. However, no study has been done so far to dissect HIF-1α-mediated effects from hypoxia or VEGF-mediated effects. By using a HIF-1α knockout (HIF-1α KO) cell system in mouse embryonic fibroblast (MEF) cells, this study analyzes cell migration and HIF-1α, hypoxia and VEGF activation. A hypoxia-mediated HIF-1α induction and VEGF transactivation were observed: both HIF-1α WT lines had significantly increased VEGF transactivation, as an indicator for HIF-1α induction, in hypoxia compared to normoxia; in contrast, HIF-1α KO line had no increased VEGF transactivation under hypoxia. HIF-1α promotes cell migration: HIF-1α-KO cells had a significantly reduced migration compared to that of the HIF-1α WT cells under both normoxia and hypoxia. The significantly reduced cell migration in HIF-1α KO cells can be partially rescued by the restoration of WT HIF-1α expression mediated by adenoviral-mediated gene transfer. Interestingly, hypoxia has no effect on cell migration: the cells had a similar cell migration rate under hypoxic and normoxic conditions for both HIF-1α WT and HIF-1α KO lines, respectively. Collectively, these data suggest that HIF-1α plays a role in MEF cell migration that is independent from hypoxia-mediated effects.

  10. HIF-1α Promotes A Hypoxia-Independent Cell Migration

    PubMed Central

    Li, Liyuan; Madu, Chikezie O.; Lu, Andrew; Lu, Yi

    2010-01-01

    Hypoxia-inducible factor-1α (HIF-1α) is known as a transactivator for VEGF gene promoter. It can be induced by hypoxia. However, no study has been done so far to dissect HIF-1α-mediated effects from hypoxia or VEGF-mediated effects. By using a HIF-1α knockout (HIF-1α KO) cell system in mouse embryonic fibroblast (MEF) cells, this study analyzes cell migration and HIF-1α, hypoxia and VEGF activation. A hypoxia-mediated HIF-1α induction and VEGF transactivation were observed: both HIF-1α WT lines had significantly increased VEGF transactivation, as an indicator for HIF-1α induction, in hypoxia compared to normoxia; in contrast, HIF-1α KO line had no increased VEGF transactivation under hypoxia. HIF-1α promotes cell migration: HIF-1α-KO cells had a significantly reduced migration compared to that of the HIF-1α WT cells under both normoxia and hypoxia. The significantly reduced cell migration in HIF-1α KO cells can be partially rescued by the restoration of WT HIF-1α expression mediated by adenoviral-mediated gene transfer. Interestingly, hypoxia has no effect on cell migration: the cells had a similar cell migration rate under hypoxic and normoxic conditions for both HIF-1α WT and HIF-1α KO lines, respectively. Collectively, these data suggest that HIF-1α plays a role in MEF cell migration that is independent from hypoxia-mediated effects. PMID:20882121

  11. Osteoactivin Promotes Migration of Oral Squamous Cell Carcinomas.

    PubMed

    Arosarena, Oneida A; Dela Cadena, Raul A; Denny, Michael F; Bryant, Evan; Barr, Eric W; Thorpe, Ryan; Safadi, Fayez F

    2016-08-01

    Nearly 50% of patients with oral squamous cell carcinoma (OSCC) die of metastases or locoregional recurrence. Metastasis is mediated by cancer cell adhesion, migration, and invasion. Osteoactivin (OA) overexpression plays a role in metastases in several malignancies. The aims were to determine how integrin interactions modulate OA-induced OSCC cell migration; and to investigate OA effects on cell survival and proliferation. We confirmed OA mRNA and protein overexpression in OSCC cell lines. We assessed OA's interactions with integrins using adhesion inhibition assays, fluorescent immunocytochemistry and co-immunoprecipitation. We investigated OA-mediated activation of mitogen-activated protein kinases (MAPKs) and cell survival. Integrin inhibition effects on OA-mediated cell migration were determined. We assessed effects of OA knock-down on cell migration and proliferation. OA is overexpressed in OSCC cell lines, and serves as a migration-promoting adhesion molecule. OA co-localized with integrin subunits, and co-immunoprecipitated with the subunits. Integrin blocking antibodies, especially those directed against the β1 subunit, inhibited cell adhesion (P = 0.03 for SCC15 cells). Adhesion to OA activated MAPKs in UMSCC14a cells and OA treatment promoted survival of SCC15 cells. Integrin-neutralizing antibodies enhanced cell migration with OA in the extracellular matrix. OA knock-down resulted in decreased proliferation of SCC15 and SCC25 cells, but did not inhibit cell migration. OA in the extracellular matrix promotes OSCC cell adhesion and migration, and may be a novel target in the prevention of HNSCC spread. J. Cell. Physiol. 231: 1761-1770, 2016. © 2015 Wiley Periodicals, Inc. PMID:26636434

  12. Osteoactivin Promotes Migration of Oral Squamous Cell Carcinomas.

    PubMed

    Arosarena, Oneida A; Dela Cadena, Raul A; Denny, Michael F; Bryant, Evan; Barr, Eric W; Thorpe, Ryan; Safadi, Fayez F

    2016-08-01

    Nearly 50% of patients with oral squamous cell carcinoma (OSCC) die of metastases or locoregional recurrence. Metastasis is mediated by cancer cell adhesion, migration, and invasion. Osteoactivin (OA) overexpression plays a role in metastases in several malignancies. The aims were to determine how integrin interactions modulate OA-induced OSCC cell migration; and to investigate OA effects on cell survival and proliferation. We confirmed OA mRNA and protein overexpression in OSCC cell lines. We assessed OA's interactions with integrins using adhesion inhibition assays, fluorescent immunocytochemistry and co-immunoprecipitation. We investigated OA-mediated activation of mitogen-activated protein kinases (MAPKs) and cell survival. Integrin inhibition effects on OA-mediated cell migration were determined. We assessed effects of OA knock-down on cell migration and proliferation. OA is overexpressed in OSCC cell lines, and serves as a migration-promoting adhesion molecule. OA co-localized with integrin subunits, and co-immunoprecipitated with the subunits. Integrin blocking antibodies, especially those directed against the β1 subunit, inhibited cell adhesion (P = 0.03 for SCC15 cells). Adhesion to OA activated MAPKs in UMSCC14a cells and OA treatment promoted survival of SCC15 cells. Integrin-neutralizing antibodies enhanced cell migration with OA in the extracellular matrix. OA knock-down resulted in decreased proliferation of SCC15 and SCC25 cells, but did not inhibit cell migration. OA in the extracellular matrix promotes OSCC cell adhesion and migration, and may be a novel target in the prevention of HNSCC spread. J. Cell. Physiol. 231: 1761-1770, 2016. © 2015 Wiley Periodicals, Inc.

  13. Commensal bacteria promote migration of mast cells into the intestine.

    PubMed

    Kunii, Junichi; Takahashi, Kyoko; Kasakura, Kazumi; Tsuda, Masato; Nakano, Kou; Hosono, Akira; Kaminogawa, Shuichi

    2011-06-01

    Mast cells differentiate from hematopoietic stem cells in the bone marrow and migrate via the circulation to peripheral tissues, where they play a pivotal role in induction of both innate and adaptive immune responses. In this study, the effect of intestinal commensal bacteria on the migration of mast cells into the intestine was investigated. Histochemical analyses showed that germ-free (GF) mice had lower mast cell densities in the small intestine than normal mice. It was also shown that GF mice had lower mast cell proportion out of lamina propria leukocytes in the small intestine and higher mast cell percentages in the blood than normal mice by flow cytometry. These results indicate that migration of mast cells from the blood to the intestine is promoted by intestinal commensal bacteria. In addition, MyD88⁻/⁻ mice had lower densities of intestinal mast cells than CV mice, suggesting that the promotive effect of commensals is, at least in part, TLR-dependent. The ligands of CXC chemokine receptor 2 (CXCR2), which is critical for homing of mast cells to the intestine, were expressed higher in intestinal tissues and in intestinal epithelial cells (IECs) of normal mice than in those of GF or MyD88⁻/⁻ mice. Collectively, it is suggested that commensals promote migration of mast cells into the intestine through the induction of CXCR2 ligands from IECs in a TLR-dependent manner.

  14. Phototherapy promotes cell migration in the presence of hydroxyurea.

    PubMed

    Zungu, I L; Mbene, A B; Hawkins Evans, D H; Houreld, N N; Abrahamse, H

    2009-03-01

    Phototherapy has been shown to cause an increase in cell proliferation and migration. This study focused on viability (trypan blue), proliferation [sodium 3'-(1-(phenylaminocarbonyl)-3,4-tetrazolium)-bis(4-methoxy-6-nitro)-benzene sulphonic acid hydrate (XTT) and adenosine triphosphate (ATP)] and migration of WS1 cells following irradiation in the presence of hydroxyurea (HU), which is an inhibitor of proliferation. Wounded cells were irradiated on days 1 and 4 with a fluence of 5 J/cm(2) with a helium-neon (He-Ne) laser at 632.8 nm. After a repair time of 24 h, cellular responses were assessed. Wounded irradiated cells without HU showed an increase in cell viability and proliferation, which was confirmed by complete wound closure by day 4. Although wounded irradiated cells treated with 5 mM HU showed incomplete wound closure, these cells showed increased migration compared with that of control cells. This study showed that laser irradiation using an He-Ne laser with a fluence of 5 J/cm(2) stimulates cell viability. The HU results confirmed that laser irradiation promotes cell migration and proliferation. PMID:18214574

  15. Nifedipine Promotes the Proliferation and Migration of Breast Cancer Cells

    PubMed Central

    Guo, Dong-Qing; Zhang, Hao; Tan, Sheng-Jiang; Gu, Yu-Chun

    2014-01-01

    Nifedipine is widely used as a calcium channel blocker (CCB) to treat angina and hypertension,but it is controversial with respect the risk of stimulation of cancers. In this study, we demonstrated that nifedipine promoted the proliferation and migration of breast cancer cells both invivo and invitro. However, verapamil, another calcium channel blocker, didn’t exert the similar effects. Nifedipine and high concentration KCl failed to alter the [Ca2+]i in MDA-MB-231 cells, suggesting that such nifedipine effect was not related with calcium channel. Moreover, nifedipine decreased miRNA-524-5p, resulting in the up-regulation of brain protein I3 (BRI3). Erk pathway was consequently activated and led to the proliferation and migration of breast cancer cells. Silencing BRI3 reversed the promoting effect of nifedipine on the breast cancer. In a summary, nifedipine stimulated the proliferation and migration of breast cancer cells via the axis of miRNA-524-5p-BRI3–Erk pathway independently of its calcium channel-blocking activity. Our findings highlight that nifedipine but not verapamil is conducive for breast cancer growth and metastasis, urging that the caution should be taken in clinic to prescribe nifedipine to women who suffering both hypertension and breast cancer, and hypertension with a tendency in breast cancers. PMID:25436889

  16. Promotion of cooperation by payoff-driven migration

    NASA Astrophysics Data System (ADS)

    Chen, Ya-Shan; Yang, Han-Xin; Guo, Wen-Zhong

    2016-05-01

    Migration plays an important role in the evolution of cooperation. Previous studies concerning mobile population often assumed that all agents move with the identical velocity. In this paper, we propose a payoff-driven migration in which the velocity of an agent depends on his/her payoff. A parameter α is introduced to adjust the influence of payoff, when α = 0 means that agents all move with the identical velocity while α > 0 means that the lower the payoff is, the faster the moving speed is, and vice versa. For the prisoner's dilemma game, we find that in comparison with the case that agents all move with the same speed, cooperation could be promoted strongly when payoff-dependent velocity is considered. Remarkably, the cooperation level is not a monotonic function of α, and there exists an optimal value of α which can lead to the maximum cooperation level. For the snowdrift game, the cooperation level increases with α.

  17. Flavonoids promoting HaCaT migration: I. Hologram quantitative structure-activity relationships.

    PubMed

    Cho, Moonjae; Yoon, Hyuk; Park, Mijoo; Kim, Young Hwa; Lim, Yoongho

    2014-03-15

    Cell migration plays an important role in multicellular development and preservation. Because wound healing requires cell migration, compounds promoting cell migration can be used for wound repair therapy. Several plant-derived polyphenols are known to promote cell migration, which improves wound healing. Previous studies of flavonoids on cell lines have focused on their inhibitory effects and not on wound healing. In addition, studies of flavonoids on wound healing have been performed using mixtures. In this study, individual flavonoids were used for cellular migration measurements. Relationships between the cell migration effects of flavonoids and their structural properties have never been reported. Here, we investigated the migration of keratinocytes caused by 100 flavonoids and examined their relationships using hologram quantitative structure-activity relationships. The structural conditions responsible for efficient cell migration on keratinocyte cell lines determined from the current study will facilitate the design of flavonoids with improved activity.

  18. A scheme to promote the world's economic development with migration.

    PubMed

    Simon, J L

    1982-01-01

    Migration's social value is generally assessed from the perspective of the receiving country. At this time the policies of rich countries allow fewer immigrants to enter than would enter under a laissez faire policy, but this may be a suboptimal policy for the world population as a whole. Those who now migrate from poor to rich countries and those who are prevented from doing so by restrictive laws certainly believe that their economic situation would be improved by such migration. A scheme for improving the worldwide welfare while making appropriate allowance for the preferences of those in the rich countries is discussed. The scheme deals with the migration of poorly schooled and semiskilled people and not the well educated. As the rich countries will not voluntarily open their borders to such immigration, a change in the international system is suggested, giving some power of taxation to an international body. This body would then pay the rich countries to take in immigrants by holding an auction among the rich countries for the immigration contracts. The scheme is analyzed, and it is argued that in the long run this approach is not as politically impossible as it initially seems. The discussion reviews the problem, the system, and the possibilities (the power of migration, the mechanisms in migration's power to raise productivity, earning patterns of immigrant cohorts, and additional possible tests) and the relative effectiveness of migration verses education in the less developed countries. It seems reasonable to send the migrants to countries that want them or can be made to want them, and an auction is a device to determine who wants something relative to someone else. A Supranational Planning Authority (SPA) could hold an auction at which countries would submit the price (per migrant or per migratory family) at which they will undertake the task of relocating migrants. The conditions of the contract would be specified, including the kind and location of

  19. Nerve growth factor and its low-affinity receptor promote Schwann cell migration.

    PubMed Central

    Anton, E S; Weskamp, G; Reichardt, L F; Matthew, W D

    1994-01-01

    Migrating Schwann cells in developing or regenerating peripheral nerves are known to express dramatically increased levels of nerve growth factor (NGF) and the low-affinity NGF receptor (LNGFR). Schwann cells do not express detectable pp140trk, the NGF-activated receptor tyrosine kinase which is essential for neuronal responses to NGF. The temporal correlation observed in Schwann cells between migration and the enhanced expression of NGF and LNGFR suggests that NGF and LNGFR may promote Schwann cell migration. To test this possibility, we examined the effects of NGF on Schwann cell migration on cryostat sections of biologically relevant NGF-poor and NGF-rich substrates--normal or denervated peripheral (sciatic) nerve, untreated or pretreated with NGF. Results show that Schwann cells migrate more rapidly on denervated than on normal sciatic nerve. Antibodies to NGF or to LNGFR strongly, but incompletely, inhibit enhanced migration on denervated nerves. Pretreatment of denervated nerve sections with NGF increases further the rate of Schwann cell migration. The same antibodies to NGF or to LNGFR abolish this response. These results suggest that one function of the elevated levels of NGF known to be present in embryonic and regenerating peripheral nerves is to promote the migration of Schwann cells. In contrast to neurons, where pp140trk appears to be the functionally critical NGF receptor, NGF responses in Schwann cells depend on LNGFR. Images PMID:8146193

  20. Expectation-driven migration promotes cooperation by group interactions

    NASA Astrophysics Data System (ADS)

    Wu, Te; Fu, Feng; Zhang, Yanling; Wang, Long

    2012-06-01

    “Voting with feet” describes the prominent social phenomenon that people tend to move away from deteriorating neighborhoods and search for and join prosperous groups. To quantify the role this kind of expectation-driven migration plays in the evolution of cooperation, here we study a simple yet effective model of cooperation based on spatial public goods games. The population structure is characterized by a square lattice with some nodes being left empty. Individuals have expectations toward their current habitats. Dissatisfied players, whose expectation is not met after interacting with all directly connected neighbors, tend to abstain from the groups of low quality by moving away and explore the physical niches of avail. How fast interaction happens relatively to selection is regulated by the time-scale ratio of game interaction to natural selection. Under strong selection, simulation results show that cooperation is greatly improved for either low, moderate, or high expectations compared to whenever the expectation-driven migration is absent. Further explorations reveal that neither too high nor too low but rather a combination of moderate expectations and rapid interaction establishes cooperation for a moderate public goods enhancement factor. There exists an optimal interval of expectation level most favoring the evolution of cooperation as the required time-scale ratio is minimized.

  1. RLIM interacts with Smurf2 and promotes TGF-{beta} induced U2OS cell migration

    SciTech Connect

    Huang, Yongsheng; Yang, Yang; Gao, Rui; Yang, Xianmei; Yan, Xiaohua; Wang, Chenji; Jiang, Sirui; Yu, Long

    2011-10-14

    Highlights: {yields} RLIM directly binds to Smurf2. {yields} RLIM enhances TGF-{beta} responsiveness in U2OS cells. {yields} RLIM promotes TGF-{beta} driven migration of osteosarcoma U2OS cells. -- Abstract: TGF-{beta} (transforming growth factor-{beta}), a pleiotropic cytokine that regulates diverse cellular processes, has been suggested to play critical roles in cell proliferation, migration, and carcinogenesis. Here we found a novel E3 ubiquitin ligase RLIM which can directly bind to Smurf2, enhancing TGF-{beta} responsiveness in osteosarcoma U2OS cells. We constructed a U2OS cell line stably over-expressing RLIM and demonstrated that RLIM promoted TGF-{beta}-driven migration of U2OS cells as tested by wound healing assay. Our results indicated that RLIM is an important positive regulator in TGF-{beta} signaling pathway and cell migration.

  2. Cinnamtannin B-1 Promotes Migration of Mesenchymal Stem Cells and Accelerates Wound Healing in Mice.

    PubMed

    Fujita, Kosuke; Kuge, Katsunori; Ozawa, Noriyasu; Sahara, Shunya; Zaiki, Kaori; Nakaoji, Koichi; Hamada, Kazuhiko; Takenaka, Yukiko; Tanahashi, Takao; Tamai, Katsuto; Kaneda, Yasufumi; Maeda, Akito

    2015-01-01

    Substances that enhance the migration of mesenchymal stem cells to damaged sites have the potential to improve the effectiveness of tissue repair. We previously found that ethanol extracts of Mallotus philippinensis bark promoted migration of mesenchymal stem cells and improved wound healing in a mouse model. We also demonstrated that bark extracts contain cinnamtannin B-1, a flavonoid with in vitro migratory activity against mesenchymal stem cells. However, the in vivo effects of cinnamtannin B-1 on the migration of mesenchymal stem cells and underlying mechanism of this action remain unknown. Therefore, we examined the effects of cinnamtannin B-1 on in vivo migration of mesenchymal stem cells and wound healing in mice. In addition, we characterized cinnamtannin B-1-induced migration of mesenchymal stem cells pharmacologically and structurally. The mobilization of endogenous mesenchymal stem cells into the blood circulation was enhanced in cinnamtannin B-1-treated mice as shown by flow cytometric analysis of peripheral blood cells. Whole animal imaging analysis using luciferase-expressing mesenchymal stem cells as a tracer revealed that cinnamtannin B-1 increased the homing of mesenchymal stem cells to wounds and accelerated healing in a diabetic mouse model. Additionally, the cinnamtannin B-1-induced migration of mesenchymal stem cells was pharmacologically susceptible to inhibitors of phosphatidylinositol 3-kinase, phospholipase C, lipoxygenase, and purines. Furthermore, biflavonoids with similar structural features to cinnamtannin B-1 also augmented the migration of mesenchymal stem cells by similar pharmacological mechanisms. These results demonstrate that cinnamtannin B-1 promoted mesenchymal stem cell migration in vivo and improved wound healing in mice. Furthermore, the results reveal that cinnamtannin B-1-induced migration of mesenchymal stem cells may be mediated by specific signaling pathways, and the flavonoid skeleton may be relevant to its effects on

  3. Cinnamtannin B-1 Promotes Migration of Mesenchymal Stem Cells and Accelerates Wound Healing in Mice.

    PubMed

    Fujita, Kosuke; Kuge, Katsunori; Ozawa, Noriyasu; Sahara, Shunya; Zaiki, Kaori; Nakaoji, Koichi; Hamada, Kazuhiko; Takenaka, Yukiko; Tanahashi, Takao; Tamai, Katsuto; Kaneda, Yasufumi; Maeda, Akito

    2015-01-01

    Substances that enhance the migration of mesenchymal stem cells to damaged sites have the potential to improve the effectiveness of tissue repair. We previously found that ethanol extracts of Mallotus philippinensis bark promoted migration of mesenchymal stem cells and improved wound healing in a mouse model. We also demonstrated that bark extracts contain cinnamtannin B-1, a flavonoid with in vitro migratory activity against mesenchymal stem cells. However, the in vivo effects of cinnamtannin B-1 on the migration of mesenchymal stem cells and underlying mechanism of this action remain unknown. Therefore, we examined the effects of cinnamtannin B-1 on in vivo migration of mesenchymal stem cells and wound healing in mice. In addition, we characterized cinnamtannin B-1-induced migration of mesenchymal stem cells pharmacologically and structurally. The mobilization of endogenous mesenchymal stem cells into the blood circulation was enhanced in cinnamtannin B-1-treated mice as shown by flow cytometric analysis of peripheral blood cells. Whole animal imaging analysis using luciferase-expressing mesenchymal stem cells as a tracer revealed that cinnamtannin B-1 increased the homing of mesenchymal stem cells to wounds and accelerated healing in a diabetic mouse model. Additionally, the cinnamtannin B-1-induced migration of mesenchymal stem cells was pharmacologically susceptible to inhibitors of phosphatidylinositol 3-kinase, phospholipase C, lipoxygenase, and purines. Furthermore, biflavonoids with similar structural features to cinnamtannin B-1 also augmented the migration of mesenchymal stem cells by similar pharmacological mechanisms. These results demonstrate that cinnamtannin B-1 promoted mesenchymal stem cell migration in vivo and improved wound healing in mice. Furthermore, the results reveal that cinnamtannin B-1-induced migration of mesenchymal stem cells may be mediated by specific signaling pathways, and the flavonoid skeleton may be relevant to its effects on

  4. Pancreatic Tumor Cell Secreted CCN1/Cyr61 Promotes Endothelial cell migration and Aberrant Neovascularization

    PubMed Central

    Maity, Gargi; Mehta, Smita; Haque, Inamul; Dhar, Kakali; Sarkar, Sandipto; Banerjee, Sushanta K.; Banerjee, Snigdha

    2014-01-01

    The complex signaling networks between cancer cells and adjacent endothelial cells make it challenging to unravel how cancer cells send extracellular messages to promote aberrant vascularization or tumor angiogenesis. Here, in vitro and in vivo models show that pancreatic cancer cell generated unique microenvironments can underlie endothelial cell migration and tumor angiogenesis. Mechanistically, we find that pancreatic cancer cell secreted CCN1/Cyr61 matricellular protein rewires the microenvironment to promote endothelial cell migration and tumor angiogenesis. This event can be overcome by Sonic Hedgehog (SHh) antibody treatment. Collectively, these studies identify a novel CCN1 signaling program in pancreatic cancer cells which activates SHh through autocrine-paracrine circuits to promote endothelial cell migration and tumor angiogenesis and suggests that CCN1 signaling of pancreatic cancer cells is vital for the regulation of tumor angiogenesis. Thus CCN1 signaling could be an ideal target for tumor vascular disruption in pancreatic cancer. PMID:24833309

  5. Histidine provides long-term neuroprotection after cerebral ischemia through promoting astrocyte migration

    PubMed Central

    Liao, Ru-jia; Jiang, Lei; Wang, Rong-rong; Zhao, Hua-wei; Chen, Ying; Li, Ya; Wang, Lu; Jie, Li-Yong; Zhou, Yu-dong; Zhang, Xiang-nan; Chen, Zhong; Hu, Wei-wei

    2015-01-01

    The formation of glial scar impedes the neurogenesis and neural functional recovery following cerebral ischemia. Histamine showed neuroprotection at early stage after cerebral ischemia, however, its long-term effect, especially on glial scar formation, hasn’t been characterized. With various administration regimens constructed for histidine, a precursor of histamine, we found that histidine treatment at a high dose at early stage and a low dose at late stage demonstrated the most remarkable long-term neuroprotection with decreased infarct volume and improved neurological function. Notably, this treatment regimen also robustly reduced the glial scar area and facilitated the astrocyte migration towards the infarct core. In wound-healing assay and transwell test, histamine significantly promoted astrocyte migration. H2 receptor antagonists reversed the promotion of astrocyte migration and the neuroprotection provided by histidine. Moreover, histamine upregulated the GTP-bound small GTPase Rac1, while a Rac1 inhibitor, NSC23766, abrogated the neuroprotection of histidine and its promotion of astrocyte migration. Our data indicated that a dose/stage-dependent histidine treatment, mediated by H2 receptor, promoted astrocyte migration towards the infarct core, which benefited long-term post-cerebral ischemia neurological recovery. Therefore, targeting histaminergic system may be an effective therapeutic strategy for long-term cerebral ischemia injury through its actions on astrocytes. PMID:26481857

  6. Lipid raft association restricts CD44-ezrin interaction and promotion of breast cancer cell migration.

    PubMed

    Donatello, Simona; Babina, Irina S; Hazelwood, Lee D; Hill, Arnold D K; Nabi, Ivan R; Hopkins, Ann M

    2012-12-01

    Cancer cell migration is an early event in metastasis, the main cause of breast cancer-related deaths. Cholesterol-enriched membrane domains called lipid rafts influence the function of many molecules, including the raft-associated protein CD44. We describe a novel mechanism whereby rafts regulate interactions between CD44 and its binding partner ezrin in migrating breast cancer cells. Specifically, in nonmigrating cells, CD44 and ezrin localized to different membranous compartments: CD44 predominantly in rafts, and ezrin in nonraft compartments. After the induction of migration (either nonspecific or CD44-driven), CD44 affiliation with lipid rafts was decreased. This was accompanied by increased coprecipitation of CD44 and active (threonine-phosphorylated) ezrin-radixin-moesin (ERM) proteins in nonraft compartments and increased colocalization of CD44 with the nonraft protein, transferrin receptor. Pharmacological raft disruption using methyl-β-cyclodextrin also increased CD44-ezrin coprecipitation and colocalization, further suggesting that CD44 interacts with ezrin outside rafts during migration. Conversely, promoting CD44 retention inside lipid rafts by pharmacological inhibition of depalmitoylation virtually abolished CD44-ezrin interactions. However, transient single or double knockdown of flotillin-1 or caveolin-1 was not sufficient to increase cell migration over a short time course, suggesting complex crosstalk mechanisms. We propose a new model for CD44-dependent breast cancer cell migration, where CD44 must relocalize outside lipid rafts to drive cell migration. This could have implications for rafts as pharmacological targets to down-regulate cancer cell migration.

  7. Modeling keratinocyte wound healing dynamics: Cell-cell adhesion promotes sustained collective migration.

    PubMed

    Nardini, John T; Chapnick, Douglas A; Liu, Xuedong; Bortz, David M

    2016-07-01

    The in vitro migration of keratinocyte cell sheets displays behavioral and biochemical similarities to the in vivo wound healing response of keratinocytes in animal model systems. In both cases, ligand-dependent Epidermal Growth Factor Receptor (EGFR) activation is sufficient to elicit collective cell migration into the wound. Previous mathematical modeling studies of in vitro wound healing assays assume that physical connections between cells have a hindering effect on cell migration, but biological literature suggests a more complicated story. By combining mathematical modeling and experimental observations of collectively migrating sheets of keratinocytes, we investigate the role of cell-cell adhesion during in vitro keratinocyte wound healing assays. We develop and compare two nonlinear diffusion models of the wound healing process in which cell-cell adhesion either hinders or promotes migration. Both models can accurately fit the leading edge propagation of cell sheets during wound healing when using a time-dependent rate of cell-cell adhesion strength. The model that assumes a positive role of cell-cell adhesion on migration, however, is robust to changes in the leading edge definition and yields a qualitatively accurate density profile. Using RNAi for the critical adherens junction protein, α-catenin, we demonstrate that cell sheets with wild type cell-cell adhesion expression maintain migration into the wound longer than cell sheets with decreased cell-cell adhesion expression, which fails to exhibit collective migration. Our modeling and experimental data thus suggest that cell-cell adhesion promotes sustained migration as cells pull neighboring cells into the wound during wound healing.

  8. Modeling keratinocyte wound healing dynamics: Cell-cell adhesion promotes sustained collective migration.

    PubMed

    Nardini, John T; Chapnick, Douglas A; Liu, Xuedong; Bortz, David M

    2016-07-01

    The in vitro migration of keratinocyte cell sheets displays behavioral and biochemical similarities to the in vivo wound healing response of keratinocytes in animal model systems. In both cases, ligand-dependent Epidermal Growth Factor Receptor (EGFR) activation is sufficient to elicit collective cell migration into the wound. Previous mathematical modeling studies of in vitro wound healing assays assume that physical connections between cells have a hindering effect on cell migration, but biological literature suggests a more complicated story. By combining mathematical modeling and experimental observations of collectively migrating sheets of keratinocytes, we investigate the role of cell-cell adhesion during in vitro keratinocyte wound healing assays. We develop and compare two nonlinear diffusion models of the wound healing process in which cell-cell adhesion either hinders or promotes migration. Both models can accurately fit the leading edge propagation of cell sheets during wound healing when using a time-dependent rate of cell-cell adhesion strength. The model that assumes a positive role of cell-cell adhesion on migration, however, is robust to changes in the leading edge definition and yields a qualitatively accurate density profile. Using RNAi for the critical adherens junction protein, α-catenin, we demonstrate that cell sheets with wild type cell-cell adhesion expression maintain migration into the wound longer than cell sheets with decreased cell-cell adhesion expression, which fails to exhibit collective migration. Our modeling and experimental data thus suggest that cell-cell adhesion promotes sustained migration as cells pull neighboring cells into the wound during wound healing. PMID:27105673

  9. Extracellular glutathione promotes migration of hydrogen peroxide-stressed cultured chick embryonic skin cells.

    PubMed

    Denunzio, Mia; Gomez, George

    2014-04-01

    The ability of glutathione to affect melanocyte survival has fostered its use in a variety of applications related to epithelial cells. Our study focused on fibroblast migration and the effects of oxidative stress. We used scratch assays to measure cell migration: fibroblasts were harvested from embryonic chicks, grown to confluence in a monolayer, and the layer was scratched to initiate migration. Migration rates were measured over 8 h using photomicrographs, and vinculin expression as an indicator focal adhesion formation was measured using immunofluorescence. Addition of 200 μM glutathione to the culture media in which the cells grew resulted in a significantly increased rate of scratch closure. When the scratch assays were performed in the presence of 100 μM H2O2 (to simulate oxidative stress), the cells ceased to migrate. Addition of 200 μM glutathione to the H2O2-treated scratched layers resulted in a restoration of the scratch closure capabilities. At the subcellular level, addition of extracellular glutathione resulted in a redistribution of vinculin into fewer but larger aggregates. In cells at the edge of scratched monolayers that were treated with H2O2, vinculin particles were distributed throughout the cell in smaller aggregates; addition of glutathione resulted in vinculin aggregates that were larger and closer to the edges of the cell, indicating that these cells were more migratory. Our results suggest that glutathione promotes fibroblast migration, possibly via a mechanism that promotes the formation of focal adhesions.

  10. The oncoprotein HBXIP promotes migration of breast cancer cells via GCN5-mediated microtubule acetylation.

    PubMed

    Li, Leilei; Liu, Bowen; Zhang, Xiaodong; Ye, Lihong

    2015-03-13

    We have documented that the oncoprotein hepatitis B X-interacting protein (HBXIP) is able to promote migration of breast cancer cells. A subset of acetylated microtubules that accumulates in the cell leading edge is necessary for cell polarization and directional migration. In this study, we explored the hypothesis that HBXIP contributes to migration of breast cancer cells by supporting microtubule acetylation in breast cancer cells. We found that HBXIP could induce acetylated microtubules accumulating into the leading protrusion in wound-induced directional migration in breast cancer cells by immunofluorescence staining analysis. Interestingly, HBXIP was able to increase the acetylation of α-tubulin in the cells by immunofluorescence staining and Western blot analysis. Furthermore, we observed that acetyltransferase GCN5 was involved in the event that HBXIP induced increase of acetylated microtubules and their expansion in protrusions in breast cancer cells by Western blot analysis and immunofluorescence staining. Moreover, GCN5 was required for the HBXIP-enhanced migration of breast cancer cells by wound healing assay. Thus, we conclude that HBXIP promotes the migration of breast cancer cells through modulating microtubule acetylation mediated by GCN5. Therapeutically, HBXIP may serve as a novel target in breast cancer.

  11. A synthetic isoflavone, DCMF, promotes human keratinocyte migration by activating Src/FAK signaling pathway.

    PubMed

    Sophors, Phorl; Kim, Young Mee; Seo, Ga Young; Huh, Jung-Sik; Lim, Yoongho; Koh, Dong Soo; Cho, Moonjae

    2016-04-01

    Flavonoids are plant secondary compounds with various pharmacological properties. We previously showed that one flavonoid, trimethoxyisoflavone (TMF), could promote wound healing by inducing keratinocyte migration. Here, we screened TMF derivatives for enhanced activity and identified one compound, 2',6 Dichloro-7-methoxyisoflavone (DCMF), as most effective at promoting migration in a scratch wound assay. Using the HaCaT keratinocyte cell line, we found DCMF treatment induced phosphorylation of both FAK and Src, and increased keratinocyte migration. DCMF-induced Src kinase could promote activation of ERK, AKT, and p38 signaling pathways, and DCMF-induced secretion of matrix metalloproteinase (MMP)-2 and MMP-9 and partial epithelial-mesenchymal transition (EMT), whereas Src inhibition abolished DCMF-induced EMT. Using an in vivo excisional wound model, we observed improved wound closure and re-epithelialization in DCMF-treated mice, as compared to controls. Collectively, our data demonstrate that DCMF induces cell migration and promotes wound healing through activation of Src/FAK, ERK, AKT, and p38 MAPK signaling. PMID:26923073

  12. Transgelin promotes migration and invasion of cancer stem cells.

    PubMed

    Lee, Eun-Kyung; Han, Gi-Yeon; Park, Hye Won; Song, Yeo-Ju; Kim, Chan-Wha

    2010-10-01

    Recent studies have suggested the existence of a small subset of cancer cells called cancer stem cells (CSCs), which possess the ability to initiate malignancies, promote tumor formation, drive metastasis, and evade conventional chemotherapies. Elucidation of the specific signaling pathway and mechanism underlying the action of CSCs might improve the efficacy of cancer treatments. In this study, we analyzed differentially expressed proteins between tumerigenic and nontumorigenic cells isolated from the human hepatocellular carcinoma (HCC) cell line, Huh7, via proteomic analysis to identify proteins correlated with specific features of CSCs. The expression level of Transgelin was 25-fold higher in tumorigenic cells than nontumorigenic cells. Similar results were also observed in tumorigenic cells derived from colorectal adenocarcinoma and prostate carcinoma. More importantly, the elevated levels of Transgelin significantly increased the invasiveness of tumorigenic cells, whereas reduced levels decreased the invasive potential. Moreover, in tumors derived from Huh7-induced xenografts, Transgelin was also co-expressed with CXCR4, which is responsible for tumor invasion. Taken together, these results indicate that the metastatic potential of CSCs arises from highly expressed Transgelin.

  13. Hypoxia promotes Rab5 activation, leading to tumor cell migration, invasion and metastasis.

    PubMed

    Silva, Patricio; Mendoza, Pablo; Rivas, Solange; Díaz, Jorge; Moraga, Carolina; Quest, Andrew F G; Torres, Vicente A

    2016-05-17

    Hypoxia, a common condition of the tumor microenvironment, is associated with poor patient prognosis, tumor cell migration, invasion and metastasis. Recent evidence suggests that hypoxia alters endosome dynamics in tumor cells, leading to augmented cell proliferation and migration and this is particularly relevant, because endosomal components have been shown to be deregulated in cancer. The early endosome protein Rab5 is a small GTPase that promotes integrin trafficking, focal adhesion turnover, Rac1 activation, tumor cell migration and invasion. However, the role of Rab5 and downstream events in hypoxia remain unknown. Here, we identify Rab5 as a critical player in hypoxia-driven tumor cell migration, invasion and metastasis. Exposure of A549 human lung carcinoma, ZR-75, MDA-MB-231 and MCF-7 human breast cancer and B16-F10 mouse melanoma cells to hypoxia increased Rab5 activation, followed by its re-localization to the leading edge and association with focal adhesions. Importantly, Rab5 was required for hypoxia-driven cell migration, FAK phosphorylation and Rac1 activation, as shown by shRNA-targeting and transfection assays with Rab5 mutants. Intriguingly, the effect of hypoxia on both Rab5 activity and migration was substantially higher in metastatic B16-F10 cells than in poorly invasive B16-F0 cells. Furthermore, exogenous expression of Rab5 in B16-F0 cells predisposed to hypoxia-induced migration, whereas expression of the inactive mutant Rab5/S34N prevented the migration of B16-F10 cells induced by hypoxia. Finally, using an in vivo syngenic C57BL/6 mouse model, Rab5 expression was shown to be required for hypoxia-induced metastasis. In summary, these findings identify Rab5 as a key mediator of hypoxia-induced tumor cell migration, invasion and metastasis.

  14. Hypoxia promotes Rab5 activation, leading to tumor cell migration, invasion and metastasis

    PubMed Central

    Silva, Patricio; Mendoza, Pablo; Rivas, Solange; Díaz, Jorge; Moraga, Carolina; Quest, Andrew F.G.; Torres, Vicente A.

    2016-01-01

    Hypoxia, a common condition of the tumor microenvironment, is associated with poor patient prognosis, tumor cell migration, invasion and metastasis. Recent evidence suggests that hypoxia alters endosome dynamics in tumor cells, leading to augmented cell proliferation and migration and this is particularly relevant, because endosomal components have been shown to be deregulated in cancer. The early endosome protein Rab5 is a small GTPase that promotes integrin trafficking, focal adhesion turnover, Rac1 activation, tumor cell migration and invasion. However, the role of Rab5 and downstream events in hypoxia remain unknown. Here, we identify Rab5 as a critical player in hypoxia-driven tumor cell migration, invasion and metastasis. Exposure of A549 human lung carcinoma, ZR-75, MDA-MB-231 and MCF-7 human breast cancer and B16-F10 mouse melanoma cells to hypoxia increased Rab5 activation, followed by its re-localization to the leading edge and association with focal adhesions. Importantly, Rab5 was required for hypoxia-driven cell migration, FAK phosphorylation and Rac1 activation, as shown by shRNA-targeting and transfection assays with Rab5 mutants. Intriguingly, the effect of hypoxia on both Rab5 activity and migration was substantially higher in metastatic B16-F10 cells than in poorly invasive B16-F0 cells. Furthermore, exogenous expression of Rab5 in B16-F0 cells predisposed to hypoxia-induced migration, whereas expression of the inactive mutant Rab5/S34N prevented the migration of B16-F10 cells induced by hypoxia. Finally, using an in vivo syngenic C57BL/6 mouse model, Rab5 expression was shown to be required for hypoxia-induced metastasis. In summary, these findings identify Rab5 as a key mediator of hypoxia-induced tumor cell migration, invasion and metastasis. PMID:27121131

  15. Hypoxia promotes Rab5 activation, leading to tumor cell migration, invasion and metastasis.

    PubMed

    Silva, Patricio; Mendoza, Pablo; Rivas, Solange; Díaz, Jorge; Moraga, Carolina; Quest, Andrew F G; Torres, Vicente A

    2016-05-17

    Hypoxia, a common condition of the tumor microenvironment, is associated with poor patient prognosis, tumor cell migration, invasion and metastasis. Recent evidence suggests that hypoxia alters endosome dynamics in tumor cells, leading to augmented cell proliferation and migration and this is particularly relevant, because endosomal components have been shown to be deregulated in cancer. The early endosome protein Rab5 is a small GTPase that promotes integrin trafficking, focal adhesion turnover, Rac1 activation, tumor cell migration and invasion. However, the role of Rab5 and downstream events in hypoxia remain unknown. Here, we identify Rab5 as a critical player in hypoxia-driven tumor cell migration, invasion and metastasis. Exposure of A549 human lung carcinoma, ZR-75, MDA-MB-231 and MCF-7 human breast cancer and B16-F10 mouse melanoma cells to hypoxia increased Rab5 activation, followed by its re-localization to the leading edge and association with focal adhesions. Importantly, Rab5 was required for hypoxia-driven cell migration, FAK phosphorylation and Rac1 activation, as shown by shRNA-targeting and transfection assays with Rab5 mutants. Intriguingly, the effect of hypoxia on both Rab5 activity and migration was substantially higher in metastatic B16-F10 cells than in poorly invasive B16-F0 cells. Furthermore, exogenous expression of Rab5 in B16-F0 cells predisposed to hypoxia-induced migration, whereas expression of the inactive mutant Rab5/S34N prevented the migration of B16-F10 cells induced by hypoxia. Finally, using an in vivo syngenic C57BL/6 mouse model, Rab5 expression was shown to be required for hypoxia-induced metastasis. In summary, these findings identify Rab5 as a key mediator of hypoxia-induced tumor cell migration, invasion and metastasis. PMID:27121131

  16. ADAM13 cleavage of cadherin-11 promotes CNC migration independently of the homophilic binding site

    PubMed Central

    Kashef, Jubin; Alfandari, Dominique

    2015-01-01

    The cranial neural crest (CNC) is a highly motile population of cells that is responsible for forming the face and jaw in all vertebrates and perturbing their migration can lead to craniofacial birth defects. Cell motility requires a dynamic modification of cell–cell and cell-matrix adhesion. In the CNC, cleavage of the cell adhesion molecule cadherin-11 by ADAM13 is essential for cell migration. This cleavage generates a shed extracellular fragment of cadherin-11 (EC1-3) that possesses pro-migratory activity via an unknown mechanism. Cadherin-11 plays an important role in modulating contact inhibition of locomotion (CIL) in the CNC to regulate directional cell migration. Here, we show that while the integral cadherin-11 requires the homophilic binding site to promote CNC migration in vivo, the EC1-3 fragment does not. In addition, we show that increased ADAM13 activity or expression of the EC1-3 fragment increases CNC invasiveness in vitro and blocks the repulsive CIL response in colliding cells. This activity requires the presence of an intact homophilic binding site on the EC1-3 suggesting that the cleavage fragment may function as a competitive inhibitor of cadherin-11 adhesion in CIL but not to promote cell migration in vivo. PMID:26206614

  17. ADAM13 cleavage of cadherin-11 promotes CNC migration independently of the homophilic binding site.

    PubMed

    Abbruzzese, Genevieve; Becker, Sarah F; Kashef, Jubin; Alfandari, Dominique

    2016-07-15

    The cranial neural crest (CNC) is a highly motile population of cells that is responsible for forming the face and jaw in all vertebrates and perturbing their migration can lead to craniofacial birth defects. Cell motility requires a dynamic modification of cell-cell and cell-matrix adhesion. In the CNC, cleavage of the cell adhesion molecule cadherin-11 by ADAM13 is essential for cell migration. This cleavage generates a shed extracellular fragment of cadherin-11 (EC1-3) that possesses pro-migratory activity via an unknown mechanism. Cadherin-11 plays an important role in modulating contact inhibition of locomotion (CIL) in the CNC to regulate directional cell migration. Here, we show that while the integral cadherin-11 requires the homophilic binding site to promote CNC migration in vivo, the EC1-3 fragment does not. In addition, we show that increased ADAM13 activity or expression of the EC1-3 fragment increases CNC invasiveness in vitro and blocks the repulsive CIL response in colliding cells. This activity requires the presence of an intact homophilic binding site on the EC1-3 suggesting that the cleavage fragment may function as a competitive inhibitor of cadherin-11 adhesion in CIL but not to promote cell migration in vivo.

  18. PDGFBB promotes PDGFR{alpha}-positive cell migration into artificial bone in vivo

    SciTech Connect

    Yoshida, Shigeyuki; Iwasaki, Ryotaro; Kawana, Hiromasa; Miyauchi, Yoshiteru; Hoshi, Hiroko; Miyamoto, Hiroya; Mori, Tomoaki; Kanagawa, Hiroya; Katsuyama, Eri; Fujie, Atsuhiro; Hao, Wu; and others

    2012-05-18

    Highlights: Black-Right-Pointing-Pointer We examined effects of PDGFBB in PDGFR{alpha} positive cell migration in artificial bones. Black-Right-Pointing-Pointer PDGFBB was not expressed in osteoblastic cells but was expressed in peripheral blood cells. Black-Right-Pointing-Pointer PDGFBB promoted PDGFR{alpha} positive cell migration into artificial bones but not osteoblast proliferation. Black-Right-Pointing-Pointer PDGFBB did not inhibit osteoblastogenesis. -- Abstract: Bone defects caused by traumatic bone loss or tumor dissection are now treated with auto- or allo-bone graft, and also occasionally by artificial bone transplantation, particularly in the case of large bone defects. However, artificial bones often exhibit poor affinity to host bones followed by bony union failure. Thus therapies combining artificial bones with growth factors have been sought. Here we report that platelet derived growth factor bb (PDGFBB) promotes a significant increase in migration of PDGF receptor {alpha} (PDGFR{alpha})-positive mesenchymal stem cells/pre-osteoblastic cells into artificial bone in vivo. Growth factors such as transforming growth factor beta (TGF{beta}) and hepatocyte growth factor (HGF) reportedly inhibit osteoblast differentiation; however, PDGFBB did not exhibit such inhibitory effects and in fact stimulated osteoblast differentiation in vitro, suggesting that combining artificial bones with PDGFBB treatment could promote host cell migration into artificial bones without inhibiting osteoblastogenesis.

  19. [Macrophages promote the migration of neural stem cells into mouse spinal cord injury site].

    PubMed

    Cheng, Zhijian; Zhu, Wen; Li, Haopeng; He, Xijing

    2016-09-01

    Objective To explore the role of macrophages in the migration of neural stem cells (NSCs) in vivo and in vitro . Methods NSCs with green fluorescent protein (GFP) were isolated from GFP transgenic mice and the immunofluorescence cytochemical staining of nestin was used to identify NSCs. After spinal cord injury was induced, the tissue level of macrophage chemotactic protein-1 (MCP-1) mRNA was detected using quantitative real time PCR. The migration of GFP-NSCs was investigated 1 week after GFP-NSCs were injected into both sides of the damaged area. The effect of macrophage on the migration of NSCs in vitro was tested by Transwell(TM) system and the content of MCP-1 was detected by ELISA. Results NSCs highly expressed nestin. Compared with the control group, the level of MCP-1 mRNA significantly increased in the spinal cord injury group. The NSCs which were injected into the spinal cord migrated into the center of the injured site where F4/80 was highly expressed. Macrophages significantly increased the number of migrating NSCs in vitro and the secretion of MCP-1. Conclusion Macrophages induce NSC migrating into the spinal cord injury site possibly through promoting the secretion of MCP-1. PMID:27609570

  20. Nitric oxide promotes epidermal stem cell migration via cGMP-Rho GTPase signalling.

    PubMed

    Zhan, Rixing; He, Weifeng; Wang, Fan; Yao, Zhihui; Tan, Jianglin; Xu, Rui; Zhou, Junyi; Wang, Yuzhen; Li, Haisheng; Wu, Jun; Luo, Gaoxing

    2016-01-01

    The migration and reepithelization of epidermal stem cells (ESCs) are the most critical processes in wound healing. The gaseous messenger nitric oxide (NO) has multiple biological effects, but its actions on ESCs are poorly understood. In this study, an NO donor, S-nitroso-N-acetylpenicillamine (SNAP), was found to facilitate the in vitro migration of human ESCs (huESCs) in both live-imaging and scratch models. In addition, pull-down assays demonstrated that SNAP could activate the small GTPases RhoA and Rac1 of the Rho family, but not Cdc42. Moreover, the effects of SNAP on the migration and F-actin polymerization of ESCs could be blocked by inhibitors of cGMP, PKG, RhoA or Rac1, and by a specific siRNA of RhoA or Rac1, but not by a Cdc42 inhibitor or siRNA. Furthermore, the roles of NO in ESC migration via cGMP-Rho GTPase signalling in vivo were confirmed by tracing 5-bromo-2-deoxyuridine (BrdU)-labelled cells in a superficial, partial-thickness scald mouse model. Thus, the present study demonstrated that the NO donor SNAP could promote huESC migration in vitro. Furthermore, NO was found to induce ESC migration via cGMP-Rho GTPase RhoA and Rac1 signalling, but not Cdc42 signalling, both in vivo and in vitro. PMID:27469024

  1. Nitric oxide promotes epidermal stem cell migration via cGMP-Rho GTPase signalling

    PubMed Central

    Zhan, Rixing; He, Weifeng; Wang, Fan; Yao, Zhihui; Tan, Jianglin; Xu, Rui; Zhou, Junyi; Wang, Yuzhen; Li, Haisheng; Wu, Jun; LUO, Gaoxing

    2016-01-01

    The migration and reepithelization of epidermal stem cells (ESCs) are the most critical processes in wound healing. The gaseous messenger nitric oxide (NO) has multiple biological effects, but its actions on ESCs are poorly understood. In this study, an NO donor, S-nitroso-N-acetylpenicillamine (SNAP), was found to facilitate the in vitro migration of human ESCs (huESCs) in both live-imaging and scratch models. In addition, pull-down assays demonstrated that SNAP could activate the small GTPases RhoA and Rac1 of the Rho family, but not Cdc42. Moreover, the effects of SNAP on the migration and F-actin polymerization of ESCs could be blocked by inhibitors of cGMP, PKG, RhoA or Rac1, and by a specific siRNA of RhoA or Rac1, but not by a Cdc42 inhibitor or siRNA. Furthermore, the roles of NO in ESC migration via cGMP-Rho GTPase signalling in vivo were confirmed by tracing 5-bromo-2-deoxyuridine (BrdU)-labelled cells in a superficial, partial-thickness scald mouse model. Thus, the present study demonstrated that the NO donor SNAP could promote huESC migration in vitro. Furthermore, NO was found to induce ESC migration via cGMP-Rho GTPase RhoA and Rac1 signalling, but not Cdc42 signalling, both in vivo and in vitro. PMID:27469024

  2. Lipid Raft Association Restricts CD44-Ezrin Interaction and Promotion of Breast Cancer Cell Migration

    PubMed Central

    Donatello, Simona; Babina, Irina S.; Hazelwood, Lee D.; Hill, Arnold D.K.; Nabi, Ivan R.; Hopkins, Ann M.

    2012-01-01

    Cancer cell migration is an early event in metastasis, the main cause of breast cancer-related deaths. Cholesterol-enriched membrane domains called lipid rafts influence the function of many molecules, including the raft-associated protein CD44. We describe a novel mechanism whereby rafts regulate interactions between CD44 and its binding partner ezrin in migrating breast cancer cells. Specifically, in nonmigrating cells, CD44 and ezrin localized to different membranous compartments: CD44 predominantly in rafts, and ezrin in nonraft compartments. After the induction of migration (either nonspecific or CD44-driven), CD44 affiliation with lipid rafts was decreased. This was accompanied by increased coprecipitation of CD44 and active (threonine-phosphorylated) ezrin-radixin-moesin (ERM) proteins in nonraft compartments and increased colocalization of CD44 with the nonraft protein, transferrin receptor. Pharmacological raft disruption using methyl-β-cyclodextrin also increased CD44-ezrin coprecipitation and colocalization, further suggesting that CD44 interacts with ezrin outside rafts during migration. Conversely, promoting CD44 retention inside lipid rafts by pharmacological inhibition of depalmitoylation virtually abolished CD44-ezrin interactions. However, transient single or double knockdown of flotillin-1 or caveolin-1 was not sufficient to increase cell migration over a short time course, suggesting complex crosstalk mechanisms. We propose a new model for CD44-dependent breast cancer cell migration, where CD44 must relocalize outside lipid rafts to drive cell migration. This could have implications for rafts as pharmacological targets to down-regulate cancer cell migration. PMID:23031255

  3. Co-culture with Sertoli cells promotes proliferation and migration of umbilical cord mesenchymal stem cells

    SciTech Connect

    Zhang, Fenxi; Hong, Yan; Liang, Wenmei; Ren, Tongming; Jing, Suhua; Lin, Juntang

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer Co-culture of Sertoli cells (SCs) with human umbilical cord mesenchymal stem cells (UCMSCs). Black-Right-Pointing-Pointer Presence of SCs dramatically increased proliferation and migration of UCMSCs. Black-Right-Pointing-Pointer Presence of SCs stimulated expression of Mdm2, Akt, CDC2, Cyclin D, CXCR4, MAPKs. -- Abstract: Human umbilical cord mesenchymal stem cells (hUCMSCs) have been recently used in transplant therapy. The proliferation and migration of MSCs are the determinants of the efficiency of MSC transplant therapy. Sertoli cells are a kind of 'nurse' cells that support the development of sperm cells. Recent studies show that Sertoli cells promote proliferation of endothelial cells and neural stem cells in co-culture. We hypothesized that co-culture of UCMSCs with Sertoli cells may also promote proliferation and migration of UCMSCs. To examine this hypothesis, we isolated UCMSCs from human cords and Sertoli cells from mouse testes, and co-cultured them using a Transwell system. We found that UCMSCs exhibited strong proliferation ability and potential to differentiate to other cell lineages such as osteocytes and adipocytes. The presence of Sertoli cells in co-culture significantly enhanced the proliferation and migration potential of UCMSCs (P < 0.01). Moreover, these phenotypic changes were accompanied with upregulation of multiple genes involved in cell proliferation and migration including phospho-Akt, Mdm2, phospho-CDC2, Cyclin D1, Cyclin D3 as well as CXCR4, phospho-p44 MAPK and phospho-p38 MAPK. These findings indicate that Sertoli cells boost UCMSC proliferation and migration potential.

  4. Bm-TFF2, a toad trefoil factor, promotes cell migration, survival and wound healing

    SciTech Connect

    Zhang, Yong; Yu, Guoyu; Xiang, Yang; Wu, Jianbo; Jiang, Ping; Lee, Wenhui; Zhang, Yun

    2010-07-30

    Research highlights: {yields} Bm-TFF2 binds to epithelial cells and induces cell migration and wound healing. {yields} Bm-TFF2 suppresses cell apoptosis. {yields} Bm-TFF2 has no effect on cell proliferation. -- Abstract: Toad skin is naked and continually confronted by various injurious factors. Constant skin renewal and repairs occur frequently. However, the mechanisms of the renewal and repair have not clearly elucidated. In our previous work, a trefoil factor (TFF), Bm-TFF2, has been purified from the Bombina maxima skin and characterized as a platelet agonist. The mRNA of TFFs in toad skin was up-regulated greatly during the metamorphosis, indicating a pivotal role of TFFs in amphibian skin. Here, we presented the effects of Bm-TFF2 on the cell migration, apoptosis and proliferation. Bm-TFF2 bound to epithelial cells and showed strong cell motility activity. At the concentrations of 1-100 nM, Bm-TFF2-induced migration of human epithelial AGS and HT-29 cells, and rat intestinal epithelial IEC-6 cell lines. The in vitro wound healing assay also verified the activity of Bm-TFF2. Bm-TFF2 could also inhibit cell apoptosis induced by ceramide and sodium butyrate. The cell migration-promoting activity was abolished by MEK1 inhibitors, U0126 and PD98059, suggesting that ERK1/2 activation is crucial for Bm-TFF2 to stimulate cell migration. Taken together, Bm-TFF2 promoted wound healing by stimulating cell migration via MAPK pathway and preventing cell apoptosis. The potent biological activity of Bm-TFF2 makes it a useful molecular tool for further studies of structure-function relationship of the related human TFFs.

  5. MYC-nick promotes cell migration by inducing fascin expression and Cdc42 activation

    PubMed Central

    Anderson, Sarah; Poudel, Kumud Raj; Roh-Johnson, Minna; Brabletz, Thomas; Yu, Ming; Borenstein-Auerbach, Nofit; Grady, William N.; Bai, Jihong; Moens, Cecilia B.; Eisenman, Robert N.; Conacci-Sorrell, Maralice

    2016-01-01

    MYC-nick is a cytoplasmic, transcriptionally inactive member of the MYC oncoprotein family, generated by a proteolytic cleavage of full-length MYC. MYC-nick promotes migration and survival of cells in response to chemotherapeutic agents or withdrawal of glucose. Here we report that MYC-nick is abundant in colonic and intestinal tumors derived from mouse models with mutations in the Wnt, TGF-β, and PI3K pathways. Moreover, MYC-nick is elevated in colon cancer cells deleted for FBWX7, which encodes the major E3 ligase of full-length MYC frequently mutated in colorectal cancers. MYC-nick promotes the migration of colon cancer cells assayed in 3D cultures or grown as xenografts in a zebrafish metastasis model. MYC-nick accelerates migration by activating the Rho GTPase Cdc42 and inducing fascin expression. MYC-nick, fascin, and Cdc42 are frequently up-regulated in cells present at the invasive front of human colorectal tumors, suggesting a coordinated role for these proteins in tumor migration. PMID:27566402

  6. The reorientation of cell nucleus promotes the establishment of front-rear polarity in migrating fibroblasts.

    PubMed

    Maninová, Miloslava; Klímová, Zuzana; Parsons, J Thomas; Weber, Michael J; Iwanicki, Marcin P; Vomastek, Tomáš

    2013-06-12

    The establishment of cell polarity is an essential step in the process of cell migration. This process requires precise spatiotemporal coordination of signaling pathways that in most cells create the typical asymmetrical profile of a polarized cell with nucleus located at the cell rear and the microtubule organizing center (MTOC) positioned between the nucleus and the leading edge. During cell polarization, nucleus rearward positioning promotes correct microtubule organizing center localization and thus the establishment of front-rear polarity and directional migration. We found that cell polarization and directional migration require also the reorientation of the nucleus. Nuclear reorientation is manifested as temporally restricted nuclear rotation that aligns the nuclear axis with the axis of cell migration. We also found that nuclear reorientation requires physical connection between the nucleus and cytoskeleton mediated by the LINC (linker of nucleoskeleton and cytoskeleton) complex. Nuclear reorientation is controlled by coordinated activity of lysophosphatidic acid (LPA)-mediated activation of GTPase Rho and the activation of integrin, FAK (focal adhesion kinase), Src, and p190RhoGAP signaling pathway. Integrin signaling is spatially induced at the leading edge as FAK and p190RhoGAP are predominantly activated or localized at this location. We suggest that integrin activation within lamellipodia defines cell front, and subsequent FAK, Src, and p190RhoGAP signaling represents the polarity signal that induces reorientation of the nucleus and thus promotes the establishment of front-rear polarity.

  7. MYC-nick promotes cell migration by inducing fascin expression and Cdc42 activation.

    PubMed

    Anderson, Sarah; Poudel, Kumud Raj; Roh-Johnson, Minna; Brabletz, Thomas; Yu, Ming; Borenstein-Auerbach, Nofit; Grady, William N; Bai, Jihong; Moens, Cecilia B; Eisenman, Robert N; Conacci-Sorrell, Maralice

    2016-09-13

    MYC-nick is a cytoplasmic, transcriptionally inactive member of the MYC oncoprotein family, generated by a proteolytic cleavage of full-length MYC. MYC-nick promotes migration and survival of cells in response to chemotherapeutic agents or withdrawal of glucose. Here we report that MYC-nick is abundant in colonic and intestinal tumors derived from mouse models with mutations in the Wnt, TGF-β, and PI3K pathways. Moreover, MYC-nick is elevated in colon cancer cells deleted for FBWX7, which encodes the major E3 ligase of full-length MYC frequently mutated in colorectal cancers. MYC-nick promotes the migration of colon cancer cells assayed in 3D cultures or grown as xenografts in a zebrafish metastasis model. MYC-nick accelerates migration by activating the Rho GTPase Cdc42 and inducing fascin expression. MYC-nick, fascin, and Cdc42 are frequently up-regulated in cells present at the invasive front of human colorectal tumors, suggesting a coordinated role for these proteins in tumor migration. PMID:27566402

  8. Extravillous trophoblast cells-derived exosomes promote vascular smooth muscle cell migration

    PubMed Central

    Salomon, Carlos; Yee, Sarah; Scholz-Romero, Katherin; Kobayashi, Miharu; Vaswani, Kanchan; Kvaskoff, David; Illanes, Sebastian E.; Mitchell, Murray D.; Rice, Gregory E.

    2014-01-01

    Background: Vascular smooth muscle cells (VSMCs) migration is a critical process during human uterine spiral artery (SpA) remodeling and a successful pregnancy. Extravillous trophoblast cells (EVT) interact with VSMC and enhance their migration, however, the mechanisms by which EVT remodel SpA remain to be fully elucidated. We hypothesize that exosomes released from EVT promote VSMC migration. Methods: JEG-3 and HTR-8/SVneo cell lines were used as models for EVT. Cells were cultured at 37°C and humidified under an atmosphere of 5% CO2-balanced N2 to obtain 8% O2. Cell-conditioned media were collected, and exosomes (exo-JEG-3 and exo- HTR-8/SVneo) isolated by differential and buoyant density centrifugation. The effects of exo-EVT on VSMC migration were established using a real-time, live-cell imaging system (Incucyte™). Exosomal proteins where identified by mass spectrometry and submitted to bioinformatic pathway analysis (Ingenuity software). Results: HTR-8/SVneo cells were significantly more (~30%) invasive than JEG-3 cells. HTR-8/SVneo cells released 2.6-fold more exosomes (6.39 × 108 ± 2.5 × 108 particles/106 cells) compared to JEG-3 (2.86 × 108 ± 0.78 × 108 particles/106 cells). VSMC migration was significantly increased in the presence of exo-JEG-3 and exo-HTR-8/SVneo compared to control (−exosomes) (21.83 ± 0.49 h and 15.57 ± 0.32, respectively, vs. control 25.09 ± 0.58 h, p < 0.05). Sonication completely abolished the effect of exosomes on VSMC migration. Finally, mass spectrometry analysis identified unique exosomal proteins for each EVT cell line-derived exosomes. Conclusion: The data obtained in this study are consistent with the hypothesis that the release, content, and bioactivity of exosomes derived from EVT-like cell lines is cell origin-dependent and differentially regulates VSMC migration. Thus, an EVT exosomal signaling pathway may contribute to SpA remodeling by promoting the migration of VSMC out of the vessel walls. PMID:25157233

  9. Downregulation of SENP1 inhibits cell proliferation, migration and promotes apoptosis in human glioma cells

    PubMed Central

    ZHANG, QIU-SHENG; ZHANG, MENG; HUANG, XIAN-JIAN; LIU, XIAO-JIA; LI, WEI-PING

    2016-01-01

    Small ubiquitin-related modifier protein (SUMO) is an evolutionarily conserved protein in a broad range of eukaryotic organisms. De-SUMOylation, the reverse reaction of SUMOylation, is regulated by a family of SUMO-specific proteases (SENPs). SENP1 is a member of the de-SUMOylation protease family involved in the de-SUMOylation of a variety of SUMOylated proteins. The present study demonstrates that small hairpin RNA (shRNA)-mediated downregulation of SENP1 inhibits cell proliferation and migration, and promotes apoptosis in human glioma cells. Firstly, LN-299 cells were transfected with a plasmid expressing SENP1 shRNA (pGenesil-1-SENP1). The messenger RNA and protein expression of SENP1 was detected by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Cell proliferation in vitro was assessed using a methyl thiazolyl tetrazolium assay. Flow cytometry (FCM) was used to detect the apoptosis of LN-299 cells. The effect of the downregulation of SENP1 on cell migration was detected by a Transwell migration system. The present results showed that, compared with the control shRNA group, the expression of SENP1 was significantly reduced in the SENP1 shRNA group. The proliferation was markedly inhibited in the SENP1 shRNA group. FCM findings revealed that apoptosis increased significantly in the SENP1 shRNA group. In addition, it was found that downregulation of SENP1 evidently suppressed tumor cell migration. Downregulation of SENP1 expression inhibited the proliferation and migration and promoted apoptosis in LN-299 cells. These results indirectly demonstrate that SENP1 is likely to play a critical role in human glioma cells. PMID:27347128

  10. Adiponectin Reduces Hepatic Stellate Cell Migration by Promoting Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) Secretion*

    PubMed Central

    Ramezani-Moghadam, Mehdi; Wang, Jianhua; Ho, Vikki; Iseli, Tristan J.; Alzahrani, Badr; Xu, Aimin; Van der Poorten, David; Qiao, Liang; George, Jacob; Hebbard, Lionel

    2015-01-01

    Hepatic stellate cells (HSC) are central players in liver fibrosis that when activated, proliferate, migrate to sites of liver injury, and secrete extracellular matrix. Obesity, a known risk factor for liver fibrosis is associated with reduced levels of adiponectin, a protein that inhibits liver fibrosis in vivo and limits HSC proliferation and migration in vitro. Adiponectin-mediated activation of adenosine monophosphate-activated kinase (AMPK) inhibits HSC proliferation, but the mechanism by which it limits HSC migration to sites of injury is unknown. Here we sought to elucidate how adiponectin regulates HSC motility. Primary rat HSCs were isolated and treated with adiponectin in migration assays. The in vivo actions of adiponectin were examined by treating mice with carbon tetrachloride for 12 weeks and then injecting them with adiponectin. Cell and tissue samples were collected and analyzed for gene expression, signaling, and histology. Serum from patients with liver fibrosis was examined for adiponectin and tissue inhibitor of metalloproteinase-1 (TIMP-1) protein. Adiponectin administration into mice increased TIMP-1 gene and protein expression. In cultured HSCs, adiponectin promoted TIMP-1 expression and through binding of TIMP-1 to the CD63/β1-integrin complex reduced phosphorylation of focal adhesion kinase to limit HSC migration. In mice with liver fibrosis, adiponectin had similar effects and limited focal adhesion kinase phosphorylation. Finally, in patients with advanced fibrosis, there was a positive correlation between serum adiponectin and TIMP-1 levels. In sum, these data show that adiponectin stimulates TIMP-1 secretion by HSCs to retard their migration and contributes to the anti-fibrotic effects of adiponectin. PMID:25575598

  11. Par3 controls neural crest migration by promoting microtubule catastrophe during contact inhibition of locomotion.

    PubMed

    Moore, Rachel; Theveneau, Eric; Pozzi, Sara; Alexandre, Paula; Richardson, Joanna; Merks, Anne; Parsons, Maddy; Kashef, Jubin; Linker, Claudia; Mayor, Roberto

    2013-12-01

    There is growing evidence that contact inhibition of locomotion (CIL) is essential for morphogenesis and its failure is thought to be responsible for cancer invasion; however, the molecular bases of this phenomenon are poorly understood. Here we investigate the role of the polarity protein Par3 in CIL during migration of the neural crest, a highly migratory mesenchymal cell type. In epithelial cells, Par3 is localised to the cell-cell adhesion complex and is important in the definition of apicobasal polarity, but the localisation and function of Par3 in mesenchymal cells are not well characterised. We show in Xenopus and zebrafish that Par3 is localised to the cell-cell contact in neural crest cells and is essential for CIL. We demonstrate that the dynamics of microtubules are different in different parts of the cell, with an increase in microtubule catastrophe at the collision site during CIL. Par3 loss-of-function affects neural crest migration by reducing microtubule catastrophe at the site of cell-cell contact and abrogating CIL. Furthermore, Par3 promotes microtubule catastrophe by inhibiting the Rac-GEF Trio, as double inhibition of Par3 and Trio restores microtubule catastrophe at the cell contact and rescues CIL and neural crest migration. Our results demonstrate a novel role of Par3 during neural crest migration, which is likely to be conserved in other processes that involve CIL such as cancer invasion or cell dispersion.

  12. COPD promotes migration of A549 lung cancer cells: the role of chemokine CCL21

    PubMed Central

    Kuźnar-Kamińska, Barbara; Mikuła-Pietrasik, Justyna; Sosińska, Patrycja; Książek, Krzysztof; Batura-Gabryel, Halina

    2016-01-01

    Patients with COPD develop lung cancer more frequently than healthy smokers. At the same time, molecular mediators promoting various aspects of cancer cell progression are still elusive. In this report, we examined whether COPD can be coupled with increased migration of non-small-cell lung cancer cells A549 and, if so, whether this effect may be related to altered production and activity of chemokines CCL21, CXCL5, and CXCL12. The study showed that the migration of A549 cells through the polycarbonate membrane and basement membrane extract toward a chemotactic gradient elicited by serum from patients with COPD was markedly higher as compared with serum from healthy donors. The concentration of CCL21 and CXCL12, but not CXCL5, in serum from patients with COPD was also increased. Experiments in which CCL21- and CXCL12-dependent signaling was blocked revealed that increased migration of the cancer cells upon treatment with serum from patients with COPD was mediated exclusively by CCL21. Collectively, our results indicate that COPD may contribute to the progression of lung cancer via CCL21-dependent intensification of cancer cell migration. PMID:27307721

  13. COPD promotes migration of A549 lung cancer cells: the role of chemokine CCL21.

    PubMed

    Kuźnar-Kamińska, Barbara; Mikuła-Pietrasik, Justyna; Sosińska, Patrycja; Książek, Krzysztof; Batura-Gabryel, Halina

    2016-01-01

    Patients with COPD develop lung cancer more frequently than healthy smokers. At the same time, molecular mediators promoting various aspects of cancer cell progression are still elusive. In this report, we examined whether COPD can be coupled with increased migration of non-small-cell lung cancer cells A549 and, if so, whether this effect may be related to altered production and activity of chemokines CCL21, CXCL5, and CXCL12. The study showed that the migration of A549 cells through the polycarbonate membrane and basement membrane extract toward a chemotactic gradient elicited by serum from patients with COPD was markedly higher as compared with serum from healthy donors. The concentration of CCL21 and CXCL12, but not CXCL5, in serum from patients with COPD was also increased. Experiments in which CCL21- and CXCL12-dependent signaling was blocked revealed that increased migration of the cancer cells upon treatment with serum from patients with COPD was mediated exclusively by CCL21. Collectively, our results indicate that COPD may contribute to the progression of lung cancer via CCL21-dependent intensification of cancer cell migration. PMID:27307721

  14. Lactobacillus rhamnosus GG Lysate Increases Re-Epithelialization of Keratinocyte Scratch Assays by Promoting Migration.

    PubMed

    Mohammedsaeed, Walaa; Cruickshank, Sheena; McBain, Andrew J; O'Neill, Catherine A

    2015-11-05

    A limited number of studies have investigated the potential of probiotics to promote wound healing in the digestive tract. The aim of the current investigation was to determine whether probiotic bacteria or their extracts could be beneficial in cutaneous wound healing. A keratinocyte monolayer scratch assay was used to assess re-epithelialization; which comprises keratinocyte proliferation and migration. Primary human keratinocyte monolayers were scratched then exposed to lysates of Lactobacillus (L) rhamnosus GG, L. reuteri, L. plantarum or L. fermentum. Re-epithelialization of treated monolayers was compared to that of untreated controls. Lysates of L. rhamnosus GG and L. reuteri significantly increased the rate of re-epithelialization, with L. rhamnosus GG being the most efficacious. L. reuteri increased keratinocyte proliferation while L. rhamnosus GG lysate significantly increased proliferation and migration. Microarray analysis of L. rhamnosus GG treated scratches showed increased expression of multiple genes including the chemokine CXCL2 and its receptor CXCR2. These are involved in normal wound healing where they stimulate keratinocyte proliferation and/or migration. Increased protein expression of both CXCL2 and CXCR2 were confirmed by ELISA and immunoblotting. These data demonstrate that L. rhamnosus GG lysate accelerates re-epithelialization of keratinocyte scratch assays, potentially via chemokine receptor pairs that induce keratinocyte migration.

  15. Dynamic myosin activation promotes collective morphology and migration by locally balancing oppositional forces from surrounding tissue

    PubMed Central

    Aranjuez, George; Burtscher, Ashley; Sawant, Ketki; Majumder, Pralay; McDonald, Jocelyn A.

    2016-01-01

    Migrating cells need to overcome physical constraints from the local microenvironment to navigate their way through tissues. Cells that move collectively have the additional challenge of negotiating complex environments in vivo while maintaining cohesion of the group as a whole. The mechanisms by which collectives maintain a migratory morphology while resisting physical constraints from the surrounding tissue are poorly understood. Drosophila border cells represent a genetic model of collective migration within a cell-dense tissue. Border cells move as a cohesive group of 6−10 cells, traversing a network of large germ line–derived nurse cells within the ovary. Here we show that the border cell cluster is compact and round throughout their entire migration, a shape that is maintained despite the mechanical pressure imposed by the surrounding nurse cells. Nonmuscle myosin II (Myo-II) activity at the cluster periphery becomes elevated in response to increased constriction by nurse cells. Furthermore, the distinctive border cell collective morphology requires highly dynamic and localized enrichment of Myo-II. Thus, activated Myo-II promotes cortical tension at the outer edge of the migrating border cell cluster to resist compressive forces from nurse cells. We propose that dynamic actomyosin tension at the periphery of collectives facilitates their movement through restrictive tissues. PMID:27122602

  16. COPD promotes migration of A549 lung cancer cells: the role of chemokine CCL21.

    PubMed

    Kuźnar-Kamińska, Barbara; Mikuła-Pietrasik, Justyna; Sosińska, Patrycja; Książek, Krzysztof; Batura-Gabryel, Halina

    2016-01-01

    Patients with COPD develop lung cancer more frequently than healthy smokers. At the same time, molecular mediators promoting various aspects of cancer cell progression are still elusive. In this report, we examined whether COPD can be coupled with increased migration of non-small-cell lung cancer cells A549 and, if so, whether this effect may be related to altered production and activity of chemokines CCL21, CXCL5, and CXCL12. The study showed that the migration of A549 cells through the polycarbonate membrane and basement membrane extract toward a chemotactic gradient elicited by serum from patients with COPD was markedly higher as compared with serum from healthy donors. The concentration of CCL21 and CXCL12, but not CXCL5, in serum from patients with COPD was also increased. Experiments in which CCL21- and CXCL12-dependent signaling was blocked revealed that increased migration of the cancer cells upon treatment with serum from patients with COPD was mediated exclusively by CCL21. Collectively, our results indicate that COPD may contribute to the progression of lung cancer via CCL21-dependent intensification of cancer cell migration.

  17. Interleukin-8 promotes cell migration through integrin αvβ6 upregulation in colorectal cancer.

    PubMed

    Sun, Qi; Sun, Fengkai; Wang, Ben; Liu, Song; Niu, Weibo; Liu, Enyu; Peng, Cheng; Wang, Jiayong; Gao, Huijie; Liang, Benjia; Niu, Zhengchuan; Zou, Xueqing; Niu, Jun

    2014-11-28

    Colorectal cancer (CRC), which is notorious for high morbidity and mortality around the world, shows a predilection for metastasis to liver. Interleukin-8 (IL-8), a chemokine with a defining CXC amino acid motif, has been reported to promote CRC cell migration and is associated with poor prognosis of CRC. However, the underlying molecular mechanism of IL-8-mediated migration remains obscure. In this study, we first demonstrated the cross talk between IL-8 and integrin αvβ6. We analyzed 139 human CRC samples, and found that the immunohistochemical expression of αvβ6 was significantly correlated with expression of IL-8. Furthermore, IL-8 increased the migration through integrin αvβ6 in human CRC cells, and both CXCR1 and CXCR2 were primarily involved during the process. IL-8 upregulated αvβ6 expression in a dose-dependent manner through activation of ERK and Ets-1 signaling pathway. Taken together, our results indicated that IL-8 enhances the migration of CRC cells by increasing αvβ6 integrin expression through the ERK/Ets-1 pathway. Targeting integrin αvβ6 in IL-8 expressing tumors might be a potential therapeutic strategy for CRC patients.

  18. FOXO3a promotes gastric cancer cell migration and invasion through the induction of cathepsin L

    PubMed Central

    Zhang, Wen; Yuan, Wei; Zhao, Naiqing; Li, Qian; Cui, Yuehong; Wang, Yan; Li, Wei; Sun, Yihong; Liu, Tianshu

    2016-01-01

    Forkhead box O3A (FOXO3a) is an important transcription factor involved in various human cancers. However, the role of FOXO3a in regulating the invasion and metastasis of gastric cancer cells has not been clarified. Here, we report that FOXO3a overexpression promoted migration and invasion of gastric cancer cells by upregulating cathepsin L. FOXO3a knockdown suppressed migration and invasion and also downregulated cathepsin L expression in gastric cancer cells. Silencing cathepsin L in these cells suppressed FOXO3a overexpression-induced cell migration and invasion. Mechanistic studies revealed that FOXO3a increased cathepsin L promoter activation, and cathepsin L overexpression repressed E-cadherin expression, causing gastric cancer cells to undergo epithelial-mesenchymal transition (EMT). Our data reveal a previously unexplored function of FOXO3a in gastric cancer invasion by regulating proteins involved in extracellular matrix (ECM) degradation and EMT. We suggest that FOXO3a may be of prognostic value and a potential therapeutic target in blocking tumor metastasis. PMID:27127880

  19. MALAT1 promotes colorectal cancer cell proliferation/migration/invasion via PRKA kinase anchor protein 9.

    PubMed

    Yang, Min-Hui; Hu, Zhi-Yan; Xu, Chuan; Xie, Lin-Ying; Wang, Xiao-Yan; Chen, Shi-You; Li, Zu-Guo

    2015-01-01

    Our previous studies have shown that the 3' end of metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is involved in colorectal cancer (CRC) cell proliferation and migration/invasion in vitro. The role and mechanism of MALAT1 in CRC metastasis in vivo, however, remain largely unknown. In the present study, we found that MALAT1 was up-regulated in human primary CRC tissues with lymph node metastasis. Overexpression of MALAT1 via RNA activation promoted CRC cell proliferation, invasion and migration in vitro, and stimulated tumor growth and metastasis in mice in vivo. Conversely, knockdown of MALAT1 inhibited CRC tumor growth and metastasis. MALAT1 regulated at least 243 genes in CRC cells in a genome-wide expression profiling. Among these genes, PRKA kinase anchor protein 9 (AKAP-9) was significantly up-regulated at both mRNA and protein levels. AKAP-9 was highly expressed in CRC cells with metastatic potential and human primary CRC tissues with lymph node metastasis, but not in normal cells or tissues. Importantly, knockdown of AKAP-9 blocked MALAT1-mediated CRC cell proliferation, migration and invasion. These data indicate that MALAT1 may promote CRC tumor development via its target protein AKAP-9.

  20. Downregulation of SOK1 promotes the migration of MCF-7 cells

    SciTech Connect

    Chen, Xu-Dong; Cho, Chien-Yu

    2011-04-08

    Highlights: {yields} SOK1 is a member of GCK-III subfamily. It is activated by oxidative stress or chemical anoxia. {yields} Barr's group have found that autophosphorylation of SOK1 is triggered by binding to the Golgi matrix protein GM130 and made the cells migration through dimeric adaptor protein 14-3-3. {yields} But what we found is that downregulation of SOK1 promotes cell migration and leads to the upregulation of GM130 and Tyr861 of FAK in MCF-7 cells. -- Abstract: SOK1 is a member of the germinal center kinase (GCK-III) subfamily but little is known about it, particularly with respect to its role in signal transduction pathways relative to tumor metastasis. By stably transfecting SOK1 siRNA into the MCF-7 breast cancer cell line we found that SOK1 promotes the migration of MCF-7 cells, as determined using wound-healing and Boyden chamber assays. However, cell proliferation assays revealed that silencing SOK1 had no effect on cell growth relative to the normal cells. Silencing SOK1 also had an effect on the expression and phosphorylation status of a number of proteins in MCF-7 cells, including FAK and GM130, whereby a decrease in SOK1 led to an increase in the expression of these proteins.

  1. Formylpeptide Receptors Promote the Migration and Differentiation of Rat Neural Stem Cells

    PubMed Central

    Wang, Guan; Zhang, Liang; Chen, Xingxing; Xue, Xin; Guo, Qiaonan; Liu, Mingyong; Zhao, Jianhua

    2016-01-01

    Neural stem cells (NSCs) bear characteristics for proliferation, migration and differentiation into three main neural cell type(s): neurons, astrocytes and/or oligodendrocytes. Formylpeptide receptors (Fprs), belonging to the family of G protein-coupled chemoattractant receptors, have been detected on neurons in the central nervous system (CNS). Here, we report that Fpr1 and Fpr2 are expressed on NSCs as detected with immunohistochemistry, RT-PCR and WB assays. In addition, Fpr1 and Fpr2 promoted NSC migration through F-actin polymerization and skewed NSC differentiation to neurons. Our study demonstrates a unique role of Fpr1 and Fpr2 in NSCs and opens a novel window for cell replacement therapies for brain and spinal cord injury. PMID:27173446

  2. Securin promotes migration and invasion via matrix metalloproteinases in glioma cells

    PubMed Central

    YAN, HAICHENG; WANG, WEI; DOU, CHANGWU; TIAN, FUMING; QI, SONGTAO

    2015-01-01

    Human securin, encoded by pituitary tumor transforming gene 1, is implicated in several oncogenic processes in the pathogenesis of brain tumors, including glioma. The aim of the present study was to examine the effect of securin on the migration and invasion of glioma cells. The results revealed that the overexpression of securin in glioma LN-229 cells significantly increased the invasion and transmigration abilities. By contrast, these abilities were significantly reduced by the downregulation of securin in glioma U373 cells. Furthermore, the results demonstrated that securin overexpression and downregulation significantly increased and decreased the levels of matrix metalloproteinase 2 and 9, respectively. These findings indicate a promotive role for securin in glioma migration and invasion, which may involve the action of matrix metalloproteinases. PMID:26137166

  3. Dentin Matrix Protein-1 Isoforms Promote Differential Cell Attachment and Migration*S⃞

    PubMed Central

    von Marschall, Zofia; Fisher, Larry W.

    2008-01-01

    Dentin matrix protein-1 (DMP1), bone sialoprotein (BSP), and osteopontin (OPN) are three SIBLINGs (small integrin-binding ligand, N-linked glycoproteins) co-expressed/secreted by skeletal and active ductal epithelial cells. Although etiological mechanisms remain unclear, DMP1 is the only one of these three genes currently known to have mutations resulting in human disease, and yet it remains the least studied. All three contain the highly conserved integrin-binding tripeptide, RGD, and experiments comparing the cell attachment and haptotactic migration-enhancing properties of DMP1 to BSP and OPN were performed using human skeletal (MG63 and primary dental pulp cells) and salivary gland (HSG) cells. Mutation of any SIBLING's RGD destroyed all attachment and migration activity. Using itsαVβ5 integrin, HSG cells attached to BSP but not to DMP1 or OPN. However, HSG cells could not migrate onto BSP in a modified Boyden chamber assay. Expression of αVβ3 integrin enhanced HSG attachment to DMP1 and OPN and promoted haptotactic migration onto all three proteins. Interchanging the first four coding exons or the conserved amino acids adjacent to the RGD of DMP1 with corresponding sequences of BSP did not enhance the ability of DMP1 to bindαVβ5. For αVβ3-expressing cells, intact DMP1, its BMP1-cleaved C-terminal fragment, and exon six lacking all post-translational modifications worked equally well but the proteoglycan isoform of DMP1 had greatly reduced ability for cell attachment and migration. The sequence specificity of the proposed BMP1-cleavage site of DMP1 was verified by mutation analysis. Direct comparison of the three proteins showed that cells discriminate among these SIBLINGs and among DMP1 isoforms. PMID:18819913

  4. Loss of GATA3 in bladder cancer promotes cell migration and invasion.

    PubMed

    Li, Yi; Ishiguro, Hitoshi; Kawahara, Takashi; Kashiwagi, Eiji; Izumi, Koji; Miyamoto, Hiroshi

    2014-04-01

    The transcription factor GATA3 is known as a breast tumor suppressor as well as a urothelial marker, and its loss is often seen in high-grade invasive bladder cancer. Nonetheless, GATA3 functions in bladder cancer cells remain largely unknown. In this study, we assessed the effects of GATA3 silencing via RNA interference on cell migration, invasion, and proliferation of bladder cancer. GATA3 expression was downregulated in all four bladder cancer lines examined, compared with a non-neoplastic urothelial line SVHUC. Knockdown of GATA3 in the bladder cancer lines (5637, TCC-SUP, J82) resulted in promotion of cell migration and invasion as well as increases in the expression of their related molecules, such as vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9, and the activity of MMP-2 and MMP-9. GATA3 loss was also associated with an increasing level of a mesenchymal marker N-cadherin and a decreasing level of an epithelial marker β-catenin. Consistent with these findings, enforced expression of GATA3 in UMUC3 inhibited cell migration and invasion. However, GATA3 showed marginal effects on bladder cancer cell viability and the expression of cell cycle- or apoptosis-related molecules. Additionally, in contrast to bladder cancer lines, no significant effects of GATA3 silencing on cell migration were seen in SVHUC. These findings suggest that GATA3 plays an important role in the prevention of bladder cancer progression and metastasis by inhibiting cell migration and invasion as well as epithelial-to-mesenchymal transition.

  5. Gcsf-Chr19 promotes neutrophil migration to damaged tissue through blood vessels in zebrafish.

    PubMed

    Galdames, Jorge A; Zuñiga-Traslaviña, Constanza; Reyes, Ariel E; Feijóo, Carmen G

    2014-07-01

    G-CSF is an essential cytokine that regulates proliferation and differentiation of granulocytes from hematopoietic stem and progenitor cells. In mammals G-CSF has been identified as a key factor that promotes the release of neutrophils from the bone marrow into the blood circulation. In silico analysis indicates that zebrafish has two gcsf genes, gcsf-chr12 in chromosome 12 and gcsf-chr19 in chromosome 19. Gcsf-Chr12 participates in emergency myelopoiesis, but, in contrast to its mammalian orthologue, is not involved in neutrophil migration toward damaged tissue. In turn, the function of Gcsf-Chr19 has not been examined yet. In this study, we analyzed the role of Gcsf-Chr19 in regulating neutrophil migration toward the wound. Our results indicated that during the first h after caudal fin transection, neutrophils migrate from the hematopoietic tissue toward the injury, using the extracellular matrix as a substrate. Later, between 3 and 4 h postdamage, the recruitment mainly occurs through the bloodstream, and only a few neutrophils still use the extracellular matrix to migrate. During this process, the transcriptional levels of gcsf-chr19 are considerably increased, reaching a peak 1 h postdamage. The knockdown of Gcsf-chr19 indicated that the percentage of neutrophils that reach the wound decreased after the first h postinjury, suggesting that the knockdown specifically affects neutrophils that travel to the wound through blood vessels. Together, our data provide novel information about the regulation of neutrophil migration in zebrafish, positioning Gcsf-Chr19 as a key signal during the course of an inflammatory process triggered by severe damage.

  6. A novel role of microRNA 17-5p in the modulation of circadian rhythm.

    PubMed

    Gao, Qian; Zhou, Lan; Yang, Su-Yu; Cao, Ji-Min

    2016-01-01

    The circadian clock helps living organisms to adjust their physiology and behaviour to adapt environmental day-night cycles. The period length of circadian rhythm reflects the endogenous cycle transition rate and is modulated by environmental cues or internal molecules, and the latter are of substantial importance but remain poorly revealed. Here, we demonstrated that microRNA 17-5p (miR-17-5p), which has been associated with tumours, was an important factor in controlling the circadian period. MiR-17-5p was rhythmically expressed in synchronised fibroblasts and mouse master clock suprachiasmatic nuclei (SCN). MiR-17-5p and the gene Clock exhibited a reciprocal regulation: miR-17-5p inhibited the translation of Clock by targeting the 3'UTR (untranslated region) of Clock mRNA, whereas the CLOCK protein directly bound to the promoter of miR-17 and enhanced its transcription and production of miR-17-5p. In addition, miR-17-5p suppressed the expression of Npas2. At the cellular level, bidirectional changes in miR-17-5p or CLOCK resulted in CRY1 elevation. Accordingly, in vivo, both increase and decrease of miR-17-5p in the mouse SCN led to an increase in CRY1 level and shortening of the free-running period. We conclude that miR-17-5p has an important role in the inspection and stabilisation of the circadian-clock period by interacting with Clock and Npas2 and potentially via the output of CRY1. PMID:27440219

  7. A novel role of microRNA 17-5p in the modulation of circadian rhythm

    PubMed Central

    Gao, Qian; Zhou, Lan; Yang, Su-Yu; Cao, Ji-Min

    2016-01-01

    The circadian clock helps living organisms to adjust their physiology and behaviour to adapt environmental day-night cycles. The period length of circadian rhythm reflects the endogenous cycle transition rate and is modulated by environmental cues or internal molecules, and the latter are of substantial importance but remain poorly revealed. Here, we demonstrated that microRNA 17-5p (miR-17-5p), which has been associated with tumours, was an important factor in controlling the circadian period. MiR-17-5p was rhythmically expressed in synchronised fibroblasts and mouse master clock suprachiasmatic nuclei (SCN). MiR-17-5p and the gene Clock exhibited a reciprocal regulation: miR-17-5p inhibited the translation of Clock by targeting the 3′UTR (untranslated region) of Clock mRNA, whereas the CLOCK protein directly bound to the promoter of miR-17 and enhanced its transcription and production of miR-17-5p. In addition, miR-17-5p suppressed the expression of Npas2. At the cellular level, bidirectional changes in miR-17-5p or CLOCK resulted in CRY1 elevation. Accordingly, in vivo, both increase and decrease of miR-17-5p in the mouse SCN led to an increase in CRY1 level and shortening of the free-running period. We conclude that miR-17-5p has an important role in the inspection and stabilisation of the circadian-clock period by interacting with Clock and Npas2 and potentially via the output of CRY1. PMID:27440219

  8. Resistin-Like Molecule-β Promotes Invasion and Migration of Gastric Carcinoma Cells

    PubMed Central

    Jiang, Rui; Zhao, Chunming; Wang, Xinyu; Wang, Shengxi; Sun, Xiaogang; Tian, Yang; Song, Wei

    2016-01-01

    Background Resistin-like molecule-β (RELMβ) is a novel secretory protein from intestinal goblet cells and participates in epithelial differentiation, tumor occurrence, and immune response. RELMβ is absent in normal gastric mucosa but is abundantly expressed in gastric carcinoma tissues, and is correlated with tumor invasion and metastasis. Epithelial-mesenchymal transition (EMT) is an important mechanism governing tumor cell invasion. This study thus investigated the modulation of RELMβ in gastric cancer metastasis and its correlation with EMT. Material/Methods We used RELMβ-low expression AGS cell line of gastric cancer and normal mucosa cell line GES1 as in vitro models, on which RELMβ0-expressing vector was transfected. The invasion and migration of cells were quantified by Transwell assay. EMT-related protein including E-cadherin, N-cadherin, Snail, and Vimentin were detected by Western blotting in transfected AGS cells. Results RELMβ transfection significantly potentiated invasion and migration abilities of AGS cells, whose RELMβ protein level was significantly elevated compared to those in untransfected AGS or GES1 cells. After RELMβ transfection, EMT-related proteins, including N-cadherin, Snail, and Vimentin levels, were elevated, but E-cadherin expression was depressed. Conclusions RELMβ-overexpression can facilitate invasion and migration of gastric carcinoma cells and it increases the expression of EMT-related proteins, such as N-cadherin, Snail, Vimentin, but decreases E-cadherin level, thus promoting the progression of EMT. PMID:27001185

  9. PFTK1 Promotes Gastric Cancer Progression by Regulating Proliferation, Migration and Invasion

    PubMed Central

    Huang, Hua; Yang, Qichang; Cai, Jing; Wang, Qiuhong; Zhu, Junya; Shao, Mengting; Xiao, Jinzhang; Cao, Jie; Gu, Xiaodan; Zhang, Shusen; Wang, Yingying

    2015-01-01

    PFTK1, also known as PFTAIRE1, CDK14, is a novel member of Cdc2-related serine/threonine protein kinases. Recent studies show that PFTK1 is highly expressed in several malignant tumors such as hepatocellular carcinoma, esophageal cancer, breast cancer, and involved in regulation of cell cycle, tumors proliferation, migration, and invasion that further influence the prognosis of tumors. However, the expression and physiological significance of PFTK1 in gastric cancer remain unclear. In this study, we analyzed the expression and clinical significance of PFTK1 by Western blot in 8 paired fresh gastric cancer tissues, nontumorous gastric mucosal tissues and immunohistochemistry on 161 paraffinembedded slices. High PFTK1 expression was correlated with the tumor grade, lymph node invasion as well as Ki-67. Through Cell Counting Kit (CCK)-8 assay, flow cytometry, colony formation, wound healing and transwell assays, the vitro studies demonstrated that PFTK1 overexpression promoted proliferation, migration and invasion of gastric cancer cells, while PFTK1 knockdown led to the opposite results. Our findings for the first time supported that PFTK1 might play an important role in the regulation of gastric cancer proliferation, migration and would provide a novel promising therapeutic strategy against human gastric cancer. PMID:26488471

  10. Hyperexpressed Netrin-1 Promoted Neural Stem Cells Migration in Mice after Focal Cerebral Ischemia

    PubMed Central

    Lu, Haiyan; Song, Xiaoyan; Wang, Feng; Wang, Guodong; Wu, Yuncheng; Wang, Qiaoshu; Wang, Yongting; Yang, Guo-Yuan; Zhang, Zhijun

    2016-01-01

    Endogenous Netrin-1 (NT-1) protein was significantly increased after cerebral ischemia, which may participate in the repair after transient cerebral ischemic injury. In this work, we explored whether NT-1 can be steadily overexpressed by adeno-associated virus (AAV) and the exogenous NT-1 can promote neural stem cells migration from the subventricular zone (SVZ) region after cerebral ischemia. Adult CD-1 mice were injected stereotacticly with AAV carrying NT-1 gene (AAV-NT-1). Mice underwent 60 min of middle cerebral artery (MCA) occlusion 1 week after injection. We found that NT-1 mainly expressed in neuron and astrocyte, and the expression level of NT-1 significantly increased 1 week after AAV-NT-1 gene transfer and lasted for 28 days, even after transient middle cerebral artery occlusion (tMCAO) as well (p < 0.05). Immunohistochemistry results showed that the number of neural stem cells was greatly increased in the SVZ region of AAV-NT-1-transduced mice compared with control mice. Our study showed that overexpressed NT-1 promoted neural stem cells migration from SVZ. This result suggested that NT-1 is a promising factor for repairing and remodeling after focal cerebral ischemia. PMID:27746720

  11. Sympathetic stimulation facilitates thrombopoiesis by promoting megakaryocyte adhesion, migration, and proplatelet formation.

    PubMed

    Chen, Shilei; Du, Changhong; Shen, Mingqiang; Zhao, Gaomei; Xu, Yang; Yang, Ke; Wang, Xinmiao; Li, Fengju; Zeng, Dongfeng; Chen, Fang; Wang, Song; Chen, Mo; Wang, Cheng; He, Ting; Wang, Fengchao; Wang, Aiping; Cheng, Tianmin; Su, Yongping; Zhao, Jinghong; Wang, Junping

    2016-02-25

    The effect of sympathetic stimulation on thrombopoiesis is not well understood. Here, we demonstrate that both continual noise and exhaustive exercise elevate peripheral platelet levels in normal and splenectomized mice, but not in dopamine β-hydroxylase-deficient (Dbh(-/-)) mice that lack norepinephrine (NE) and epinephrine (EPI). Further investigation demonstrates that sympathetic stimulation via NE or EPI injection markedly promotes platelet recovery in mice with thrombocytopenia induced by 6.0 Gy of total-body irradiation and in mice that received bone marrow transplants after 10.0 Gy of lethal irradiation. Unfavorably, sympathetic stress-stimulated thrombopoiesis may also contribute to the pathogenesis of atherosclerosis by increasing both the amount and activity of platelets in apolipoprotein E-deficient (ApoE(-/-)) mice. In vitro studies reveal that both NE and EPI promote megakaryocyte adhesion, migration, and proplatelet formation (PPF) in addition to the expansion of CD34(+) cells, thereby facilitating platelet production. It is found that α2-adrenoceptor-mediated extracellular signal-regulated kinase 1/2 (ERK1/2) activation is involved in NE- and EPI-induced megakaryocyte adhesion and migration, and PPF is regulated by ERK1/2 activation-mediated RhoA GTPase signaling. Our data deeply characterize the role of sympathetic stimulation in the regulation of thrombopoiesis and reevaluate its physiopathological implications. PMID:26644453

  12. In vitro inhibition of murine macrophage migration by Bordetella pertussis lymphocytosis-promoting factor.

    PubMed Central

    Meade, B D; Kind, P D; Ewell, J B; McGrath, P P; Manclark, C R

    1984-01-01

    Lymphocytosis promoting factor (LPF) of Bordetella pertussis is a protein toxin which may have a role in the pathogenesis of pertussis. Since macrophages have an important role in the control of respiratory infections, the in vitro effects of LPF on macrophages from C3H/HeN and C3H/HeJ mice and on a murine macrophage-like cell line, RAW264, were examined. LPF inhibited random migration of resident peritoneal macrophages as well as the chemotaxis of peritoneal macrophages and the cell line. Fifty percent inhibition of chemotaxis occurred at 0.2 to 0.3 ng of LPF per ml for the macrophages and at 1 to 2 ng of LPF per ml for the cell line. When LPF was either heated at 80 degrees C for 5 min or premixed with specific antibodies, it failed to inhibit migration. At 20 ng/ml, LPF inhibited chemotaxis by more than 80% and also decreased Fc-mediated phagocytosis by 25 to 35%. At this dose, LPF was not a chemoattractant for murine macrophages and did not reduce macrophage viability, adherence, or opsonized zymosan-stimulated superoxide release. When LPF-treated macrophages were added to tissue culture dishes and then examined microscopically after 4 h, the LPF-treated cells adhered but failed to spread and elongate as well as control macrophages. These data indicate that LPF specifically inhibits macrophage migration in vitro and suggest that a possible role for LPF in pathogenesis is to inhibit migration of macrophages to the site of B. pertussis infection. Images PMID:6088394

  13. FOXM1 promotes invasion and migration of colorectal cancer cells partially dependent on HSPA5 transactivation.

    PubMed

    Luo, Xiaoyong; Yao, Jinke; Nie, Peipei; Yang, Zhiyuan; Feng, Hongbo; Chen, Pinjia; Shi, Xinpeng; Zou, Zhengzhi

    2016-05-01

    In this study, to investigate whether endoplastic reticulum (ER) stress correlated with FOXM1 in colorectal cancer, we analysed the mRNA levels of FOXM1 and ER stress markers HSPA5 and spliced XBP1 by qRT-PCR. FOXM1 mRNA levels were found to positively correlate with HSPA5 in colorectal cancer. However, no significant correlation between FOXM1 and spliced XBP1 mRNA levels was found. Theses results suggested the positive correlation between FOXM1 and HSPA5 in colorectal cancer was not associated with ER stress. Next, we provided evidences that FOXM1 promoted HSPA5 transcription by directly binding to and stimulating HSPA5 promoter. Moreover, a FOXM1-binding site mapped between -1019 and -1012 bp of the proximal HSPA5 promoter was identified. In addition, we found that enhancement of cell migration and invasion by FOXM1 was significantly attenuated by depletion of HSPA5 in colorectal cancer cell. Furthermore, FOXM1 triggered colorectal cancer cell migration and invasion was involved in activities of cell-surface HSPA5. Lastly, our results suggested FOXM1 facilitated the activities and expressions of MMP2 and 9 associated with cell-surface HSPA5 in colorectal cancer cells. Moreover, statistically significant positive correlations between FOXM1 and MMP2 mRNA expression, between HSPA5 and MMP2 were found in colorectal cancer tissue specimens. Together, our results suggested that FOXM1-HSPA5 signaling might be considered as a novel molecular target for designing novel therapeutic regimen to control colorectal cancer metastasis and progression.

  14. FOXM1 promotes invasion and migration of colorectal cancer cells partially dependent on HSPA5 transactivation

    PubMed Central

    Yang, Zhiyuan; Feng, Hongbo; Chen, Pinjia; Shi, Xinpeng; Zou, Zhengzhi

    2016-01-01

    In this study, to investigate whether endoplastic reticulum (ER) stress correlated with FOXM1 in colorectal cancer, we analysed the mRNA levels of FOXM1 and ER stress markers HSPA5 and spliced XBP1 by qRT-PCR. FOXM1 mRNA levels were found to positively correlate with HSPA5 in colorectal cancer. However, no significant correlation between FOXM1 and spliced XBP1 mRNA levels was found. Theses results suggested the positive correlation between FOXM1 and HSPA5 in colorectal cancer was not associated with ER stress. Next, we provided evidences that FOXM1 promoted HSPA5 transcription by directly binding to and stimulating HSPA5 promoter. Moreover, a FOXM1-binding site mapped between -1019 and -1012 bp of the proximal HSPA5 promoter was identified. In addition, we found that enhancement of cell migration and invasion by FOXM1 was significantly attenuated by depletion of HSPA5 in colorectal cancer cell. Furthermore, FOXM1 triggered colorectal cancer cell migration and invasion was involved in activities of cell-surface HSPA5. Lastly, our results suggested FOXM1 facilitated the activities and expressions of MMP2 and 9 associated with cell-surface HSPA5 in colorectal cancer cells. Moreover, statistically significant positive correlations between FOXM1 and MMP2 mRNA expression, between HSPA5 and MMP2 were found in colorectal cancer tissue specimens. Together, our results suggested that FOXM1-HSPA5 signaling might be considered as a novel molecular target for designing novel therapeutic regimen to control colorectal cancer metastasis and progression. PMID:27034162

  15. FOXM1 promotes invasion and migration of colorectal cancer cells partially dependent on HSPA5 transactivation.

    PubMed

    Luo, Xiaoyong; Yao, Jinke; Nie, Peipei; Yang, Zhiyuan; Feng, Hongbo; Chen, Pinjia; Shi, Xinpeng; Zou, Zhengzhi

    2016-05-01

    In this study, to investigate whether endoplastic reticulum (ER) stress correlated with FOXM1 in colorectal cancer, we analysed the mRNA levels of FOXM1 and ER stress markers HSPA5 and spliced XBP1 by qRT-PCR. FOXM1 mRNA levels were found to positively correlate with HSPA5 in colorectal cancer. However, no significant correlation between FOXM1 and spliced XBP1 mRNA levels was found. Theses results suggested the positive correlation between FOXM1 and HSPA5 in colorectal cancer was not associated with ER stress. Next, we provided evidences that FOXM1 promoted HSPA5 transcription by directly binding to and stimulating HSPA5 promoter. Moreover, a FOXM1-binding site mapped between -1019 and -1012 bp of the proximal HSPA5 promoter was identified. In addition, we found that enhancement of cell migration and invasion by FOXM1 was significantly attenuated by depletion of HSPA5 in colorectal cancer cell. Furthermore, FOXM1 triggered colorectal cancer cell migration and invasion was involved in activities of cell-surface HSPA5. Lastly, our results suggested FOXM1 facilitated the activities and expressions of MMP2 and 9 associated with cell-surface HSPA5 in colorectal cancer cells. Moreover, statistically significant positive correlations between FOXM1 and MMP2 mRNA expression, between HSPA5 and MMP2 were found in colorectal cancer tissue specimens. Together, our results suggested that FOXM1-HSPA5 signaling might be considered as a novel molecular target for designing novel therapeutic regimen to control colorectal cancer metastasis and progression. PMID:27034162

  16. HEF1, a Novel Target of Wnt Signaling, Promotes Colonic Cell Migration and Cancer Progression

    PubMed Central

    Li, Yingchun; Bavarva, Jasmin H.; Wang, Zemin; Guo, Jianhui; Qian, Chiping; Thibodeau, Stephen N.; Golemis, Erica A.; Liu, Wanguo

    2011-01-01

    Misregulation of the canonical Wnt/β-catenin pathway and aberrant activation of Wnt signaling target genes are common in colorectal cancer and contribute to cancer progression. Altered expression of HEF1 (Human Enhancer of Filamentation 1, also known as NEDD9 or Cas-L) has been implicated in progression of melanoma, breast, and colorectal cancer. However, the regulation of HEF1 and the role of HEF1 in colorectal cancer tumorigenesis are not fully understood. We here identify HEF1 as a novel Wnt signaling target. The expression of HEF1 was up-regulated by Wnt3a, β-catenin, and Dvl2 in a dose-dependent fashion, and was suppressed following β-catenin down-regulation by shRNA. In addition, elevated HEF1 mRNA and protein levels were observed in colorectal cancer cell lines and primary tumor tissues, as well as in the colon and adenoma polyps of Apcmin/+ mice. Moreover, HEF1 levels in human colorectal tumor tissues increased with the tumor grade. Chromatin immunoprecipitation (ChIP) assays and HEF1 promoter analyses revealed three functional TCF-binding sites in the promoter of HEF1 responsible for HEF1 induction by Wnt signaling. Ectopic expression of HEF1 increased cell proliferation and colony formation, while down-regulation of HEF1 in SW480 cells by shRNA had the opposite effects and inhibited the xenograft tumor growth. Furthermore, overexpression of HEF1 in SW480 cells promoted cell migration and invasion. Together, our results determined a novel role of HEF1 as a mediator of the canonical Wnt/β-catenin signaling pathway for cell proliferation, migration, and tumorigenesis, as well as an important player in colorectal tumorigenesis and progression. HEF1 may represent an attractive candidate for drug targeting in colorectal cancer. PMID:21317929

  17. Angiopoietin-1 promotes endothelial cell proliferation and migration through AP-1-dependent autocrine production of interleukin-8.

    PubMed

    Abdel-Malak, Nelly A; Srikant, Coimbatore B; Kristof, Arnold S; Magder, Sheldon A; Di Battista, John A; Hussain, Sabah N A

    2008-04-15

    Angiopoietin-1 (Ang-1), ligand for the endothelial cell-specific Tie-2 receptors, promotes migration and proliferation of endothelial cells, however, whether these effects are promoted through the release of a secondary mediator remains unclear. In this study, we assessed whether Ang-1 promotes endothelial cell migration and proliferation through the release of interleukin-8 (IL-8). Ang-1 elicited in human umbilical vein endothelial cells (HUVECs) a dose- and time-dependent increase in IL-8 production as a result of induction of mRNA and enhanced mRNA stability of IL-8 transcripts. IL-8 production is also elevated in HUVECs transduced with retroviruses expressing Ang-1. Neutralization of IL-8 in these cells with a specific antibody significantly attenuated proliferation and migration and induced caspase-3 activation. Exposure to Ang-1 triggered a significant increase in DNA binding of activator protein-1 (AP-1) to a relatively short fragment of IL-8 promoter. Upstream from the AP-1 complex, up-regulation of IL-8 transcription by Ang-1 was mediated through the Erk1/2, SAPK/JNK, and PI-3 kinase pathways, which triggered c-Jun phosphorylation on Ser63 and Ser73. These results suggest that promotion of endothelial migration and proliferation by Ang-1 is mediated, in part, through the production of IL-8, which acts in an autocrine fashion to suppress apoptosis and facilitate cell proliferation and migration.

  18. NFAT5 promotes proliferation and migration of lung adenocarcinoma cells in part through regulating AQP5 expression

    SciTech Connect

    Guo, Kai; Jin, Faguang

    2015-09-25

    The osmoregulated transcription factor nuclear factor of activated T-cells 5(NFAT5), has been found to play important roles in the development of many kinds of human cancers, including breast cancer, colon carcinoma, renal cell carcinoma and melanoma. The aim of the present study was to determine whether NFAT5 is involved in the proliferation and migration of lung adenocarcinoma cells. We found that NFAT5 was upregulated in lung adenocarcinoma cells and knockdown of NFAT5 decreased proliferation and migration of the cells, accompanied by a significant reduction in the expression of AQP5. AQP5 was upregulated in lung adenocarcinoma cells and knockdown of AQP5 also inhibited proliferation and migration of the cells as knockdown of NFAT5 did. Moreover, overexpression of NFAT5 promoted proliferation and migration of lung adenocarcinoma cells, accompanied by a significant increase in the expression of AQP5. These results indicate that NFAT5 plays important roles in proliferation and migration of human lung adenocarcinoma cells through regulating AQP5 expression, providing a new therapeutic option for lung adenocarcinoma therapy. - Highlights: • NFAT5 expression is higher in lung adenocarcinoma cells compared with normal cells. • NFAT5 knockdown decreases proliferation and migration of lung adenocarcinoma cells. • Knockdown of NFAT5 reduces AQP5 expression in human lung adenocarcinoma cells. • Overexpression of NFAT5 promotes proliferation and migration of lung adenocarcinoma cells. • Overexpression of NFAT5 increases AQP5 expression in human lung adenocarcinoma cells.

  19. Twist1 Directly Regulates Genes That Promote Cell Proliferation and Migration in Developing Heart Valves

    PubMed Central

    Lee, Mary P.; Yutzey, Katherine E.

    2011-01-01

    Twist1, a basic helix-loop-helix transcription factor, is expressed in mesenchymal precursor populations during embryogenesis and in metastatic cancer cells. In the developing heart, Twist1 is highly expressed in endocardial cushion (ECC) valve mesenchymal cells and is down regulated during valve differentiation and remodeling. Previous studies demonstrated that Twist1 promotes cell proliferation, migration, and expression of primitive extracellular matrix (ECM) molecules in ECC mesenchymal cells. Furthermore, Twist1 expression is induced in human pediatric and adult diseased heart valves. However, the Twist1 downstream target genes that mediate increased cell proliferation and migration during early heart valve development remain largely unknown. Candidate gene and global gene profiling approaches were used to identify transcriptional targets of Twist1 during heart valve development. Candidate target genes were analyzed for evolutionarily conserved regions (ECRs) containing E-box consensus sequences that are potential Twist1 binding sites. ECRs containing conserved E-box sequences were identified for Twist1 responsive genes Tbx20, Cdh11, Sema3C, Rab39b, and Gadd45a. Twist1 binding to these sequences in vivo was determined by chromatin immunoprecipitation (ChIP) assays, and binding was detected in ECCs but not late stage remodeling valves. In addition identified Twist1 target genes are highly expressed in ECCs and have reduced expression during heart valve remodeling in vivo, which is consistent with the expression pattern of Twist1. Together these analyses identify multiple new genes involved in cell proliferation and migration that are differentially expressed in the developing heart valves, are responsive to Twist1 transcriptional function, and contain Twist1-responsive regulatory sequences. PMID:22242143

  20. PAK2 promotes migration and proliferation of salivary gland adenoid cystic carcinoma

    PubMed Central

    Deng, Wei-Wei; Wu, Lei; Bu, Lin-Lin; Liu, Jian-Feng; Li, Yi-Cun; Ma, Si-Rui; Yu, Guang-Tao; Mao, Liang; Zhang, Wen-Feng; Sun, Zhi-Jun

    2016-01-01

    P21 activated kinase 2 (PAK2) is a member of Group I PAKs family and highly expressed in various cancers. Current studies have demonstrated that PAK2 played a pivotal role in tumor progression. However, the role of PAK2 in salivary adenoid cystic carcinoma is still unclear. This study aims to explore the expression and the function of PAK2 in AdCC. Human salivary gland tissue microarray, including 18 normal salivary glands (NSG), 12 pleomorphic adenoma (PMA) and 72 AdCC, and immunohistochemistry were used to evaluate the expression of PAK2. The result showed that PAK2 was significantly increased in AdCC compared with NSG and PMA. Then the Pearson correlation analysis using serial tissue sections showed a close correlation of PAK2 with Cyclin D1, Phospho-STAT3 at Tyrosine 705 (p-STAT3) and Ki-67. Further in vitro study utilizing PAK2 knockdown via siRNA transfection revealed significantly reduced migration and proliferation of AdCC cell lines compared with control group. Knockdown of PAK2 decreased the expression of Cyclin D1 in AdCC cell lines. In addition, the inhibition of STAT3 reduced the expression of PAK2 in AdCC cell lines. These findings suggested that PAK2 promotes AdCC cell migration and proliferation and may be a potential therapeutic target. PMID:27648129

  1. PAK2 promotes migration and proliferation of salivary gland adenoid cystic carcinoma

    PubMed Central

    Deng, Wei-Wei; Wu, Lei; Bu, Lin-Lin; Liu, Jian-Feng; Li, Yi-Cun; Ma, Si-Rui; Yu, Guang-Tao; Mao, Liang; Zhang, Wen-Feng; Sun, Zhi-Jun

    2016-01-01

    P21 activated kinase 2 (PAK2) is a member of Group I PAKs family and highly expressed in various cancers. Current studies have demonstrated that PAK2 played a pivotal role in tumor progression. However, the role of PAK2 in salivary adenoid cystic carcinoma is still unclear. This study aims to explore the expression and the function of PAK2 in AdCC. Human salivary gland tissue microarray, including 18 normal salivary glands (NSG), 12 pleomorphic adenoma (PMA) and 72 AdCC, and immunohistochemistry were used to evaluate the expression of PAK2. The result showed that PAK2 was significantly increased in AdCC compared with NSG and PMA. Then the Pearson correlation analysis using serial tissue sections showed a close correlation of PAK2 with Cyclin D1, Phospho-STAT3 at Tyrosine 705 (p-STAT3) and Ki-67. Further in vitro study utilizing PAK2 knockdown via siRNA transfection revealed significantly reduced migration and proliferation of AdCC cell lines compared with control group. Knockdown of PAK2 decreased the expression of Cyclin D1 in AdCC cell lines. In addition, the inhibition of STAT3 reduced the expression of PAK2 in AdCC cell lines. These findings suggested that PAK2 promotes AdCC cell migration and proliferation and may be a potential therapeutic target.

  2. Hypoxia-induced mitogenic factor enhances angiogenesis by promoting proliferation and migration of endothelial cells

    SciTech Connect

    Tong Qiangsong; Zheng Liduan; Li Bo; Wang Danming; Huang Chuanshu; Matuschak, George M.; Li Dechun . E-mail: dli2@slu.edu

    2006-11-01

    Our previous studies have indicated that hypoxia-induced mitogenic factor (HIMF) has angiogenic properties in an in vivo matrigel plug model and HIMF upregulates expression of vascular endothelial growth factor (VEGF) in mouse lungs and cultured lung epithelial cells. However, whether HIMF exerts angiogenic effects through modulating endothelial cell function remains unknown. In this study, mouse aortic rings cultured with recombinant HIMF protein resulted in enhanced vascular sprouting and increased endothelial cell spreading as confirmed by Dil-Ac-LDL uptake, von Willebrand factor and CD31 staining. In cultured mouse endothelial cell line SVEC 4-10, HIMF dose-dependently enhanced cell proliferation, in vitro migration and tubulogenesis, which was not attenuated by SU1498, a VEGFR2/Flk-1 receptor tyrosine kinase inhibitor. Moreover, HIMF stimulation resulted in phosphorylation of Akt, p38 and ERK1/2 kinases in SVEC 4-10 cells. Treatment of mouse aortic rings and SVEC 4-10 cells with LY294002, but not SB203580, PD098059 or U0126, abolished HIMF-induced vascular sprouting and angiogenic responses. In addition, transfection of a dominant-negative mutant of phosphatidylinositol 3-kinase (PI-3K), {delta}p85, blocked HIMF-induced phosphorylation of Akt, endothelial activation and tubulogenesis. These results indicate that HIMF enhances angiogenesis by promoting proliferation and migration of endothelial cells via activation of the PI-3K/Akt pathways.

  3. P-cadherin promotes collective cell migration via a Cdc42-mediated increase in mechanical forces

    PubMed Central

    Plutoni, Cédric; Bazellieres, Elsa; Le Borgne-Rochet, Maïlys; Comunale, Franck; Brugues, Agusti; Séveno, Martial; Planchon, Damien; Thuault, Sylvie; Morin, Nathalie; Bodin, Stéphane; Trepat, Xavier

    2016-01-01

    Collective cell migration (CCM) is essential for organism development, wound healing, and metastatic transition, the primary cause of cancer-related death, and it involves cell–cell adhesion molecules of the cadherin family. Increased P-cadherin expression levels are correlated with tumor aggressiveness in carcinoma and aggressive sarcoma; however, how P-cadherin promotes tumor malignancy remains unknown. Here, using integrated cell biology and biophysical approaches, we determined that P-cadherin specifically induces polarization and CCM through an increase in the strength and anisotropy of mechanical forces. We show that this mechanical regulation is mediated by the P-cadherin/β-PIX/Cdc42 axis; P-cadherin specifically activates Cdc42 through β-PIX, which is specifically recruited at cell–cell contacts upon CCM. This mechanism of cell polarization and migration is absent in cells expressing E- or R-cadherin. Thus, we identify a specific role of P-cadherin through β-PIX–mediated Cdc42 activation in the regulation of cell polarity and force anisotropy that drives CCM. PMID:26783302

  4. Overexpression of TAZ promotes cell proliferation, migration and epithelial-mesenchymal transition in ovarian cancer

    PubMed Central

    Chen, Guangyuan; Xie, Jiabin; Huang, Ping; Yang, Zhihong

    2016-01-01

    The Hippo pathway is dysregulated in multiple types of human cancer, including ovarian cancer. Nuclear expression of yes-associated protein 1 (YAP1), a downstream transcription coactivator of the Hippo pathway, has been demonstrated to promote tumorigenesis in ovarian cancer and may serve as a poor prognostic indicator. However, transcriptional coactivator with PDZ binding motif (TAZ), a downstream target of the Hippo pathway and paralog of YAP in mammalian cells, has not been fully investigated in ovarian cancer. The present study aimed to investigate the dysregulation and biological function of TAZ in ovarian cancer. Reverse transcription-quantitative polymerase chain reaction and western blotting revealed that TAZ mRNA and protein levels, respectively, were upregulated in ovarian cancer, and a meta-analysis of ovarian cancer microarray datasets identified that increased expression of TAZ mRNA is correlated with poor prognosis in patients with ovarian cancer. In addition, TAZ-knockdown in ovarian cancer cells demonstrated that TAZ regulates the migration, proliferation and epithelial-mesenchymal transition of ovarian cancer cells. Furthermore, pharmacological disruption of the YAP/TAZ/TEA domain protein complex resulted in a decrease in ovarian cancer cell migration, proliferation and vimentin expression. The results of the present study indicate that the overexpression of TAZ is important in the development and progression of ovarian cancer, and may function as a potential drug target for treatment of this disease entity. PMID:27588129

  5. PAK2 promotes migration and proliferation of salivary gland adenoid cystic carcinoma.

    PubMed

    Deng, Wei-Wei; Wu, Lei; Bu, Lin-Lin; Liu, Jian-Feng; Li, Yi-Cun; Ma, Si-Rui; Yu, Guang-Tao; Mao, Liang; Zhang, Wen-Feng; Sun, Zhi-Jun

    2016-01-01

    P21 activated kinase 2 (PAK2) is a member of Group I PAKs family and highly expressed in various cancers. Current studies have demonstrated that PAK2 played a pivotal role in tumor progression. However, the role of PAK2 in salivary adenoid cystic carcinoma is still unclear. This study aims to explore the expression and the function of PAK2 in AdCC. Human salivary gland tissue microarray, including 18 normal salivary glands (NSG), 12 pleomorphic adenoma (PMA) and 72 AdCC, and immunohistochemistry were used to evaluate the expression of PAK2. The result showed that PAK2 was significantly increased in AdCC compared with NSG and PMA. Then the Pearson correlation analysis using serial tissue sections showed a close correlation of PAK2 with Cyclin D1, Phospho-STAT3 at Tyrosine 705 (p-STAT3) and Ki-67. Further in vitro study utilizing PAK2 knockdown via siRNA transfection revealed significantly reduced migration and proliferation of AdCC cell lines compared with control group. Knockdown of PAK2 decreased the expression of Cyclin D1 in AdCC cell lines. In addition, the inhibition of STAT3 reduced the expression of PAK2 in AdCC cell lines. These findings suggested that PAK2 promotes AdCC cell migration and proliferation and may be a potential therapeutic target. PMID:27648129

  6. Pim Kinases Promote Migration and Metastatic Growth of Prostate Cancer Xenografts

    PubMed Central

    Santio, Niina M.; Eerola, Sini K.; Paatero, Ilkka; Yli-Kauhaluoma, Jari; Anizon, Fabrice; Moreau, Pascale; Tuomela, Johanna; Härkönen, Pirkko; Koskinen, Päivi J.

    2015-01-01

    Background and methods Pim family proteins are oncogenic kinases implicated in several types of cancer and involved in regulation of cell proliferation, survival as well as motility. Here we have investigated the ability of Pim kinases to promote metastatic growth of prostate cancer cells in two xenograft models for human prostate cancer. We have also evaluated the efficacy of Pim-selective inhibitors to antagonize these effects. Results We show here that tumorigenic growth of both subcutaneously and orthotopically inoculated prostate cancer xenografts is enhanced by stable overexpression of either Pim-1 or Pim-3. Moreover, Pim-overexpressing orthotopic prostate tumors are highly invasive and able to migrate not only to the nearby prostate-draining lymph nodes, but also into the lungs to form metastases. When the xenografted mice are daily treated with the Pim-selective inhibitor DHPCC-9, both the volumes as well as the metastatic capacity of the tumors are drastically decreased. Interestingly, the Pim-promoted metastatic growth of the orthotopic xenografts is associated with enhanced angiogenesis and lymphangiogenesis. Furthermore, forced Pim expression also increases phosphorylation of the CXCR4 chemokine receptor, which may enable the tumor cells to migrate towards tissues such as the lungs that express the CXCL12 chemokine ligand. Conclusions Our results indicate that Pim overexpression enhances the invasive properties of prostate cancer cells in vivo. These effects can be reduced by the Pim-selective inhibitor DHPCC-9, which can reach tumor tissues without serious side effects. Thus, Pim-targeting therapies with DHPCC-9-like compounds may help to prevent progression of local prostate carcinomas to fatally metastatic malignancies. PMID:26075720

  7. miR-124 promotes the neuronal differentiation of mouse inner ear neural stem cells

    PubMed Central

    Jiang, Di; Du, Jintao; Zhang, Xuemei; Zhou, Wei; Zong, Lin; Dong, Chang; Chen, Kaitian; Chen, Yu; Chen, Xihui; Jiang, Hongyan

    2016-01-01

    MicroRNAs (miRNAs or miRs) act as key regulators in neuronal development, synaptic morphogenesis and plasticity. However, their role in the neuronal differentiation of inner ear neural stem cells (NSCs) remains unclear. In this study, 6 miRNAs were selected and their expression patterns during the neuronal differentiation of inner ear NSCs were examined by RT-qPCR. We demonstrated that the culture of spiral ganglion stem cells present in the inner ears of newborn mice gave rise to neurons in vitro. The expression patterns of miR-124, miR-132, miR-134, miR-20a, miR-17-5p and miR-30a-5p were examined during a 14-day neuronal differentiation period. We found that miR-124 promoted the neuronal differentiation of and neurite outgrowth in mouse inner ear NSCs, and that the changes in the expression of tropomyosin receptor kinase B (TrkB) and cell division control protein 42 homolog (Cdc42) during inner ear NSC differentiation were associated with miR-124 expression. Our findings indicate that miR-124 plays a role in the neuronal differentiation of inner ear NSCs. This finding may lead to the development of novel strategies for restoring hearing in neurodegenerative diseases.

  8. Cyclophilin A promotes cell migration via the Abl-Crk signaling pathway

    PubMed Central

    Saleh, Tamjeed; Jankowski, Wojciech; Sriram, Ganapathy; Rossi, Paolo; Shah, Shreyas; Lee, Ki-Bum; Cruz, Lissette Alicia; Rodriguez, Alexis J.; Birge, Raymond B.

    2015-01-01

    Summary Cyclophilin A (CypA) is over-expressed in a number of human cancer types, but the mechanisms by which CypA promotes oncogenic properties of cells are not understood. Here we demonstrate that CypA binds to and prevents the CrkII adaptor protein from switching to the inhibited state. CrkII is involved in cell motility and invasion by mediating signaling through its SH2 and SH3 domains. CrkII Tyr221 phosphorylation by the Abl or EGFR kinases induces an inhibited state of CrkII, by means of an intramolecular SH2-pTyr221 interaction, causing signaling interruption. We show that the CrkII phosphorylation site constitutes a binging site for CypA. Recruitment of CypA sterically restricts the accessibility of Tyr221 to kinases, thereby suppressing CrkII phosphorylation and promoting the active state. Structural, biophysical, and in vivo data show that CypA augments CrkII-mediated signaling. A strong stimulation of cell migration is observed in cancer cells wherein both CypA and CrkII are greatly up-regulated. PMID:26656091

  9. Oxysterols and EBI2 promote osteoclast precursor migration to bone surfaces and regulate bone mass homeostasis

    PubMed Central

    Nevius, Erin; Pinho, Flavia; Dhodapkar, Meera; Jin, Huiyan; Nadrah, Kristina; Horowitz, Mark C.; Kikuta, Junichi; Ishii, Masaru

    2015-01-01

    Bone surfaces attract hematopoietic and nonhematopoietic cells, such as osteoclasts (OCs) and osteoblasts (OBs), and are targeted by bone metastatic cancers. However, the mechanisms guiding cells toward bone surfaces are essentially unknown. Here, we show that the Gαi protein–coupled receptor (GPCR) EBI2 is expressed in mouse monocyte/OC precursors (OCPs) and its oxysterol ligand 7α,25-dihydroxycholesterol (7α,25-OHC) is secreted abundantly by OBs. Using in vitro time-lapse microscopy and intravital two-photon microscopy, we show that EBI2 enhances the development of large OCs by promoting OCP motility, thus facilitating cell–cell interactions and fusion in vitro and in vivo. EBI2 is also necessary and sufficient for guiding OCPs toward bone surfaces. Interestingly, OCPs also secrete 7α,25-OHC, which promotes autocrine EBI2 signaling and reduces OCP migration toward bone surfaces in vivo. Defective EBI2 signaling led to increased bone mass in male mice and protected female mice from age- and estrogen deficiency–induced osteoporosis. This study identifies a novel pathway involved in OCP homing to the bone surface that may have significant therapeutic potential. PMID:26438360

  10. Macrophage migration inhibitory factor promotes cyst growth in polycystic kidney disease

    PubMed Central

    Chen, Li; Zhou, Xia; Fan, Lucy X.; Yao, Ying; Swenson-Fields, Katherine I.; Gadjeva, Mihaela; Wallace, Darren P.; Peters, Dorien J.M.; Yu, Alan; Grantham, Jared J.; Li, Xiaogang

    2015-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is characterized by renal cyst formation, inflammation, and fibrosis. Macrophages infiltrate cystic kidneys, but the role of these and other inflammatory factors in disease progression are poorly understood. Here, we identified macrophage migration inhibitory factor (MIF) as an important regulator of cyst growth in ADPKD. MIF was upregulated in cyst-lining epithelial cells in polycystin-1–deficient murine kidneys and accumulated in cyst fluid of human ADPKD kidneys. MIF promoted cystic epithelial cell proliferation by activating ERK, mTOR, and Rb/E2F pathways and by increasing glucose uptake and ATP production, which inhibited AMP-activated protein kinase signaling. MIF also regulated cystic renal epithelial cell apoptosis through p53-dependent signaling. In polycystin-1–deficient mice, MIF was required for recruitment and retention of renal macrophages, which promoted cyst expansion, and Mif deletion or pharmacologic inhibition delayed cyst growth in multiple murine ADPKD models. MIF-dependent macrophage recruitment was associated with upregulation of monocyte chemotactic protein 1 (MCP-1) and inflammatory cytokine TNF-α. TNF-α induced MIF expression, and MIF subsequently exacerbated TNF-α expression in renal epithelial cells, suggesting a positive feedback loop between TNF-α and MIF during cyst development. Our study indicates MIF is a central and upstream regulator of ADPKD pathogenesis and provides a rationale for further exploration of MIF as a therapeutic target for ADPKD. PMID:25961459

  11. Progranulin stimulated by LPA promotes the migration of aggressive breast cancer cells.

    PubMed

    Swamydas, Muthulekha; Nguyen, Do; Allen, Lauren D; Eddy, Jill; Dréau, Didier

    2011-12-01

    Activator and inhibitor roles for the 88-kDa-secreted glycoprotein progranulin (PGRN) have been demonstrated in ovarian cancer cells. Here, we investigated the effects of PGRN in breast cancer migration. Testing MCF7, MDA-MB-453, and MDA-MB-231 human breast cancer cells and the MCF10A breast epithelial cell line, we demonstrate that LPA-induced PGRN stimulation led to a significant increase in cell invasion of MDA-MB-453 and MDA-MB-231 cells only (p<0.05). Moreover, incubation with an anti-PGRN antibody, an inhibitor of the ERK pathway (PD98059) or both in combination inhibited the ability of MDA-MB-231 cells to invade. Furthermore, the expression of focal adhesion kinases promoted by LPA-induced PGRN was also inhibited by PD98059 alone or in combination with an anti-PGRN antibody (p<0.05). Taken together, these results suggest that the LPA activation of PGRN involving the ERK pathway is critical to promote MDA-MB-231 breast cancer cell invasion.

  12. Regenerating gene family member 4 promotes growth and migration of gastric cancer through protein kinase B pathway.

    PubMed

    Huang, Jiamiao; Yang, Ya; Yang, Jian; Li, Xian

    2014-01-01

    Regenerating gene family member 4 (REG4), a secreted protein, is overexpressed in several cancers, including gastric cancer. The present study was undertaken to determine the roles of REG4 in the growth of gastric cancer in the nude mice and in the proliferation and migration in human gastric cancer cell line and its downstream signaling pathway. Gastric cancer models were elicited by intraperitoneally injecting MKN45 human gastric cancer cells and the tumor size was measured every other day. The expressions of REG4 mRNA and protein were increased in the gastric cancer tissues from gastric cancer patients. REG4 increased the gastric tumor weight and size in the nude mice, and promoted the proliferation and migration of gastric cancer cells MKN45. Adeno-associated viral (AAV)-mediated knockdown of REG4 decreased the gastric tumor weight and size in the nude mice, and suppressed the proliferation and migration of MKN45 cells. REG4 increased the expression of phosphorylated protein kinase B (Akt). Triciribine hydrate (TCN), the inhibitor of Akt, decreased the gastric tumor weight and size in the nude mice and abolished REG4-induced weight and size increase of the tumor. TCN also inhibited proliferation and migration and abolished REG4-induced proliferation and migration increase of human gastric cell line MKN45. These results indicate that REG4 promotes the growth, proliferation and migration of gastric cancer through Akt pathway. PMID:25356179

  13. FRK inhibits migration and invasion of human glioma cells by promoting N-cadherin/β-catenin complex formation.

    PubMed

    Shi, Qiong; Song, Xu; Wang, Jun; Gu, Jia; Zhang, Weijian; Hu, Jinxia; Zhou, Xiuping; Yu, Rutong

    2015-01-01

    Fyn-related kinase (FRK), a member of Src-related tyrosine kinases, is recently reported to function as a potent tumor suppressor in several cancer types. Our previous study has also shown that FRK over-expression inhibited the migration and invasion of glioma cells. However, the mechanism of FRK effect on glioma cell migration and invasion, a feature of human malignant gliomas, is still not clear. In this study, we found that FRK over-expression increased the protein level of N-cadherin, but not E-cadherin. Meanwhile, FRK over-expression promoted β-catenin translocation to the plasma membrane, where it formed complex with N-cadherin, while decreased β-catenin level in the nuclear fraction. In addition, down-regulation of N-cadherin by siRNA promoted the migration and invasion of glioma U251 and U87 cells and abolished the inhibitory effect of FRK on glioma cell migration and invasion. In summary, these results indicate that FRK inhibits migration and invasion of human glioma cells by promoting N-cadherin/β-catenin complex formation.

  14. A novel strategy to enhance mesenchymal stem cell migration capacity and promote tissue repair in an injury specific fashion.

    PubMed

    Xinaris, C; Morigi, M; Benedetti, V; Imberti, B; Fabricio, A S; Squarcina, E; Benigni, A; Gagliardini, E; Remuzzi, G

    2013-01-01

    Mesenchymal stem cells (MSCs) of bone marrow origin appear to be an attractive candidate for cell-based therapies. However, the major barrier to the effective implementation of MSC-based therapies is the lack of specific homing of exogenously infused cells and overall the inability to drive them to the diseased or damaged tissue. In order to circumvent these limitations, we developed a preconditioning strategy to optimize MSC migration efficiency and potentiate their beneficial effect at the site of injury. Initially, we screened different molecules by using an in vitro injury-migration setting, and subsequently, we evaluated the effectiveness of the different strategies in mice with acute kidney injury (AKI). Our results showed that preconditioning of MSCs with IGF-1 before infusion improved cell migration capacity and restored normal renal function after AKI. The present study demonstrates that promoting migration of MSCs could increase their therapeutic potential and indicates a new therapeutic paradigm for organ repair.

  15. RACK1 promoted the growth and migration of the cancer cells in the progression of esophageal squamous cell carcinoma.

    PubMed

    Hu, Fengqing; Tao, Zhen; Wang, Mingsong; Li, Guoqing; Zhang, Yunjiao; Zhong, Hong; Xiao, Haibo; Xie, Xiao; Ju, Mei

    2013-12-01

    Dysregulation of hedgehog signaling has been involved in esophageal squamous cell carcinoma (ESCC) by the mechanisms that are not fully understood. The receptor for activated protein kinase C (RACK1) is involved in the progression of multiple cancers. However, its expression and function in ESCC have not been investigated. Here, we found that the expression of RACK1 was upregulated in ESCC clinical samples. Moreover, over-expression of RACK1 in ESCC cells promoted cell proliferation and migration, while downregulation of RACK1 impaired the proliferation and migration of ESCC cells in vitro and in vivo. Mechanistically, RACK1 promoted the proliferation and migration of ESCC cells by activating hedgehog signaling. Taken together, our study suggested RACK1 might be an important therapeutic target in ESCC.

  16. Monocyte ADAM17 promotes diapedesis during transendothelial migration: Identification of steps and substrates targeted by metalloproteinases

    PubMed Central

    Tsubota, Yoshiaki; Frey, Jeremy M.; Tai, Phillip W.L.; Welikson, Robert E.; Raines, Elaine W.

    2013-01-01

    Despite expanded definition of the leukocyte adhesion cascade and mechanisms underlying individual steps, very little is known about regulatory mechanisms controlling sequential shifts between steps. We tested the hypothesis that metalloproteinases provide a mechanism to rapidly transition monocytes between different steps. Our study identifies diapedesis as a step targeted by metalloproteinase activity. Time-lapse video microscopy shows that the presence of a metalloproteinase inhibitor results in a doubling of the time required for human monocytes to complete diapedesis on unactivated or inflamed human endothelium, under both static and physiological-flow conditions. Thus, diapedesis is promoted by metalloproteinase activity. In contrast, neither adhesion of monocytes nor their locomotion over the endothelium is altered by metalloproteinase inhibition. We further demonstrate that metalloproteinase inhibition significantly elevates monocyte cell-surface levels of integrins CD11b/CD18 (Mac-1) specifically during transendothelial migration. Interestingly, such alterations are not detected for other endothelial- and monocyte-adhesion molecules that are presumed metalloproteinase substrates. Two major transmembrane metalloproteinases, ADAM17 and ADAM10, are identified as enzymes that control constitutive cleavage of Mac-1. We further establish that knockdown of monocyte ADAM17, but not endothelial ADAM10 or ADAM17, or monocyte ADAM10, reproduces the diapedesis delay observed with metalloproteinase inhibition. Therefore, we conclude that monocyte ADAM17 facilitates the completion of transendothelial migration by accelerating the rate of diapedesis. We propose that the progression of diapedesis may be regulated by spatial and temporal cleavage of Mac-1, which is triggered upon interaction with endothelium. PMID:23479224

  17. Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE

    PubMed Central

    Carmona, Guillaume; Perera, Upamali; Gillett, Cheryl; Naba, Alexandra; Law, Ah-Lai; Sharma, Ved P.; Wang, Jian; Wyckoff, Jeffrey; Balsamo, Michele; Mosis, Fuad; De Piano, Mario; Monypenny, James; Woodman, Natalie; McConnell, Russell E.; Mouneimne, Ghassan; Van Hemelrijck, Mieke; Cao, Yihai; Condeelis, John; Hynes, Richard O.; Gertler, Frank B.; Krause, Matthias

    2016-01-01

    Cancer invasion is a hallmark of metastasis. The mesenchymal mode of cancer cell invasion is mediated by elongated membrane protrusions driven by the assembly of branched F-actin networks. How deregulation of actin regulators promotes cancer cell invasion is still enigmatic. We report that increased expression and membrane localization of the actin regulator Lamellipodin correlates with reduced metastasis-free survival and poor prognosis in breast cancer patients. In agreement we find that Lamellipodin depletion reduced lung metastasis in an orthotopic mouse breast cancer model. Invasive 3D cancer cell migration as well as invadopodia formation, and matrix degradation were impaired upon Lamellipodin depletion. Mechanistically, we show that Lamellipodin promotes invasive 3D cancer cell migration via both actin-elongating Ena/VASP proteins and the Scar/WAVE complex, which stimulates actin branching. In contrast, Lamellipodin interaction with Scar/WAVE but not Ena/VASP is required for random 2D cell migration. We identify a phosphorylation-dependent mechanism that regulates selective recruitment of these effectors to Lamellipodin: Abl-mediated Lamellipodin phosphorylation promotes its association with both Scar/WAVE and Ena/VASP, while Src-dependent phosphorylation enhances binding to Scar/WAVE but not Ena/VASP. Through these selective, regulated interactions Lamellipodin mediates directional sensing of EGF gradients and invasive 3D migration of breast cancer cells. Our findings imply that increased Lamellipodin levels enhance Ena/VASP and Scar/WAVE activities at the plasma membrane to promote 3D invasion and metastasis. PMID:26996666

  18. WISP1 overexpression promotes proliferation and migration of human vascular smooth muscle cells via AKT signaling pathway.

    PubMed

    Lu, Shun; Liu, Hao; Lu, Lihe; Wan, Heng; Lin, Zhiqi; Qian, Kai; Yao, Xingxing; Chen, Qing; Liu, Wenjun; Yan, Jianyun; Liu, Zhengjun

    2016-10-01

    Proliferation and migration of vascular smooth muscle cells (VSMCs) play crucial roles in the development of vascular restenosis. Our previous study showed that CCN4, namely Wnt1 inducible signaling pathway protein 1 (WISP1), significantly promotes proliferation and migration of rat VSMCs, but its mechanism remains unclear. This study aims to investigate whether and how WISP1 stimulates proliferation and migration of human VSMCs. Western blot analysis showed that FBS treatment increased WISP1 protein levels in human VSMCs in a dose-dependent manner. Overexpression of WISP1 using adenovirus encoding WISP1 (AD-WISP1) significantly increased proliferation rate of human VSMCs by 2.98-fold compared with empty virus (EV)-transfected cells, shown by EdU incorporation assay. Additionally, Scratch-induced wound healing assay revealed that adenovirus-mediated overexpression of WISP1 significantly increased cell migration compared with EV-transfected cells from 6h (4.56±1.14% vs. 11.23±2.25%, P<0.05) to 48h (25.25±5.51% vs. 97.54±13.12%, P<0.01) after injury. Transwell Migration Assay confirmed that WISP1 overexpression significantly promoted human VSMC migration by 2.25-fold compared with EV. Furthermore, WISP1 overexpression stimulated Akt signaling activation in human VSMCs. Blockage of Akt signaling by Akt inhibitor AZD5363 or PI3K inhibitor LY294002, led to an inhibitory effect of WISP1-induced proliferation and migration in human VSMCs. Moreover, we found that WISP1 overexpression stimulated GSK3α/β phosphorylation, and increased expression of cyclin D1 and MMP9 in human VSMCs, and this effect was abolished by AZD5363. Collectively, we demonstrated that Akt signaling pathway mediates WISP1-induced migration and proliferation of human VSMCs, suggesting that WISP1 may act as a novel potential therapeutic target for vascular restenosis.

  19. Leptin promotes breast cancer cell migration and invasion via IL-18 expression and secretion.

    PubMed

    Li, Kuangfa; Wei, Lan; Huang, Yunxiu; Wu, Yang; Su, Min; Pang, Xueli; Wang, Nian; Ji, Feihu; Zhong, Changli; Chen, Tingmei

    2016-06-01

    In recent years, crosstalk between tumor microenvironment and cancer cells have received increasing attention. Accumulating research data suggests that leptin, a key adipokine secreted from adipocytes, plays important roles in breast cancer development. In our study, the effects of leptin on polarization of tumor-associated macrophages (TAMs) and promotion of the invasiveness of tumor cells were investigated. THP1 cells were used to differentiate M2 polarization macrophages. After stimulated by leptin, we established a co-culture system of tumor cells and macrophages to evaluate the function of leptin-induced macrophages in the migration and invasion of breast cancer cells. The gene and protein expressions were analyzed and the underlying mechanisms were evaluated. Moreover, pathological human specimens, and xenografts in nude mice, were detected to strengthen the in vitro results. Leptin elevated the expression of an array of cytokines in TAMs, IL-18 was the most increased, with an activation of the NF-κB/NF-κB1 signalling pathway. Additionally, after treated with leptin, TAMs significantly promoted the migration and invasion of breast cancer cells. However, these effects of leptin were abolished by the co-incubation of Bay11‑7082, a pharmacological NF-κB inhibitor. Leptin also directly stimulated IL-18 expression in breast cancer cells, which, differently, was via the PI3K/AKT-ATF-2 signaling pathway. In vivo studies showed that malignant breast carcinoma exhibited strong higher expression of Leptin, IL-8, and TAMs markers. Xenograft tumor-bearing mouse models showed that leptin significantly increased tumor volume, enhanced lung metastases, and increased expression of IL-8 and TAM markers, which were abolished by depletion of macrophages by clophosome-clodronate liposomes (CCL). Leptin could induce IL-18 expression both in TAMs and breast cancer cells. Leptin-induced IL-18 expression was regulated via NF-κB/NF-κB1 signaling in TAMs, while via PI3K

  20. 1-integrin and MT1-MMP promote tumor cell migration in 2D but not in 3D fibronectin microenvironments

    NASA Astrophysics Data System (ADS)

    Corall, Silke; Haraszti, Tamas; Bartoschik, Tanja; Spatz, Joachim Pius; Ludwig, Thomas; Cavalcanti-Adam, Elisabetta Ada

    2014-03-01

    Cell migration is a crucial event for physiological processes, such as embryonic development and wound healing, as well as for pathological processes, such as cancer dissemination and metastasis formation. Cancer cell migration is a result of the concerted action of matrix metalloproteinases (MMPs), expressed by cancer cells to degrade the surrounding matrix, and integrins, the transmembrane receptors responsible for cell binding to matrix proteins. While it is known that cell-microenvironment interactions are essential for migration, the role of the physical state of such interactions remains still unclear. In this study we investigated human fibrosarcoma cell migration in two-dimensional (2D) and three-dimensional (3D) fibronectin (FN) microenvironments. By using antibody blocking approach and cell-binding site mutation, we determined that -integrin is the main mediator of fibrosarcoma cell migration in 2D FN, whereas in 3D fibrillar FN, the binding of - and -integrins is not necessary for cell movement in the fibrillar network. Furthermore, while the general inhibition of MMPs with GM6001 has no effect on cell migration in both 2D and 3D FN matrices, we observed opposing effect after targeted silencing of a membrane-bound MMP, namely MT1-MMP. In 2D fibronectin, silencing of MT1-MMP results in decreased migration speed and loss of directionality, whereas in 3D FN matrices, cell migration speed is increased and integrin-mediated signaling for actin dynamics is promoted. Our results suggest that the fibrillar nature of the matrix governs the migratory behavior of fibrosarcoma cells. Therefore, to hinder migration and dissemination of diseased cells, matrix molecules should be directly targeted, rather than specific subtypes of receptors at the cell membrane.

  1. Crosstalk between colon cancer cells and macrophages via inflammatory mediators and CD47 promotes tumour cell migration.

    PubMed

    Zhang, Yuan; Sime, Wondossen; Juhas, Maria; Sjölander, Anita

    2013-10-01

    Tumour-associated macrophages (TAMs) of the M2 phenotype are present in the stroma of many tumours and are frequently associated with the progression of several types of cancer. We investigated the role of M2 macrophages in colon cancer progression and found that human colon cancer tissue had elevated numbers of CD68(+) (macrophage marker) cells and CD206(+) (M2 macrophage marker) cells and increased CD47 expression. To explore potential interplay between colon cancer cells and M2 macrophages, we differentiated the monocyte cell line THP-1 into M1 and M2 macrophages (CD206(high) and Th2 cytokine-secreting cells), respectively. M2 macrophages migrated faster than M1 macrophages towards SW480-conditioned medium. Similarly, M2 macrophage-conditioned medium induced SW480 cell migration and CD47 expression. Factors released by macrophages were involved in this induction. In addition, SW480 cells migrated faster when co-cultured with M2 macrophages. Inhibition of CD47 with blocking antibodies or siRNA significantly reduced the migration of SW480 cells in the presence of M2 macrophages. This effect was further decreased via blocking antibodies against the CD47 ligand signal-regulatory protein α (SIRPα). Additionally, cancer cells also secreted significant levels of IL-10, thereby promoting M2 macrophage differentiation. These findings indicate that a TAM-enriched tumour microenvironment promotes colon cancer cell migration and metastasis.

  2. A secretion of the mollusc Cryptomphalus aspersa promotes proliferation, migration and survival of keratinocytes and dermal fibroblasts in vitro.

    PubMed

    Cruz, M C Iglesias-de la; Sanz-Rodríguez, F; Zamarrón, A; Reyes, E; Carrasco, E; González, S; Juarranz, A

    2012-04-01

    Regenerative properties of skin decrease with age, and thus, the search for substances that minimize cutaneous ageing has increased in the last few years. The secretion of the mollusc Cryptomphalus Aspersa (SCA) is a natural product that bears regenerative properties when applied topically. The purpose of this work is to study the in vitro effects of SCA on cell proliferation and migration, as well as on cell-cell (E-cadherin and β-catenin) and cell-substrate (vinculin and β1-integrin) adhesion proteins expression, using a human keratinocyte cell line (HaCaT cells) and primary dermal fibroblasts (HF). We tested the effects of SCA on cell proliferation using a colorimetric assay. In addition, SCA-induced changes on cell migration were studied by wound-healing assays. Besides, Western blot and immunofluorescence microscopy were carried out to test the expression of different cell adhesion proteins. We found that SCA promotes proliferation and migration of HaCaT cells in a time- and dose-dependent manner. Moreover, treatment with SCA increases the migratory behaviour and the expression of adhesion molecules in both HaCaT and HF. Finally, SCA also improves cell survival and promotes phosphorylation of FAK and nuclear localization of β-catenin. These results shed light on the molecular mechanisms underlying the regenerative properties of SCA, based on its promoting effect on skin cell migration, proliferation and survival. Moreover, these results support future clinical uses of SCA in the regeneration of wounded tissues.

  3. XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer

    SciTech Connect

    Wang, Ting; Han, Shuai; Wu, Zhipeng; Han, Zhitao; Yan, Wangjun; Liu, Tielong; Wei, Haifeng; Song, Dianwen; Zhou, Wang Yang, Xinghai Xiao, Jianru

    2015-08-21

    Bone metastasis occurs in approximately 30–40% patients with advanced non-small cell lung cancer (NSCLC), but the mechanism underlying this bone metastasis remains poorly understood. The chemokine super family is believed to play an important role in tumor metastasis in lung cancer. The chemokine receptor XCR1 has been identified to promote cell proliferation and migration in oral cancer and ovarian carcinoma, but the role of XCR1 in lung cancer has not been reported. In this study, we demonstrated for the first time that XCR1 was overexpressed in lung cancer bone metastasis as compared with that in patients with primary lung cancer. In addition, the XCR1 ligand XCL1 promoted the proliferation and migration of lung cancer cells markedly, and knockdown of XCR1 by siRNA abolished the effect of XCL1 in cell proliferation and migration. Furthermore, we identified JAK2/STAT3 as a novel downstream pathway of XCR1, while XCL1/XCR1 increased the mRNA level of the downstream of JAK2/STAT3 including PIM1, JunB, TTP, MMP2 and MMP9. These results indicate that XCR1 is a new potential therapeutic target for the treatment of lung cancer bone metastasis. - Highlights: • XCR1 is overexpressed in bone metastasis compared with primary NSCLC. • XCR1 activation by XCL1 promotes lung cancer cell proliferation and migration. • JAK2/STAT3 is a novel potential downstream pathway of XCR1.

  4. Cell-permeable p38 MAP kinase promotes migration of adult neural stem/progenitor cells

    PubMed Central

    Hamanoue, Makoto; Morioka, Kazuhito; Ohsawa, Ikuroh; Ohsawa, Keiko; Kobayashi, Masaaki; Tsuburaya, Kayo; Akasaka, Yoshikiyo; Mikami, Tetsuo; Ogata, Toru; Takamatsu, Ken

    2016-01-01

    Endogenous neural stem/progenitor cells (NPCs) can migrate toward sites of injury, but the migration activity of NPCs is insufficient to regenerate damaged brain tissue. In this study, we showed that p38 MAP kinase (p38) is expressed in doublecortin-positive adult NPCs. Experiments using the p38 inhibitor SB203580 revealed that endogenous p38 participates in NPC migration. To enhance NPC migration, we generated a cell-permeable wild-type p38 protein (PTD-p38WT) in which the HIV protein transduction domain (PTD) was fused to the N-terminus of p38. Treatment with PTD-p38WT significantly promoted the random migration of adult NPCs without affecting cell survival or differentiation; this effect depended on the cell permeability and kinase activity of the fusion protein. These findings indicate that PTD-p38WT is a novel and useful tool for unraveling the roles of p38, and that this protein provides a reasonable approach for regenerating the injured brain by enhancing NPC migration. PMID:27067799

  5. Promotion of PDGF-induced endothelial cell migration by phosphorylated VASP depends on PKA anchoring via AKAP.

    PubMed

    Zhang, Deling; Ouyang, Jingping; Wang, Nian; Zhang, Yahui; Bie, Jinghua; Zhang, Yemin

    2010-02-01

    Vasodilator-stimulated phosphoprotein (VASP), an important substrate of PKA, plays a critical role in remodeling of actin cytoskeleton and actin-based cell motility. However, how PKA accurately transfers extracellular signals to VASP and then how phosphorylation of VASP regulates endothelial cell migration have not been clearly defined. Protein kinase A anchoring proteins (AKAPs) are considered to regulate intracellular-specific signal targeting of PKA via AKAP-mediated PKA anchoring. Thus, our study investigated the relationship among AKAP anchoring of PKA, PKA activity, and VASP phosphorylation, which is to clarify the exact role of VASP and its upstream regulatory mechanism in PKA-dependent migration. Our results show that chemotactic factor PDGF activated PKA, increased phosphorylation of VASP at Ser157, and enhanced ECV304 endothelial cell migration. However, phosphorylation site-directed mutation of VASP at Ser157 attenuated the chemotactic effect of PDGF on endothelial cells, suggesting phosphorylation of VASP at Ser157 promotes PKA-mediated endothelial cell migration. Furthermore, disrupting PKA anchoring to AKAP or PKA activity significantly attenuated the PKA activity, VASP phosphorylation, and subsequent cell migration. Meanwhile, disrupting PKA anchoring to AKAP abolished PDGF-induced lamellipodia formation and special VASP accumulation at leading edge of lamellipodia. These results indicate that PKA activation and PKA-mediated substrate responses in VASP phosphorylation and localization depend on PKA anchoring via AKAP in PDGF-induced endothelial cell migration. In conclusion, AKAP anchoring of PKA is an essential upstream event in regulation of PKA-mediated VASP phosphorylation and subsequent endothelial cell migration, which contributes to explore new methods for controlling endothelial cell migration related diseases and angiogenesis.

  6. Local migration promotes competitive restraint in a host-pathogen 'tragedy of the commons'.

    PubMed

    Kerr, Benjamin; Neuhauser, Claudia; Bohannan, Brendan J M; Dean, Antony M

    2006-07-01

    Fragmented populations possess an intriguing duplicity: even if subpopulations are reliably extinction-prone, asynchrony in local extinctions and recolonizations makes global persistence possible. Migration is a double-edged sword in such cases: too little migration prevents recolonization of extinct patches, whereas too much synchronizes subpopulations, raising the likelihood of global extinction. Both edges of this proverbial sword have been explored by manipulating the rate of migration within experimental populations. However, few experiments have examined how the evolutionary ecology of fragmented populations depends on the pattern of migration. Here, we show that the migration pattern affects both coexistence and evolution within a community of bacterial hosts (Escherichia coli) and viral pathogens (T4 coliphage) distributed across a large network of subpopulations. In particular, different patterns of migration select for distinct pathogen strategies, which we term 'rapacious' and 'prudent'. These strategies define a 'tragedy of the commons': rapacious phage displace prudent variants for shared host resources, but prudent phage are more productive when alone. We find that prudent phage dominate when migration is spatially restricted, while rapacious phage evolve under unrestricted migration. Thus, migration pattern alone can determine whether a de novo tragedy of the commons is resolved in favour of restraint.

  7. Soluble tissue factor has unique angiogenic activities that selectively promote migration and differentiation but not proliferation of endothelial cells

    SciTech Connect

    He Yingbo; Chang Guodong; Zhan Shunli; Song Xiaomin; Wang Xiaofeng; Luo Yongzhang

    2008-06-06

    The level of circulating tissue factor (TF) is up-regulated in human angiogenesis-related malignancies. However, whether circulating TF has angiogenic activities has not been determined. Soluble TF (sTF) is the main domain of circulating TF. Here, using cell migration, wound healing, and tubule formation assays, human recombinant sTF was found to significantly promote the migration and differentiation of endothelial cells. The stress fiber formation and rearrangement induced by sTF observed through immunofluorescence microscope may be responsible for the stimulatory migration effect of sTF. Nevertheless, sTF had no effects on endothelial cell proliferation. Interestingly, sTF can be internalized by endothelial cells, which implies a novel mechanism for sTF in angiogenesis. These results suggest that sTF has unique angiogenic activities and may serve as a potential therapeutic target to treat diseases associated with angiogenesis such as cancer and rheumatoid arthritis.

  8. Microcystin-LR promotes migration and invasion of colorectal cancer through matrix metalloproteinase-13 up-regulation.

    PubMed

    Miao, Chen; Ren, Yan; Chen, Meng; Wang, Zhen; Wang, Ting

    2016-05-01

    Microcystin-LR (MC-LR) is an environmental toxin from blooms of cyanobacteria and it has been shown to be one of the environmental carcinogens for the progression of colorectal carcinoma. However, there is no direct evidence that MC-LR can induce colorectal cancer migration and invasion. In the present study, 0.04 or 40 µg/kg/d (human tolerable daily intake value of MC-LR) MC-LR treatment was observed to induce Matrix Metalloproteinase-13 (MMP-13) expression in tumor tissues and local invasion in DLD-1 xenograft model. The results are consistent with those of cell test showing that MC-LR treatment enhanced migration and invasion of DLD-1, HT-29, and SW480 cells and are also correlated with the increased mRNA and protein levels of MMP-13 by Quantitative real-time PCR, Luciferase assay, and Western blot assay respectively in DLD-1 cells and HT-29 cells after MC-LR exposure. In addition, MMP-13 siRNA inhibited MC-LR induced migration and invasion enhancement and MMP-13 over-expression in DLD-1 cells and HT-29 cells. This is the first paper confirming MC-LR-induced MMP-13 expression can promote colorectal cancer invasion and migration. Further investigation revealed that phosphorylation of AKT increased in MC-LR-treated cells, and the phosphatidylinositol 3-kinase/Akt. (PI3-K/AKT) inhibitor LY294002 effectively abolished MC-LR-enhanced migration and invasion and MMP-13 expression. Therefore, based on these observations, we concluded that the activation of PI3K/AKT by MC-LR results in MMP-13 expression, leading to the migration and invasion of DLD-1 cells and HT-29 cells. The study provides a mechanistic insight into the promoting colorectal cancer functions of MC-LR.

  9. TGF-α/HA complex promotes tympanic membrane keratinocyte migration and proliferation via ErbB1 receptor

    SciTech Connect

    Mei Teh, Bing; Redmond, Sharon L.; Shen, Yi; Atlas, Marcus D.; Marano, Robert J.; Dilley, Rodney J.

    2013-04-01

    Tympanic membrane perforations are common and represent a management challenge to clinicians. Current treatments for chronic perforations involve a graft surgery and require general anaesthesia, including associated costs and morbidities. Bioactive molecules (e.g. growth factors, cytokines) play an important role in promoting TM wound healing following perforation and the use of growth factors as a topical treatment for tympanic membrane perforations has been suggested as an alternative to surgery. However, the choice of bioactive molecules best suited to promote wound healing has yet to be identified. We investigated the effects of hyaluronic acid, vitronectin, TGF-α, IL-24 and their combinations on migration, proliferation and adhesion of cultured human tympanic membrane-derived keratinocytes (hTM), in addition to their possible mechanisms of action. We found that TGF-α, TGF-α/HA and TGF-α/IL-24 promoted wound healing by significantly increasing both migration and proliferation. TGF-α and/or HA treated cells showed comparable cell–cell adhesion whilst maintaining an epithelial cell phenotype. With the use of receptor binding inhibitors for ErbB1 (AG1478) and CD44 (BRIC235), we revealed that the activation of ErbB1 is required for TGF-α/HA-mediated migration and proliferation. These results suggest factors that may be incorporated into a tissue-engineered membrane or directly as topical treatment for tympanic membrane perforations and hence reduce the need for a surgery. - Highlights: ► TGF-α, TGF-α/HA and TGF-α/IL-24 improved hTM keratinocyte migration and proliferation. ► TGF-α and/or HA maintained epithelial cell phenotype. ► TGF-α/HA-mediated migration and proliferation requires activation of ErbB1 receptor.

  10. Tamarind Seed Xyloglucans Promote Proliferation and Migration of Human Skin Cells through Internalization via Stimulation of Proproliferative Signal Transduction Pathways.

    PubMed

    Nie, W; Deters, A M

    2013-01-01

    Xyloglucans (XGs) of Tamarindus indica L. Fabaceae are used as drug vehicles or as ingredients of cosmetics. Two xyloglucans were extracted from T. indica seed with cold water (TSw) and copper complex precipitation (TSc). Both were analyzed in regard to composition and influence on cell viability, proliferation, cell cycle progression, migration, MAPK phosphorylation, and gene expression of human skin keratinocytes (NHEK and HaCaT) and fibroblasts (NHDF) in vitro. TSw and TSc differed in molecular weight, rhamnose content, and ratios of xylose, arabinose, galactose, and glucose. Both XGs improved keratinocytes and fibroblast proliferation, promoted the cell cycle, and stimulated migration and intracellular enzyme activity of NHDF after endosomal uptake. Only TSw significantly enhanced HaCaT migration and extracellular enzyme activity of NHDF and HaCaT. TSw and TSc predominantly enhanced the phosphorylation of molecules that referred to Erk signaling in NHEK. In NHDF parts of the integrin signaling and SAPK/JNK pathway were affected. Independent of cell type TSw marginally regulated the expression of genes, which referred to membrane proteins, cytoskeleton, cytokine signaling, and ECM as well as to processes of metabolism and transcription. Results show that T. indica xyloglucans promote skin regeneration by a direct influence on cell proliferation and migration.

  11. IL-17A promotes migration and tumor killing capability of B cells in esophageal squamous cell carcinoma

    PubMed Central

    Lu, Lin; Weng, Chengyin; Mao, Haibo; Fang, Xisheng; Liu, Xia; Wu, Yong; Cao, Xiaofei; Li, Baoxiu; Chen, Xiaojun; Gan, Qinquan; Xia, Jianchuan; Liu, Guolong

    2016-01-01

    We have previously reported that the accumulation of IL-17-producing cells could mediate tumor protective immunity by promoting the migration of NK cells, T cells and dendritic cells in esophageal squamous cell carcinoma (ESCC) patients. However, there were no reports concerning the effect of IL-17A on tumor infiltrating B cells. In this study, we investigated the accumulation of CD20+ B cells in the ESCC tumor nests and further addressed the effect of IL-17A on the migration and cytotoxicity of B cells. There was positive correlation between the levels of CD20+ B cells and IL-17+ cells. IL-17A could promote the ESCC tumor cells to produce more chemokines CCL2, CCL20 and CXCL13, which were associated with the migration of B cells. In addition, IL-17A enhanced the IgG-mediated antibody and complement mediated cytotoxicity of B cells against tumor cells. IL-17A-stimulated B cells gained more effective direct killing capability through enhanced expression of Granzyme B and FasL. The effect of IL-17A on the migration and cytotoxicity of B cells was IL-17A pathway dependent, which could be inhibited by IL-17A inhibitor. This study provides further understanding of the roles of IL-17A in humoral response, which may contribute to the development of novel tumor immunotherapy strategy. PMID:26942702

  12. IL-17A promotes migration and tumor killing capability of B cells in esophageal squamous cell carcinoma.

    PubMed

    Lu, Lin; Weng, Chengyin; Mao, Haibo; Fang, Xisheng; Liu, Xia; Wu, Yong; Cao, Xiaofei; Li, Baoxiu; Chen, Xiaojun; Gan, Qinquan; Xia, Jianchuan; Liu, Guolong

    2016-04-19

    We have previously reported that the accumulation of IL-17-producing cells could mediate tumor protective immunity by promoting the migration of NK cells, T cells and dendritic cells in esophageal squamous cell carcinoma (ESCC) patients. However, there were no reports concerning the effect of IL-17A on tumor infiltrating B cells. In this study, we investigated the accumulation of CD20+ B cells in the ESCC tumor nests and further addressed the effect of IL-17A on the migration and cytotoxicity of B cells. There was positive correlation between the levels of CD20+ B cells and IL-17+ cells. IL-17A could promote the ESCC tumor cells to produce more chemokines CCL2, CCL20 and CXCL13, which were associated with the migration of B cells. In addition, IL-17A enhanced the IgG-mediated antibody and complement mediated cytotoxicity of B cells against tumor cells. IL-17A-stimulated B cells gained more effective direct killing capability through enhanced expression of Granzyme B and FasL. The effect of IL-17A on the migration and cytotoxicity of B cells was IL-17A pathway dependent, which could be inhibited by IL-17A inhibitor. This study provides further understanding of the roles of IL-17A in humoral response, which may contribute to the development of novel tumor immunotherapy strategy.

  13. Erk regulation of actin capping and bundling by Eps8 promotes cortex tension and leader bleb-based migration.

    PubMed

    Logue, Jeremy S; Cartagena-Rivera, Alexander X; Baird, Michelle A; Davidson, Michael W; Chadwick, Richard S; Waterman, Clare M

    2015-07-11

    Within the confines of tissues, cancer cells can use blebs to migrate. Eps8 is an actin bundling and capping protein whose capping activity is inhibited by Erk, a key MAP kinase that is activated by oncogenic signaling. We tested the hypothesis that Eps8 acts as an Erk effector to modulate actin cortex mechanics and thereby mediate bleb-based migration of cancer cells. Cells confined in a non-adhesive environment migrate in the direction of a very large 'leader bleb.' Eps8 bundling activity promotes cortex tension and intracellular pressure to drive leader bleb formation. Eps8 capping and bundling activities act antagonistically to organize actin within leader blebs, and Erk mediates this effect. An Erk biosensor reveals concentrated kinase activity within leader blebs. Bleb contents are trapped by the narrow neck that separates the leader bleb from the cell body. Thus, Erk activity promotes actin bundling by Eps8 to enhance cortex tension and drive the bleb-based migration of cancer cells under non-adhesive confinement.

  14. Erk regulation of actin capping and bundling by Eps8 promotes cortex tension and leader bleb-based migration

    PubMed Central

    Logue, Jeremy S; Cartagena-Rivera, Alexander X; Baird, Michelle A; Davidson, Michael W; Chadwick, Richard S; Waterman, Clare M

    2015-01-01

    Within the confines of tissues, cancer cells can use blebs to migrate. Eps8 is an actin bundling and capping protein whose capping activity is inhibited by Erk, a key MAP kinase that is activated by oncogenic signaling. We tested the hypothesis that Eps8 acts as an Erk effector to modulate actin cortex mechanics and thereby mediate bleb-based migration of cancer cells. Cells confined in a non-adhesive environment migrate in the direction of a very large ‘leader bleb.’ Eps8 bundling activity promotes cortex tension and intracellular pressure to drive leader bleb formation. Eps8 capping and bundling activities act antagonistically to organize actin within leader blebs, and Erk mediates this effect. An Erk biosensor reveals concentrated kinase activity within leader blebs. Bleb contents are trapped by the narrow neck that separates the leader bleb from the cell body. Thus, Erk activity promotes actin bundling by Eps8 to enhance cortex tension and drive the bleb-based migration of cancer cells under non-adhesive confinement. DOI: http://dx.doi.org/10.7554/eLife.08314.001 PMID:26163656

  15. Tamarind Seed Xyloglucans Promote Proliferation and Migration of Human Skin Cells through Internalization via Stimulation of Proproliferative Signal Transduction Pathways.

    PubMed

    Nie, W; Deters, A M

    2013-01-01

    Xyloglucans (XGs) of Tamarindus indica L. Fabaceae are used as drug vehicles or as ingredients of cosmetics. Two xyloglucans were extracted from T. indica seed with cold water (TSw) and copper complex precipitation (TSc). Both were analyzed in regard to composition and influence on cell viability, proliferation, cell cycle progression, migration, MAPK phosphorylation, and gene expression of human skin keratinocytes (NHEK and HaCaT) and fibroblasts (NHDF) in vitro. TSw and TSc differed in molecular weight, rhamnose content, and ratios of xylose, arabinose, galactose, and glucose. Both XGs improved keratinocytes and fibroblast proliferation, promoted the cell cycle, and stimulated migration and intracellular enzyme activity of NHDF after endosomal uptake. Only TSw significantly enhanced HaCaT migration and extracellular enzyme activity of NHDF and HaCaT. TSw and TSc predominantly enhanced the phosphorylation of molecules that referred to Erk signaling in NHEK. In NHDF parts of the integrin signaling and SAPK/JNK pathway were affected. Independent of cell type TSw marginally regulated the expression of genes, which referred to membrane proteins, cytoskeleton, cytokine signaling, and ECM as well as to processes of metabolism and transcription. Results show that T. indica xyloglucans promote skin regeneration by a direct influence on cell proliferation and migration. PMID:24106497

  16. Tamarind Seed Xyloglucans Promote Proliferation and Migration of Human Skin Cells through Internalization via Stimulation of Proproliferative Signal Transduction Pathways

    PubMed Central

    Nie, W.; Deters, A. M.

    2013-01-01

    Xyloglucans (XGs) of Tamarindus indica L. Fabaceae are used as drug vehicles or as ingredients of cosmetics. Two xyloglucans were extracted from T. indica seed with cold water (TSw) and copper complex precipitation (TSc). Both were analyzed in regard to composition and influence on cell viability, proliferation, cell cycle progression, migration, MAPK phosphorylation, and gene expression of human skin keratinocytes (NHEK and HaCaT) and fibroblasts (NHDF) in vitro. TSw and TSc differed in molecular weight, rhamnose content, and ratios of xylose, arabinose, galactose, and glucose. Both XGs improved keratinocytes and fibroblast proliferation, promoted the cell cycle, and stimulated migration and intracellular enzyme activity of NHDF after endosomal uptake. Only TSw significantly enhanced HaCaT migration and extracellular enzyme activity of NHDF and HaCaT. TSw and TSc predominantly enhanced the phosphorylation of molecules that referred to Erk signaling in NHEK. In NHDF parts of the integrin signaling and SAPK/JNK pathway were affected. Independent of cell type TSw marginally regulated the expression of genes, which referred to membrane proteins, cytoskeleton, cytokine signaling, and ECM as well as to processes of metabolism and transcription. Results show that T. indica xyloglucans promote skin regeneration by a direct influence on cell proliferation and migration. PMID:24106497

  17. RhoA activation promotes transendothelial migration of monocytes via ROCK.

    PubMed

    Honing, Henk; van den Berg, Timo K; van der Pol, Susanne M A; Dijkstra, Christine D; van der Kammen, Rob A; Collard, John G; de Vries, Helga E

    2004-03-01

    Monocyte infiltration into inflamed tissue requires the initial arrest of the cells on the endothelium followed by firm adhesion and their subsequent migration. Migration of monocytes and other leukocytes is believed to involve a coordinated remodeling of the actin cytoskeleton. The small GTPases RhoA, Rac1, and Cdc42 are critical regulators of actin reorganization. In this study, we have investigated the role of Rho-like GTPases RhoA, Rac1, and Cdc42 in the adhesion and migration of monocytes across brain endothelial cells by expressing their constitutively active or dominant-negative constructs in NR8383 rat monocytic cells. Monocytes expressing the active form of Cdc42 show a reduced migration, whereas Rac1 expression did not affect adhesion or migration. In contrast, expression of the active form of RhoA in monocytes leads to a dramatic increase in their adhesion and migration across endothelial cells. The effect of RhoA was found to be mediated by its down-stream effector Rho kinase (ROCK), as pretreatment with the selective ROCK inhibitor Y-27632 prevented this enhanced adhesion and migration. These results demonstrate that RhoA activation in monocytes is sufficient to enhance adhesion and migration across monolayers of endothelial cells. PMID:14634067

  18. RhoA activation promotes transendothelial migration of monocytes via ROCK.

    PubMed

    Honing, Henk; van den Berg, Timo K; van der Pol, Susanne M A; Dijkstra, Christine D; van der Kammen, Rob A; Collard, John G; de Vries, Helga E

    2004-03-01

    Monocyte infiltration into inflamed tissue requires the initial arrest of the cells on the endothelium followed by firm adhesion and their subsequent migration. Migration of monocytes and other leukocytes is believed to involve a coordinated remodeling of the actin cytoskeleton. The small GTPases RhoA, Rac1, and Cdc42 are critical regulators of actin reorganization. In this study, we have investigated the role of Rho-like GTPases RhoA, Rac1, and Cdc42 in the adhesion and migration of monocytes across brain endothelial cells by expressing their constitutively active or dominant-negative constructs in NR8383 rat monocytic cells. Monocytes expressing the active form of Cdc42 show a reduced migration, whereas Rac1 expression did not affect adhesion or migration. In contrast, expression of the active form of RhoA in monocytes leads to a dramatic increase in their adhesion and migration across endothelial cells. The effect of RhoA was found to be mediated by its down-stream effector Rho kinase (ROCK), as pretreatment with the selective ROCK inhibitor Y-27632 prevented this enhanced adhesion and migration. These results demonstrate that RhoA activation in monocytes is sufficient to enhance adhesion and migration across monolayers of endothelial cells.

  19. Cdon promotes neural crest migration by regulating N-cadherin localization.

    PubMed

    Powell, Davalyn R; Williams, Jason S; Hernandez-Lagunas, Laura; Salcedo, Ernesto; O'Brien, Jenean H; Artinger, Kristin Bruk

    2015-11-15

    Neural crest cells (NCCs) are essential embryonic progenitor cells that are unique to vertebrates and form a remarkably complex and coordinated system of highly motile cells. Migration of NCCs occurs along specific pathways within the embryo in response to both environmental cues and cell-cell interactions within the neural crest population. Here, we demonstrate a novel role for the putative Sonic hedgehog (Shh) receptor and cell adhesion regulator, cdon, in zebrafish neural crest migration. cdon is expressed in developing premigratory NCCs but is downregulated once the cells become migratory. Knockdown of cdon results in aberrant migration of trunk NCCs: crestin positive cells can emigrate out of the neural tube but stall shortly after the initiation of migration. Live cell imaging analysis demonstrates reduced directedness of migration, increased velocity and mispositioned cell protrusions. In addition, transplantation analysis suggests that cdon is required cell-autonomously for directed NCC migration in the trunk. Interestingly, N-cadherin is mislocalized following cdon knockdown suggesting that the role of cdon in NCCs is to regulate N-cadherin localization. Our results reveal a novel role for cdon in zebrafish neural crest migration, and suggest a mechanism by which Cdon is required to localize N-cadherin to the cell membrane in migratory NCCs for directed migration.

  20. Cdon promotes neural crest migration by regulating N-cadherin localization.

    PubMed

    Powell, Davalyn R; Williams, Jason S; Hernandez-Lagunas, Laura; Salcedo, Ernesto; O'Brien, Jenean H; Artinger, Kristin Bruk

    2015-11-15

    Neural crest cells (NCCs) are essential embryonic progenitor cells that are unique to vertebrates and form a remarkably complex and coordinated system of highly motile cells. Migration of NCCs occurs along specific pathways within the embryo in response to both environmental cues and cell-cell interactions within the neural crest population. Here, we demonstrate a novel role for the putative Sonic hedgehog (Shh) receptor and cell adhesion regulator, cdon, in zebrafish neural crest migration. cdon is expressed in developing premigratory NCCs but is downregulated once the cells become migratory. Knockdown of cdon results in aberrant migration of trunk NCCs: crestin positive cells can emigrate out of the neural tube but stall shortly after the initiation of migration. Live cell imaging analysis demonstrates reduced directedness of migration, increased velocity and mispositioned cell protrusions. In addition, transplantation analysis suggests that cdon is required cell-autonomously for directed NCC migration in the trunk. Interestingly, N-cadherin is mislocalized following cdon knockdown suggesting that the role of cdon in NCCs is to regulate N-cadherin localization. Our results reveal a novel role for cdon in zebrafish neural crest migration, and suggest a mechanism by which Cdon is required to localize N-cadherin to the cell membrane in migratory NCCs for directed migration. PMID:26256768

  1. Fibroblast-derived tenascin-C promotes Schwann cell migration through β1-integrin dependent pathway during peripheral nerve regeneration.

    PubMed

    Zhang, Zhanhu; Yu, Bin; Gu, Yun; Zhou, Songlin; Qian, Tianmei; Wang, Yongjun; Ding, Guohui; Ding, Fei; Gu, Xiaosong

    2016-03-01

    Peripheral nerve regeneration requires precise coordination and dynamic interaction among various types of cells in the tissue. It remains unclear, however, whether the cellular crosstalk between fibroblasts and Schwann cells (SCs) is related to phenotype modulation of SCs, a critical cellular process after peripheral nerve injury. In this study, microarray analysis revealed that a total of 6,046 genes were differentially expressed in the proximal nerve segment after sciatic nerve transection in rats, and bioinformatics analysis further identified tenascin-C (TNC), an extracellular matrix (ECM) protein, as a key gene regulator. TNC was abundantly produced by nerve fibroblasts accumulating at the lesion site, rather than by SCs as usually expected. TNC significantly promoted SC migration without effects on SC proliferation in primary culture. In co-culture of fibroblasts and SCs, inhibition of TNC expression either by siRNA transfection or antibody blockade could suppress SC migration, while TNC-stimulated SC migration was mediated by TNC binding to β1-integrin receptor in SCs through activation of Rac1 effectors. The in vivo evidence showed that exogenous TNC protein enhanced SC migration and axonal regrowth. Our results highlight that TNC-mediated cellular interaction between fibroblasts and SCs may regulate SC migration through β1-integrin-dependent pathway during peripheral nerve regeneration.

  2. PBX3 promotes migration and invasion of colorectal cancer cells via activation of MAPK/ERK signaling pathway

    PubMed Central

    Han, Hai-Bo; Gu, Jin; Ji, Deng-Bo; Li, Zhao-Wei; Zhang, Yuan; Zhao, Wei; Wang, Li-Min; Zhang, Zhi-Qian

    2014-01-01

    AIM: To investigate the role of pre-B-cell leukemia homeobox (PBX)3 in migration and invasion of colorectal cancer (CRC) cells. METHODS: We detected PBX3 expression in five cell lines and surgical specimens from 111 patients with CRC using real-time reverse transcription-polymerase chain reaction. We forced expression of PBX3 in low metastatic HT-29 and SW480 cells and knocked down expression of PBX3 in highly metastatic LOVO and HCT-8 cells. Wound healing and Boyden chamber assays were used to detect cell migration and invasion after altered expression of PBX3. Western blot was performed to detect the change of signaling molecule ERK1/2 following PBX3 overexpression. RESULTS: High level of PBX3 expression was correlated with the invasive potential of CRC cells, and significantly associated with lymph node invasion (P = 0.02), distant metastasis (P = 0.04), advanced TNM stage (P = 0.03) and poor overall survival of patients (P < 0.05). Ectopic expression of PBX3 in low metastatic cells was shown to promote migration and invasion, while inhibited PBX3 expression in highly metastatic cells suppressed migration and invasion. Furthermore, upregulation of phosphorylated extracellular signal-regulated kinase (ERK)1/2 was found to be one of the targeted molecules responsible for PBX3-induced CRC cell migration and invasion. CONCLUSION: PBX3 induces invasion and metastasis of CRC cells partially through activation of the MAPK/ERK signaling pathway. PMID:25561793

  3. NFAT5 promotes proliferation and migration of lung adenocarcinoma cells in part through regulating AQP5 expression.

    PubMed

    Guo, Kai; Jin, Faguang

    2015-09-25

    The osmoregulated transcription factor nuclear factor of activated T-cells 5(NFAT5), has been found to play important roles in the development of many kinds of human cancers, including breast cancer, colon carcinoma, renal cell carcinoma and melanoma. The aim of the present study was to determine whether NFAT5 is involved in the proliferation and migration of lung adenocarcinoma cells. We found that NFAT5 was upregulated in lung adenocarcinoma cells and knockdown of NFAT5 decreased proliferation and migration of the cells, accompanied by a significant reduction in the expression of AQP5. AQP5 was upregulated in lung adenocarcinoma cells and knockdown of AQP5 also inhibited proliferation and migration of the cells as knockdown of NFAT5 did. Moreover, overexpression of NFAT5 promoted proliferation and migration of lung adenocarcinoma cells, accompanied by a significant increase in the expression of AQP5. These results indicate that NFAT5 plays important roles in proliferation and migration of human lung adenocarcinoma cells through regulating AQP5 expression, providing a new therapeutic option for lung adenocarcinoma therapy.

  4. Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE.

    PubMed

    Carmona, G; Perera, U; Gillett, C; Naba, A; Law, A-L; Sharma, V P; Wang, J; Wyckoff, J; Balsamo, M; Mosis, F; De Piano, M; Monypenny, J; Woodman, N; McConnell, R E; Mouneimne, G; Van Hemelrijck, M; Cao, Y; Condeelis, J; Hynes, R O; Gertler, F B; Krause, M

    2016-09-29

    Cancer invasion is a hallmark of metastasis. The mesenchymal mode of cancer cell invasion is mediated by elongated membrane protrusions driven by the assembly of branched F-actin networks. How deregulation of actin regulators promotes cancer cell invasion is still enigmatic. We report that increased expression and membrane localization of the actin regulator Lamellipodin correlate with reduced metastasis-free survival and poor prognosis in breast cancer patients. In agreement, we find that Lamellipodin depletion reduced lung metastasis in an orthotopic mouse breast cancer model. Invasive 3D cancer cell migration as well as invadopodia formation and matrix degradation was impaired upon Lamellipodin depletion. Mechanistically, we show that Lamellipodin promotes invasive 3D cancer cell migration via both actin-elongating Ena/VASP proteins and the Scar/WAVE complex, which stimulates actin branching. In contrast, Lamellipodin interaction with Scar/WAVE but not with Ena/VASP is required for random 2D cell migration. We identified a phosphorylation-dependent mechanism that regulates selective recruitment of these effectors to Lamellipodin: Abl-mediated Lamellipodin phosphorylation promotes its association with both Scar/WAVE and Ena/VASP, whereas Src-dependent phosphorylation enhances binding to Scar/WAVE but not to Ena/VASP. Through these selective, regulated interactions Lamellipodin mediates directional sensing of epidermal growth factor (EGF) gradients and invasive 3D migration of breast cancer cells. Our findings imply that increased Lamellipodin levels enhance Ena/VASP and Scar/WAVE activities at the plasma membrane to promote 3D invasion and metastasis.

  5. Lamellipodin and the Scar/WAVE complex cooperate to promote cell migration in vivo

    PubMed Central

    Law, Ah-Lai; Vehlow, Anne; Kotini, Maria; Dodgson, Lauren; Soong, Daniel; Theveneau, Eric; Bodo, Cristian; Taylor, Eleanor; Navarro, Christel; Perera, Upamali; Michael, Magdalene; Dunn, Graham A.; Bennett, Daimark; Mayor, Roberto

    2013-01-01

    Cell migration is essential for development, but its deregulation causes metastasis. The Scar/WAVE complex is absolutely required for lamellipodia and is a key effector in cell migration, but its regulation in vivo is enigmatic. Lamellipodin (Lpd) controls lamellipodium formation through an unknown mechanism. Here, we report that Lpd directly binds active Rac, which regulates a direct interaction between Lpd and the Scar/WAVE complex via Abi. Consequently, Lpd controls lamellipodium size, cell migration speed, and persistence via Scar/WAVE in vitro. Moreover, Lpd knockout mice display defective pigmentation because fewer migrating neural crest-derived melanoblasts reach their target during development. Consistently, Lpd regulates mesenchymal neural crest cell migration cell autonomously in Xenopus laevis via the Scar/WAVE complex. Further, Lpd’s Drosophila melanogaster orthologue Pico binds Scar, and both regulate collective epithelial border cell migration. Pico also controls directed cell protrusions of border cell clusters in a Scar-dependent manner. Taken together, Lpd is an essential, evolutionary conserved regulator of the Scar/WAVE complex during cell migration in vivo. PMID:24247431

  6. Basic fibroblast growth factor promotes melanocyte migration via increased expression of p125(FAK) on melanocytes.

    PubMed

    Wu, Ching-Shuang; Lan, Cheng-Che E; Chiou, Min-Hsi; Yu, Hsin-Su

    2006-01-01

    Vitiligo is an acquired pigmentary disorder characterized by depigmentation of skin and hair. Melanocyte migration is an important event in re-pigmentation of vitiligo. We have demonstrated that narrow-band ultraviolet B (UVB) irradiation stimulated cultured keratinocytes to release a significant amount of basic fibroblast growth factor (bFGF). Furthermore, narrow-band UVB enhanced migration of melanocytes via increased expression of phosphorylated focal adhesion kinase (p125(FAK)) on melanocytes. The aim of this study was to investigate the effect of recombinant human bFGF (rhbFGF) on melanocyte migration. The relationship between the expression of p125(FAK) and melanocyte migration induced by rhbFGF was also studied. Our results demonstrated that rhbFGF significantly enhanced migration of melanocytes and p125(FAK) expression on melanocytes. Herbimycin A, a potent p125(FAK) inhibitor, effectively abolished rhbFGF-induced melanocyte migration. The combined results indicated that p125(FAK) plays an important role in the signal transduction pathway of melanocyte migration induced by bFGF.

  7. Interaction between p68 RNA helicase and Ca2+-calmodulin promotes cell migration and metastasis

    PubMed Central

    Wang, Haizhen; Gao, Xueliang; Yang, Jenny J.; Liu, Zhi-Ren

    2012-01-01

    Summary p68 RNA helicase is a prototypical RNA helicase. Here we present evidence to show that, by interacting with Ca-calmodulin (CaM), p68 plays a role in cancer metastasis and cell migration. A peptide fragment that spans the IQ motif of p68 strongly inhibits cancer metastasis in two different animal models. The peptide interrupts p68 and CaM interaction and inhibits cell migration. Our results demonstrate that the p68-CaM interaction is essential for the formation of lamellipodia and filopodia in migrating cells. p68 interacts with microtubules in the presence of CaM. Our experiments show that interaction with microtubules stimulates p68 ATPase activity. Further, microtubule gliding assays demonstrate that p68, in the presence of CaM, can function as a microtubule motor. This motor activity may allow p68 to transport CaM to the leading edge of migrating cells. PMID:23322042

  8. Activin B promotes BMSC-mediated cutaneous wound healing by regulating cell migration via the JNK-ERK signaling pathway.

    PubMed

    Zhang, Min; Sun, Li; Wang, Xueer; Chen, Shixuan; Kong, Yanan; Liu, Nuyun; Chen, Yinghua; Jia, Qin; Zhang, Lu; Zhang, Lin

    2014-01-01

    Bone marrow-derived mesenchymal stem cells (BMSCs) are able to differentiate into various types of skin cells and participate in skin regeneration and repair. Activin signaling can regulate wound healing and reepithelialization. The present study assessed the impact of activin B on BMSC-mediated cutaneous wound healing in rats and explored the possible mechanism involved. We found that CFSE-labeled BMSCs participated in wound healing in vivo, and compared to administration with PBS, activin B, or BMSCs, activin B plus BMSCs significantly promoted wound healing and hair follicle regeneration. Activin B induced actin stress fiber formation and cell migration in BMSCs in vitro. Activation of JNK and ERK, but not p38, was required for activin B-induced actin stress fiber formation and BMSC migration. These results show that activin B may promote BMSC-mediated wound healing by inducing actin stress fiber formation and BMSC migration via the ERK and JNK signal pathways. Combined administration of BMSCs and cytokines may be a promising therapeutic strategy for the management of skin wounds.

  9. A truncated splice variant of human lysyl oxidase-like 2 promotes migration and invasion in esophageal squamous cell carcinoma.

    PubMed

    Zou, Hai-Ying; Lv, Guo-Qing; Dai, Li-Hua; Zhan, Xiu-Hui; Jiao, Ji-Wei; Liao, Lian-Di; Zhou, Tai-Mei; Li, Chun-Quan; Wu, Bing-Li; Xu, Li-Yan; Li, En-Min

    2016-06-01

    Lysyl oxidase-like 2 (LOXL2) is a member of the lysyl oxidase family, which plays an important role in extracellular matrix protein biosynthesis and tumor progression. In the present study, we identified a novel splice variant, LOXL2Δ72, which encodes a peptide having the same N- and C-termini as wild-type LOXL2 (LOXL2WT), but lacks 72 nucleotides encoding 24 amino acids. LOXL2Δ72 had dramatically reduced enzymatic activity, and was no longer secreted. However, LOXL2Δ72 promoted greater cell migration and invasion than LOXL2WT. Furthermore, a dual luciferase reporter assay indicated that LOXL2Δ72 activates distinct signal transduction pathways compared to LOXL2WT, consistent with cDNA microarray data showing different expression levels of cell migration- and invasion-related genes induced following over-expression of each LOXL2 isoform. In particular, LOXL2Δ72 distinctly promoted esophageal squamous cell carcinoma (ESCC) cell migration via up-regulating the C-C motif chemokine ligand 28 (CCL28). Our results suggest that the new LOXL2 splice variant contributes to tumor progression by novel molecular mechanisms different from LOXL2WT.

  10. HDAC1 promoted migration and invasion binding with TCF12 by promoting EMT progress in gallbladder cancer

    PubMed Central

    Zhou, Yuhong; Hou, Yingyong; Zhang, Yong; Jiang, Ying; Liu, Houbao; Shao, Yebo

    2016-01-01

    The identification of prognostic markers for gallbladder cancer is needed for clinical practice. Histone deacetylases (HDACs) play an important role in tumor development and progression by modifying histone and non-histone proteins. However, the expression of HDAC1 in patients with gallbladder cancer is still unknown. Here, we reported that HDAC1 expression was elevated in cancerous tissue and correlated with lymph node metastasis and poorer overall survival in patients with GBC. Knockdown of HDAC1 using lentivirus delivery of HDAC1-specific shRNA abrogated the migration and invasion of GBC cells in vitro. TCF-12, as the HDAC1 binding protein, has also correlates with poor prognosis in GBC patients. And there is a positive correlation between HDAC1 and TCF-12 which leading the high invasion and migration ability of GBC cells. Taken together, our data suggested that HDAC1 and TCF-12 are a potential prognostic maker and may be a molecular target for inhibiting invasion and metastasis in GBC. PMID:27092878

  11. Flight orientation behaviors promote optimal migration trajectories in high-flying insects.

    PubMed

    Chapman, Jason W; Nesbit, Rebecca L; Burgin, Laura E; Reynolds, Don R; Smith, Alan D; Middleton, Douglas R; Hill, Jane K

    2010-02-01

    Many insects undertake long-range seasonal migrations to exploit temporary breeding sites hundreds or thousands of kilometers apart, but the behavioral adaptations that facilitate these movements remain largely unknown. Using entomological radar, we showed that the ability to select seasonally favorable, high-altitude winds is widespread in large day- and night-flying migrants and that insects adopt optimal flight headings that partially correct for crosswind drift, thus maximizing distances traveled. Trajectory analyses show that these behaviors increase migration distances by 40% and decrease the degree of drift from seasonally optimal directions. These flight behaviors match the sophistication of those seen in migrant birds and help explain how high-flying insects migrate successfully between seasonal habitats.

  12. Transgelin is a marker of repopulating mesangial cells after injury and promotes their proliferation and migration.

    PubMed

    Daniel, Christoph; Lüdke, Andrea; Wagner, Andrea; Todorov, Vladimir T; Hohenstein, Bernd; Hugo, Christian

    2012-06-01

    Mesangial cell (MC) migration is essential during glomerular repair and kidney development. The aim of the study was to identify marker/player for glomerular progenitor/reserve cells migrating into the glomerulus after MC injury and during glomerulogenesis in the rat. Experimental mesangial proliferative nephritis was induced in Sprague Dawley rats by intravenous injection of OX-7 antibody. We investigated mRNA expression profiles in isolated glomeruli from on days 0, 1, 2, 3, and 5 after induction of anti-Thy1 nephritis using Affymetrix microarray technology. Using self-organizing maps, transgelin was identified as a new marker for repopulating glomerular cells. Expression of transgelin during anti-Thy1 nephritis was investigated by northern blot, real-time PCR, western blot, and immunohistochemistry. Migration and proliferation assays using isolated MCs after transgelin knockdown by siRNA were performed to investigate the potential role of transgelin during glomerular repopulation. Transgelin mRNA was not detected in healthy glomeruli. It was strongly upregulated during the repopulation process starting on day 1, continued to be increased until day 5 and disappeared on day 7. Transgelin was specifically expressed at the edge of the migratory front during glomerular repopulation as indicated by transgelin/OX-7 double staining. Transgelin expression was similar in migrating vs non-migrating MCs in vitro. Blocking of transgelin expression by siRNA treatment resulted in inhibition of MC migration and proliferation. Transgelin was also expressed in MCs during glomerulogenesis and in biopsies from patients with IgA nephritis. In conclusion, transgelin in the kidney is upregulated in repopulating MCs in vivo and supports their migratory and proliferative repair response after injury.

  13. Multiple promoters and targeted microRNAs direct the expressions of HMGB3 gene transcripts in dairy cattle.

    PubMed

    Li, Liming; Huang, Jinming; Ju, Zhihua; Li, Qiuling; Wang, Changfa; Qi, Chao; Zhang, Yan; Hou, Qinlei; Hang, Suqin; Zhong, Jifeng

    2013-06-01

    HMGB3 (high-mobility group box 3) is an X-linked member of a family of sequence-independent chromatin-binding proteins and functions as a universal sentinel for nucleic acid-mediated innate immune responses. The splice variant expression, promoter characterization and targeted microRNAs of the bovine HMGB3 gene were investigated to explore its expression pattern and possible regulatory mechanism. The results revealed that the expression of HMGB3 transcript variants 1 and 2 (HMGB3-TV1 and HMGB3-TV2) mRNA in the mastitis-infected mammary gland tissues was up-regulated by 8.46- and 5.31-fold respectively compared with that in healthy tissues (P < 0.05). HMGB3-TV1 was highly expressed in the mammary gland tissues, whereas HMGB3-TV2 was expressed primarily in liver. Functional analyses indicated that HMGB3 transcription is regulated by three distinct promoters - promoters 1, 2 and 3 (P1, P2 and P3) - resulting in two alternative transcripts with the same 3'-untranslated region. Promoter luciferase activity analysis suggested that the core sequences of P1 and P2 were mapped in the region of g.1535 to ~g.2076 and g.2074 to ~g.2491 respectively. The g.5880C>T SNP in P3 affected its base promoter activity, and different genotypes were associated with the bovine somatic count score. The expression of targets bovine miR-17-5p, miR-20b and miR-93 of the HMGB3 gene was down-regulated 1.56-, 1.72- and 2.94-fold respectively in mammary gland tissues as compared with that in healthy tissues (P < 0.05). The findings suggest that HMGB3 expression is under complex transcriptional and post-transcriptional control by alternate promoter usage, alternative splicing mechanism and microRNAs in dairy cattle. PMID:23206268

  14. Prostaglandin E2 promotes lung cancer cell migration via EP4-betaArrestin1-c-Src signalsome.

    PubMed

    Kim, Jae Il; Lakshmikanthan, Vijayabaskar; Frilot, Nicole; Daaka, Yehia

    2010-04-01

    Many human cancers express elevated levels of cyclooxygenase-2 (COX-2), an enzyme responsible for the biosynthesis of prostaglandins. Available clinical data establish the protective effect of COX-2 inhibition on human cancer progression. However, despite these encouraging outcomes, the appearance of unwanted side effects remains a major hurdle for the general application of COX-2 inhibitors as effective cancer drugs. Hence, a better understanding of the molecular signals downstream of COX-2 is needed for the elucidation of drug targets that may improve cancer therapy. Here, we show that the COX-2 product prostaglandin E(2) (PGE(2)) acts on cognate receptor EP4 to promote the migration of A549 lung cancer cells. Treatment with PGE(2) enhances tyrosine kinase c-Src activation, and blockade of c-Src activity represses the PGE(2)-mediated lung cancer cell migration. PGE(2) affects target cells by activating four receptors named EP1 to EP4. Use of EP subtype-selective ligand agonists suggested that EP4 mediates prostaglandin-induced A549 lung cancer cell migration, and this conclusion was confirmed using a short hairpin RNA approach to specifically knock down EP4 expression. Proximal EP4 effectors include heterotrimeric Gs and betaArrestin proteins. Knockdown of betaArrestin1 expression with shRNA significantly impaired the PGE(2)-induced c-Src activation and cell migration. Together, these results support the idea that increased expression of the COX-2 product PGE(2) in the lung tumor microenvironment may initiate a mitogenic signaling cascade composed of EP4, betaArrestin1, and c-Src which mediates cancer cell migration. Selective targeting of EP4 with a ligand antagonist may provide an efficient approach to better manage patients with advanced lung cancer.

  15. Androgen receptor promotes gastric cancer cell migration and invasion via AKT-phosphorylation dependent upregulation of matrix metalloproteinase 9

    PubMed Central

    Zang, Ming-de; Chang, Qing; Fan, Zhi-yuan; Li, Jian-fang; Yu, Bei-qin; Su, Li-ping; Li, Chen; Yan, Chao; Gu, Qin-long; Zhu, Zheng-gang; Yan, Min; Liu, Bingya

    2014-01-01

    Androgen receptor (AR) plays an important role in many kinds of cancers. However, the molecular mechanisms of AR in gastric cancer (GC) are poorly characterized. Here, we investigated the role of AR in GC cell migration, invasion and metastatic potential. Our data showed that AR expression was positively correlated with lymph node metastasis and late TNM stages. These findings were accompanied by activation of AKT and upregulation of matrix metalloproteinase 9 (MMP9). AR overexpression induced increases in GC cell migration, invasion and proliferation in vitro and in vivo. These effects were attenuated by inhibition of AKT, AR and MMP9. AR overexpression upregulated MMP9 protein levels, whereas this effect was counteracted by AR siRNA. Inhibition of AKT by siRNA or an inhibitor (MK-2206 2HC) decreased AR protein expression in both stably transfected and parental SGC-7901 cells. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that AR bound to the AR-binding sites of the MMP9 promoter. In summary, AR overexpression induced by AKT phosphorylation upregulated MMP9 by binding to its promoter region to promote gastric carcinogenesis. The AKT/AR/MMP9 pathway plays an important role in GC metastasis and may be a novel therapeutic target for GC treatment. PMID:25301736

  16. Thymosin {beta}4 promotes the migration of endothelial cells without intracellular Ca{sup 2+} elevation

    SciTech Connect

    Selmi, Anna; Malinowski, Mariusz; Brutkowski, Wojciech; Bednarek, Radoslaw; Cierniewski, Czeslaw S.

    2012-08-15

    Numerous studies have demonstrated the effects of T{beta}4 on cell migration, proliferation, apoptosis and inflammation after exogenous treatment, but the mechanism by which T{beta}4 functions is still unclear. Previously, we demonstrated that incubation of endothelial cells with T{beta}4 induced synthesis and secretion of various proteins, including plasminogen activator inhibitor type 1 and matrix metaloproteinases. We also showed that T{beta}4 interacts with Ku80, which may operate as a novel receptor for T{beta}4 and mediates its intracellular activity. In this paper, we provide evidence that T{beta}4 induces cellular processes without changes in the intracellular Ca{sup 2+} concentration. External treatment of HUVECs with T{beta}4 and its mutants deprived of the N-terminal tetrapeptide AcSDKP (T{beta}4{sub AcSDKPT/4A}) or the actin-binding sequence KLKKTET (T{beta}4{sub KLKKTET/7A}) resulted in enhanced cell migration and formation of tubular structures in Matrigel. Surprisingly, the increased cell motility caused by T{beta}4 was not associated with the intracellular Ca{sup 2+} elevation monitored with Fluo-4 NW or Fura-2 AM. Therefore, it is unlikely that externally added T{beta}4 induces HUVEC migration via the surface membrane receptors known to generate Ca{sup 2+} influx. Our data confirm the concept that externally added T{beta}4 must be internalized to induce intracellular mechanisms supporting endothelial cell migration.

  17. FAK competes for Src to promote migration against invasion in melanoma cells

    PubMed Central

    Kolli-Bouhafs, K; Sick, E; Noulet, F; Gies, J-P; De Mey, J; Rondé, P

    2014-01-01

    Melanoma is one of the most deadly cancers because of its high propensity to metastasis, a process that requires migration and invasion of tumor cells driven by the regulated formation of adhesives structures like focal adhesions (FAs) and invasive structures like invadopodia. FAK, the major kinase of FAs, has been implicated in many cellular processes, including migration and invasion. In this study, we investigated the role of FAK in the regulation of invasion. We report that suppression of FAK in B16F10 melanoma cells led to increased invadopodia formation and invasion through Matrigel, but impaired migration. These effects are rescued by FAK WT but not by FAKY397F reexpression. Invadopodia formation requires local Src activation downstream of FAK and in a FAK phosphorylation-dependant manner. FAK deletion correlates with increased phosphorylation of Tks-5 (tyrosine kinase substrate with five SH3 domain) and reactive oxygen species production. In conclusion, our data show that FAK is able to mediate opposite effects on cell migration and invasion. Accordingly, beneficial effects of FAK inhibition are context dependent and may depend on the cell response to environmental cues and/or on the primary or secondary changes that melanoma experienced through the invasion cycle. PMID:25118939

  18. Gold Nanorods Indirectly Promote Migration of Metastatic Human Breast Cancer Cells in Three-Dimensional Cultures.

    PubMed

    Grzincic, Elissa M; Murphy, Catherine J

    2015-07-28

    Gold nanomaterials are intensively studied for applications in disease detection, diagnosis and therapeutics, and this has motivated considerable research to determine their interaction with biomolecules, cells and cell behaviors. However, few studies look at how nanomaterials alter the extracellular matrix (ECM) and cell-ECM interactions. Nanomaterials in the body would interact with the entire cellular environment, and it is imperative to account for this when studying the impact of nanomaterials on living systems. Furthermore, recent evidence finds that migration rates of cells in 2D can be affected by nanomaterials, and uptake of the nanomaterials is not necessary to exert an effect. In this study, three-dimensional nested type I collagen matrices were utilized as a model ECM to study how gold nanorods affect the migration of MDA-MB-231 human breast cancer cells. Spontaneous cell migration through collagen containing gold nanorods was found to increase with increasing concentrations of gold nanorods, independent of intracellular uptake of the nanorods. Gold nanorods in the collagen matrix were found to alter collagen mechanical properties and structure, molecular diffusion, cellular adhesion, cell morphology, mode of migration and protease expression. Correlation between decreased cellular adhesion and rounded cell morphology and locomotion in nanorod-containing collagen suggests the induction of an amoeboid-like migratory phenotype.

  19. Cadherin-11 endocytosis through binding to clathrin promotes cadherin-11-mediated migration in prostate cancer cells.

    PubMed

    Satcher, Robert L; Pan, Tianhong; Bilen, Mehmet A; Li, Xiaoxia; Lee, Yu-Chen; Ortiz, Angelica; Kowalczyk, Andrew P; Yu-Lee, Li-Yuan; Lin, Sue-Hwa

    2015-12-15

    Cadherin-11 (Cad11) cell adhesion molecule plays a role in prostate cancer cell migration. Because disassembly of adhesion complexes through endocytosis of adhesion proteins has been shown to play a role in cell migration, we examined whether Cad11 endocytosis plays a role in Cad11-mediated migration. The mechanism by which Cad11 is internalized is unknown. Using a GST pulldown assay, we found that clathrin binds to the Cad11 cytoplasmic domain but not to that of E-cadherin. Using deletion analysis, we identified a unique sequence motif, VFEEE, in the Cad11 membrane proximal region (amino acid residues 11-15) that binds to clathrin. Endocytosis assays using K(+)-depletion buffer showed that Cad11 internalization is clathrin dependent. Proximity ligation assays showed that Cad11 colocalizes with clathrin, and immunofluorescence assays showed that Cad11 localizes in vesicles that stain for the early endosomal marker Rab5. Deletion of the VFEEE sequence from the Cad11 cytoplasmic domain (Cad11-cla-Δ5) leads to inhibition of Cad11 internalization and reduces Cad11-mediated cell migration in C4-2B and PC3-mm2 prostate cancer cells. These observations suggest that clathrin-mediated internalization of Cad11 regulates surface trafficking of Cad11 and that dynamic turnover of Cad11 regulates the migratory function of Cad11 in prostate cancer cells.

  20. PTK6 Promotes Cancer Migration and Invasion in Pancreatic Cancer Cells Dependent on ERK Signaling

    PubMed Central

    Ono, Hiroaki; Basson, Marc D.; Ito, Hiromichi

    2014-01-01

    Protein Tyrosine Kinase 6 (PTK6) is a non-receptor type tyrosine kinase that may be involved in some cancers. However, the biological role and expression status of PTK6 in pancreatic cancer is unknown. Therefore in this study, we evaluated the functional role of PTK6 on pancreatic cancer invasion. Five pancreatic cancer cell lines expressed PTK6 at varying levels. PTK6 expression was also observed in human pancreatic adenocarcinomas. PTK6 suppression by siRNA significantly reduced both cellular migration and invasion (0.59/0.49 fold for BxPC3, 0.61/0.62 for Panc1, 0.42/0.39 for MIAPaCa2, respectively, p<0.05 for each). In contrast, forced overexpression of PTK6 by transfection of a PTK6 expression vector in Panc1 and MIAPaCa2 cells increased cellular migration and invasion (1.57/1.67 fold for Panc1, 1.44/1.57 for MIAPaCa2, respectively, p<0.05). Silencing PTK6 reduced ERK1/2 activation, but not AKT or STAT3 activation, while PTK6 overexpression increased ERK1/2 activation. U0126, a specific inhibitor of ERK1/2, completely abolished the effect of PTK6 overexpression on cellular migration and invasion. These results suggest that PTK6 regulates cellular migration and invasion in pancreatic cancer via ERK signaling. PTK6 may be a novel therapeutic target for pancreatic cancer. PMID:24788754

  1. Paradoxes of Sahrawi Refugees' Educational Migration: Promoting Self-Sufficiency or Renewing Dependency?

    ERIC Educational Resources Information Center

    Fiddian-Qasmiyeh, Elena

    2011-01-01

    Education is often prioritised by refugee children and families, as well as by their political representatives and international actors alike. This article explores the specificities of the Sahrawi refugee education system, focusing in particular on the nature, motivations and implications of Sahrawi refugee youths' educational migration to Cuba…

  2. Ephrin-A5 promotes bovine muscle progenitor cell migration before mitotic activation.

    PubMed

    Li, J; Johnson, S E

    2013-03-01

    Satellite cells are the resident stem cell population of adult skeletal muscle tissue that is responsible for growth and regeneration. The cells typically congregate near the tips of the muscle fibers and in close proximity to the neural muscular junction (NMJ). Ephrin-A5 is a chemotactic molecule that participates in the correct positioning and formation of the NMJ. The objective of the experiment was to examine the effects of ephrin-A5 signaling on bovine satellite cell (BSC) biology. Primary cultures of BSC demonstrate changes in velocity with time in culture that is unique to the Paired box protein 7 (Pax7):Myogenic factor 5 (Myf5) subpopulation. Treatment of the BSC with ephrin-A5 causes a reduction (P < 0.05) in velocity with a concomitant increase (P < 0.05) in directed migration. The chemoattractant properties of ephrin-A5 occur before myogenic differentiation 1 (MyoD) expression in the myogenic precursors and are abrogated after their differentiation to committed myoblasts. Ephrin-A5 induced migration appears to require components of the Ras homolog gene family member A (RhoA) and Rho-associated protein kinase (ROCK) signaling machinery. Supplementation of culture media with a chemical ROCK inhibitor suppressed (P < 0.05) ephrin-A5 initiated BSC migration. These results contrast with treatment of BSC with hepatocyte growth factor (HGF), a key modulator of myogenic and motogenic activity. Treatment of BSC with HGF had no effect on cell motility or migration immediately after culture establishment. Twenty-four hours after culture establishment, BSC demonstrated an increase (P < 0.05) in transwell migration toward HGF. These results document that temporal and spatial gradients of chemokines and growth factors participate in the localization of BSC within the niche.

  3. Chemerin promotes the proliferation and migration of vascular smooth muscle and increases mouse blood pressure.

    PubMed

    Kunimoto, Hidemizu; Kazama, Kyosuke; Takai, Mizuho; Oda, Mayuko; Okada, Muneyoshi; Yamawaki, Hideyuki

    2015-09-01

    Blood chemerin concentration shows positive correlation not only with body mass index and serum triglyceride level but also with systolic blood pressure. While it seems likely that chemerin influences vascular smooth muscle cell (SMC) proliferation and migration, which are crucial to the development of hypertension, this remains to be clarified. In the present study, we investigated whether chemerin controls SMC proliferation and migration in vitro and also affects blood pressure in vivo. In vitro, chemerin significantly stimulated rat mesenteric arterial SMC proliferation and migration, as determined by a cell counting assay and Boyden chamber assay, respectively. The migratory effect of chemerin was confirmed in human aortic SMCs. Chemerin significantly increased ROS production in SMCs and phosphorylation of Akt (Ser(473)) and ERK, as measured by fluorescent staining and Western blot analysis, respectively. Various inhibitors (ROS inhibitor: N-acetyl-l-cysteine, phosphatidylinositol 3-kinase inhibitor: LY-294002, MAPKK inhibitor: PD-98059, NADPH oxidase inhibitor: gp91 ds-tat, and xanthine oxidase inhibitor: allopurinol) as well as chemokine-like receptor 1 small interfering RNA significantly inhibited chemerin-induced SMC proliferation and migration. Furthermore, chemerin-neutralizing antibody prevented carotid neointimal hyperplasia in the mouse ligation model. In vivo, chronic chemerin treatment (6 μg/kg, 6 wk) increased systolic blood pressure as well as phosphorylation of Akt and ERK in the mouse isolated aorta. In summary, we, for the first time, demonstrate that chemerin/chemokine-like receptor 1 stimulates SMC proliferation and migration via ROS-dependent phosphorylation of Akt/ERK, which may lead to vascular structural remodeling and an increase in systolic blood pressure.

  4. Impaired SIRT1 promotes the migration of vascular smooth muscle cell-derived foam cells.

    PubMed

    Zhang, Ming-Jie; Zhou, Yi; Chen, Lei; Wang, Xu; Pi, Yan; Long, Chun-Yan; Sun, Meng-Jiao; Chen, Xue; Gao, Chang-Yue; Li, Jing-Cheng; Zhang, Li-Li

    2016-07-01

    The formation of fat-laden foam cells, contributing to the fatty streaks of the plaques of atheroma, is the critical early process in atherosclerosis. The previous study demonstrated that vascular smooth muscle cells (VSMCs) contain a much larger burden of the excess cholesterol in comparison with monocyte-derived macrophages in human coronary atherosclerosis, as the main origin of foam cells. It is noteworthy that VSMC-derived foam cells are deposited in subintima but not media, where VSMCs normally deposit in. Therefore, migration from media to intima is an indispensable step for a VSMC to accrue neutral lipids and form foam cell. Whether this migration occurs paralleled with or prior to the formation of foam cell is still unclear. Herein, the present study was designed to test the VSMC migratory capability in the process of foam cell formation induced by oxidized low-density lipoprotein (oxLDL). In conclusion, we provide evidence that oxLDL induces the VSMC-derived foam cells formation with increased migration ability and MMP-9 expression, which were partly attributed to the impaired SIRT1 and enhanced nuclear factor-kappa B (NF-κB) activity. As activation of transient receptor potential vanilloid type 1 (TRPV1) has been reported to have anti-atherosclerotic effects, we investigated its role in oxLDL-treated VSMC migration. It is found that activating TRPV1 by capsaicin inhibits VSMC foam cell formation and the accompanied migration through rescuing the SIRT1 and suppressing NF-κB signaling. The present study provides evidence that SIRT1 may be a promising intervention target of atherosclerosis, and raises the prospect of TRPV1 in prevention and treatment of atherosclerosis.

  5. Progesterone promotes cell migration, invasion and cofilin activation in human astrocytoma cells.

    PubMed

    Piña-Medina, Ana Gabriela; Hansberg-Pastor, Valeria; González-Arenas, Aliesha; Cerbón, Marco; Camacho-Arroyo, Ignacio

    2016-01-01

    Astrocytomas are the most common and aggressive primary brain tumors in humans. Invasiveness of these tumors has been attributed in part to deregulation of cell motility-dependent cytoskeletal dynamics that involves actin-binding proteins such as cofilin. Progesterone (P4) has been found to induce migration and invasion of cells derived from breast cancer and endothelium. However, the role of P4 in migration and invasion of astrocytoma cells as well as its effects on astrocytomas cytoskeleton remodeling is not known. In this work we evaluated these aspects in D54 and U251 cells derived from human astrocytomas from the highest degree of malignancy (grade IV, glioblastoma). Our results showed that in scratch-wound assays P4 increased the number of D54 and U251 cells migrating from 3 to 48 h. Both RU486, a P4 receptor (PR) antagonist, and an oligonucleotide antisense against PR significantly blocked P4 effects. Transwell assays showed that P4 significantly increased the number of invasive cells at 24h. As in the case of migration, this effect was blocked by RU486. Finally, by Western blotting, an increase in the cofilin/p-cofilin ratio at 15 and 30 min and a decrease at 30 and 60 min in U251 and D54 cells, respectively, was observed after P4, P4+RU486 and RU486 treatments. These data suggest that P4 increases human astrocytoma cells migration and invasion through its intracellular receptor, and that cofilin activation by P4 is independent of PR action. PMID:26639431

  6. Cortactin involvement in the keratinocyte growth factor and fibroblast growth factor 10 promotion of migration and cortical actin assembly in human keratinocytes

    SciTech Connect

    Ceccarelli, Simona; Cardinali, Giorgia; Aspite, Nicaela; Picardo, Mauro; Marchese, Cinzia; Torrisi, Maria Rosaria; Mancini, Patrizia . E-mail: patrizia.mancini@uniroma1.it

    2007-05-15

    Keratinocyte growth factor (KGF/FGF7) and fibroblast growth factor 10 (FGF10/KGF2) regulate keratinocyte proliferation and differentiation by binding to the tyrosine kinase KGF receptor (KGFR). KGF induces keratinocyte motility and cytoskeletal rearrangement, whereas a direct role of FGF10 on keratinocyte migration is not clearly established. Here we analyzed the motogenic activity of FGF10 and KGF on human keratinocytes. Migration assays and immunofluorescence of actin cytoskeleton revealed that FGF10 is less efficient than KGF in promoting migration and exerts a delayed effect in inducing lamellipodia and ruffles formation. Both growth factors promoted phosphorylation and subsequent membrane translocation of cortactin, an F-actin binding protein involved in cell migration; however, FGF10-induced cortactin phosphorylation was reduced, more transient and delayed with respect to that promoted by KGF. Cortactin phosphorylation induced by both growth factors was Src-dependent, while its membrane translocation and cell migration were blocked by either Src and PI3K inhibitors, suggesting that both pathways are involved in KGF- and FGF10-dependent motility. Furthermore, siRNA-mediated downregulation of cortactin inhibited KGF- and FGF10-induced migration. These results indicate that cortactin is involved in keratinocyte migration promoted by both KGF and FGF10.

  7. Promotion of cell migration by neural cell adhesion molecule (NCAM) is enhanced by PSA in a polysialyltransferase-specific manner.

    PubMed

    Guan, Feng; Wang, Xin; He, Fa

    2015-01-01

    Neural cell adhesion molecule 140 (NCAM-140) is a glycoprotein and always highly polysialylated in cancer. Functions of polysialic acid (PSA) that binds to N-glycan termini on NCAM remain unclear. ldlD-14 cells, a CHO cell mutant deficient in UDP-Gal 4-epimerase, are useful for structural and functional studies of Gal-containing glycoproteins because their abnormal glycosylation can be converted to normal status by exogenous addition of galactose (Gal). We cloned the genes for NCAM-140 and for polysialyltransferases STX and PST (responsible for PSA synthesis) from normal murine mammary gland epithelial (NMuMG) cells and transfected them into ldlD-14 and human breast cancer cells MCF-7. The effect of PSA on NCAM-mediated cell proliferation, motility, migration and adhesion was studied. We found that NCAM-140 significantly promoted cell proliferation, motility and migration, while polysialylation of NCAM-140 catalyzed by STX, but not by PST, enhanced NCAM-mediated cell migration, but not cell proliferation or motility. In addition, PSA catalyzed by different polysialyltransferases affected the adhesion of NCAM to different extracellular matrix (ECM) components. PMID:25885924

  8. Synthetic antimicrobial and LPS-neutralising peptides suppress inflammatory and immune responses in skin cells and promote keratinocyte migration.

    PubMed

    Pfalzgraff, Anja; Heinbockel, Lena; Su, Qi; Gutsmann, Thomas; Brandenburg, Klaus; Weindl, Günther

    2016-01-01

    The stagnation in the development of new antibiotics and the concomitant high increase of resistant bacteria emphasize the urgent need for new therapeutic options. Antimicrobial peptides are promising agents for the treatment of bacterial infections and recent studies indicate that Pep19-2.5, a synthetic anti-lipopolysaccharide (LPS) peptide (SALP), efficiently neutralises pathogenicity factors of Gram-negative (LPS) and Gram-positive (lipoprotein/-peptide, LP) bacteria and protects against sepsis. Here, we investigated the potential of Pep19-2.5 and the structurally related compound Pep19-4LF for their therapeutic application in bacterial skin infections. SALPs inhibited LP-induced phosphorylation of NF-κB p65 and p38 MAPK and reduced cytokine release and gene expression in primary human keratinocytes and dermal fibroblasts. In LPS-stimulated human monocyte-derived dendritic cells and Langerhans-like cells, the peptides blocked IL-6 secretion, downregulated expression of maturation markers and inhibited dendritic cell migration. Both SALPs showed a low cytotoxicity in all investigated cell types. Furthermore, SALPs markedly promoted cell migration via EGFR transactivation and ERK1/2 phosphorylation and accelerated artificial wound closure in keratinocytes. Peptide-induced keratinocyte migration was mediated by purinergic receptors and metalloproteases. In contrast, SALPs did not affect proliferation of keratinocytes. Conclusively, our data suggest a novel therapeutic target for the treatment of patients with acute and chronic skin infections. PMID:27509895

  9. Response Gene to Complement 32 Promotes Vascular Lesion Formation through Stimulation of Smooth Muscle Cell Proliferation and Migration

    PubMed Central

    Wang, Jia-Ning; Shi, Ning; Xie, Wei-bing; Guo, Xia; Chen, Shi-You

    2011-01-01

    Objective The objectives of this study are to determine the role of response gene to complement 32 (RGC-32) in vascular lesion formation after experimental angioplasty and to explore the underlying mechanisms. Methods and Results Using a rat carotid artery balloon-injury model, we documented for the first time that neointima formation was closely associated with a significantly increased expression of RGC-32 protein. shRNA Knockdown of RGC-32 via adenovirus (Ad)-mediated gene delivery dramatically inhibited the lesion formation by 62% as compared to control groups 14 days after injury. Conversely, RGC-32 overexpression significantly promoted the neointima formation by 33%. Gain and loss of function studies in primary culture of rat aortic smooth muscle cells (RASMCs) indicated that RGC-32 is essential for both the proliferation and migration of RASMCs. RGC-32 induced RASMC proliferation by enhancing p34CDC2 activity. RGC-32 stimulated the migration of RASMC via inducing focal adhesion contact and stress fiber formation. These effects were caused by the enhanced ROKα activity due to RGC-32-induced downregulation of Rad GTPase. Conclusions RGC-32 plays an important role in vascular lesion formation following vascular injury. Increased RGC-32 expression in vascular injury appears to be a novel mechanism underlying the migration and proliferation of vascular SMCs. Therefore, targeting RGC-32 is a potential therapeutic strategy for the prevention of vascular remodeling in proliferative vascular diseases. PMID:21636805

  10. MiR-21 promoted proliferation and migration in hepatocellular carcinoma through negative regulation of Navigator-3

    SciTech Connect

    Wang, Zhipeng; Yang, Huan; Ren, Lei

    2015-09-04

    MicroRNA-21 (miR-21) has been well-established and found to be over-expressed in various human cancers and has been associated with hepatocellular carcinoma (HCC) progression. However, the underlying mechanism of miR-21 involvement in the development and progression of HCC remains to be understood. In the present study, we firstly identified that the Navigator-3 (NAV-3) gene as a novel direct target of miR-21. Knock-down of NAV-3 using shRNA can rescue the effects of anti-miR-21 inhibitor in HCC cell lines, whereas re-expression of miR-21 using transfection with miR-21 mimics phenocopied the NAV-3 knock-down model. Additionally, miR-21 levels inversely correlated with NAV-3 both in HCC cells and tissues. Knock-down of NAV-3 promoted both the proliferation and migration in HCC cells. Together, our findings suggest an important role for miR-21 in the progression of HCC, which negatively regulated Navigator-3 in the migration of HCC. - Highlights: • Navigator-3 (NAV-3) suppresses proliferation, migration and tumorigenesis of HCC cells. • NAV-3 was a novel target of miR-21. • MiR-21 negatively regulates NAV-3 in HCC.

  11. The matrix protein CCN1 (CYR61) promotes proliferation, migration and tube formation of endothelial progenitor cells

    SciTech Connect

    Yu Yang; Gao Yu; Wang, Hong; Huang Lan Qin Jun; Guo Ruiwei; Song Mingbao; Yu Shiyong; Chen Jianfei; Cui Bin; Gao Pan

    2008-10-15

    Neovascularization and re-endothelialization relies on circulating endothelial progenitor cells (EPCs), but their recruitment and angiogenic roles are subjected to regulation by the vascular microenvironment, which remains largely unknown. The present study was designed to investigate the effects of mature ECs and matrix protein CCN1 on the properties of EPCs. In a coculture system, effects of ECs on proliferation, migration and participation in tube-like formation of EPCs were evaluated, and functional assays were employed to identify the exact role of CCN1 in EPCs vitality and function. We demonstrated that ECs, as an indispensable part of the cellular milieu, significantly promoted the proliferation, migration and tube formation activities of EPCs, and more importantly, CCN1 was potentially involved in such effects of ECs. Expression of CCN1 in EPCs was significantly increased by serum, VEGF, ECs-cocultivation and ECs conditioned medium. Moreover, Ad-CCN1-mediated overexpression of CCN1 directly enhanced migration and tube formation of EPCs, whereas silencing of endogenous CCN1 in EPCs inhibits cell functions. Furthermore, CCN1 induced the expressions of chemokines and growth factors, such as MCP-1 and VEGF, suggesting a complex interaction between those proangiogenic factors. Our data suggest that matrix protein CCN1 may play an important role in microenvironment-mediated biological properties of EPCs.

  12. Synthetic antimicrobial and LPS-neutralising peptides suppress inflammatory and immune responses in skin cells and promote keratinocyte migration

    PubMed Central

    Pfalzgraff, Anja; Heinbockel, Lena; Su, Qi; Gutsmann, Thomas; Brandenburg, Klaus; Weindl, Günther

    2016-01-01

    The stagnation in the development of new antibiotics and the concomitant high increase of resistant bacteria emphasize the urgent need for new therapeutic options. Antimicrobial peptides are promising agents for the treatment of bacterial infections and recent studies indicate that Pep19-2.5, a synthetic anti-lipopolysaccharide (LPS) peptide (SALP), efficiently neutralises pathogenicity factors of Gram-negative (LPS) and Gram-positive (lipoprotein/-peptide, LP) bacteria and protects against sepsis. Here, we investigated the potential of Pep19-2.5 and the structurally related compound Pep19-4LF for their therapeutic application in bacterial skin infections. SALPs inhibited LP-induced phosphorylation of NF-κB p65 and p38 MAPK and reduced cytokine release and gene expression in primary human keratinocytes and dermal fibroblasts. In LPS-stimulated human monocyte-derived dendritic cells and Langerhans-like cells, the peptides blocked IL-6 secretion, downregulated expression of maturation markers and inhibited dendritic cell migration. Both SALPs showed a low cytotoxicity in all investigated cell types. Furthermore, SALPs markedly promoted cell migration via EGFR transactivation and ERK1/2 phosphorylation and accelerated artificial wound closure in keratinocytes. Peptide-induced keratinocyte migration was mediated by purinergic receptors and metalloproteases. In contrast, SALPs did not affect proliferation of keratinocytes. Conclusively, our data suggest a novel therapeutic target for the treatment of patients with acute and chronic skin infections. PMID:27509895

  13. SREBP-1 is an independent prognostic marker and promotes invasion and migration in breast cancer

    PubMed Central

    Bao, Jisheng; Zhu, Liping; Zhu, Qi; Su, Jianhua; Liu, Menglan; Huang, Wei

    2016-01-01

    Re-programming of lipogenic signaling has been previously demonstrated to result in significant alterations in tumor cell pathology. Sterol regulatory element-binding protein 1 (SREBP-1) is a known transcription factor of lipogenic genes. Despite the fact that its functions in proliferation and apoptosis have been elucidated in recent studies, its role in tumor cell migration and invasion, particularly in breast cancer, remains unclear. In present study, the messenger RNA and protein expression levels of SREBP-1 in cancer tissues were observed to be overexpressed compared with those in matched para-cancerous tissues (P<0.01). SREBP-1 level was highly positively correlated with tumor differentiation (P<0.001), tumor-node-metastasis stage (P=0.044) and lymph node metastasis (P<0.001). High expression of SREBP-1 predicted poor prognosis in patients with breast cancer. Additionally, multivariate analysis revealed that SREBP-1 was an independent factor of 5-year overall and disease-specific survival in breast cancer patients (P<0.01). In vitro studies revealed that the suppression of SREBP-1 expression in both MDA-MB-231 and MCF7 cells significantly inhibited cell migration and invasion (P<0.01). The present data indicate that SREBP-1 plays a critical role in breast cancer migration and invasion, and may serve as a prognostic marker of this malignancy. PMID:27703522

  14. Migrate small, sound big: functional constraints on body size promote tracheal elongation in cranes.

    PubMed

    Jones, M R; Witt, C C

    2014-06-01

    Organismal traits often represent the outcome of opposing selection pressures. Although social or sexual selection can cause the evolution of traits that constrain function or survival (e.g. ornamental feathers), it is unclear how the strength and direction of selection respond to ecological shifts that increase the severity of the constraint. For example, reduced body size might evolve by natural selection to enhance flight performance in migratory birds, but social or sexual selection favouring large body size may provide a countervailing force. Tracheal elongation is a potential outcome of these opposing pressures because it allows birds to convey an auditory signal of exaggerated body size. We predicted that the evolution of migration in cranes has coincided with a reduction in body size and a concomitant intensification of social or sexual selection for apparent large body size via tracheal elongation. We used a phylogenetic comparative approach to examine the relationships among migration distance, body mass and trachea length in cranes. As predicted, we found that migration distance correlated negatively with body size and positively with proportional trachea length. This result was consistent with our hypothesis that evolutionary reductions in body size led to intensified selection for trachea length. The most likely ultimate causes of intensified positive selection on trachea length are the direct benefits of conveying a large body size in intraspecific contests for mates and territories. We conclude that the strength of social or sexual selection on crane body size is linked to the degree of functional constraint. PMID:24800977

  15. SRPX2 promotes cell migration and invasion via FAK dependent pathway in pancreatic cancer.

    PubMed

    Gao, Zhenyuan; Zhang, Jingjing; Bi, Minghong; Han, Xiao; Han, Zhengquan; Wang, Hongya; Ou, Yimei

    2015-01-01

    Sushi repeat-containing protein, X-linked 2, abbreviated as SRPX2, is a candidate downstream target protein for E2A-HLF and involved in disorders of language cortex and cognition. Recent studies have demonstrated that elevated SRPX2 exhibits crucial roles in gastric cancer, however, underlying clinical significance and biological function of SRPX2 in pancreatic ductal adenocarcinoma (PDAC), remains unclear. Data from Oncomine database showed that higher SRPX2 expression is more commonly observed in PDAC compared with normal pancreatic duct, similar results were also found in 12 matched PDAC tissue samples, 7 PDAC cell lines and a tissue microarray containing 81 PDAC specimens as demonstrated by real-time quantitative PCR and immunohistochemistry, respectively. Besides, higher SRPX2 expression was closely correlated with advanced TNM stage. Silencing of endogenous SRPX2 expression reduced abilities of cell migration and invasion of PDAC cells. Further studies revealed that SRPX2 expression in PDAC tissues significantly correlated with the phosphorylation levels of FAK, indicating that FAK dependent pathway may be account for the effect of SRPX2 on cell migration and invasion in PDAC. Collectively, this study reveals that frequently elevated SRPX2 contributes to cell migration and invasion in PDAC and SRPX2-related pathways might be a potential therapeutic target for PDAC. PMID:26191169

  16. Lipocalin 2 promotes the migration and invasion of esophageal squamous cell carcinoma cells through a novel positive feedback loop.

    PubMed

    Du, Ze-Peng; Wu, Bing-Li; Xie, Yang-Min; Zhang, Ying-Li; Liao, Lian-Di; Zhou, Fei; Xie, Jian-Jun; Zeng, Fa-Min; Xu, Xiu-E; Fang, Wang-Kai; Li, En-Min; Xu, Li-Yan

    2015-10-01

    Lipocalin 2 (LCN2) is a poor prognostic factor in esophageal squamous cell carcinoma (ESCC), however its functional roles and molecular mechanisms of action remain to be clarified. Here, we described the functions and signaling pathways for LCN2 in ESCC. Overexpression of LCN2 in ESCC cells accelerated cell migration and invasion in vitro, and promoted lung metastasis in vivo. Blocking LCN2 expression inhibited its pro-oncogenic effect. Either overexpression of LCN2 or treatment with recombinant human LCN2 protein enhanced the activation of MEK/ERK pathway, which in turn increases endogenous LCN2 to increase MMP-9 activity. The decreased p-cofilin and increased p-ERM induced by pERK1/2 cause the cytoskeleton F-actin rearrangement and alter the behavior of ESCC cells mediated by LCN2. As a consequence, activation of MMP-9 and the rearrangement of F-actin throw light on the mechanisms for LCN2 in ESCC. These results imply that LCN2 promotes the migration and invasion of ESCC cells through a novel positive feedback loop.

  17. TMPyP4 promotes cancer cell migration at low doses, but induces cell death at high doses

    PubMed Central

    Zheng, Xiao-Hui; Nie, Xin; Liu, Hai-Ying; Fang, Yi-Ming; Zhao, Yong; Xia, Li-Xin

    2016-01-01

    TMPyP4 is widely considered as a potential photosensitizer in photodynamic therapy and a G-quadruplex stabilizer for telomerase-based cancer therapeutics. However, its biological effects including a possible adverse-effect are poorly understood. In this study, whole genome RNA-seq analysis was used to explore the alteration in gene expression induced by TMPyP4. Unexpectedly, we find that 27.67% of changed genes were functionally related to cell adhesion. Experimental evidences from cell adhesion assay, scratch-wound and transwell assay indicate that TMPyP4 at conventional doses (≤0.5 μM) increases cell-matrix adhesion and promotes the migration of tumor cells. In contrast, a high dose of TMPyP4 (≥2 μM) inhibits cell proliferation and induces cell death. The unintended “side-effect” of TMPyP4 on promoting cell migration suggests that a relative high dose of TMPyP4 is preferred for therapeutic purpose. These findings contribute to better understanding of biological effects induced by TMPyP4 and provide a new insight into the complexity and implication for TMPyP4 based cancer therapy. PMID:27221067

  18. High-frequency low-level diode laser irradiation promotes proliferation and migration of primary cultured human gingival epithelial cells.

    PubMed

    Ejiri, Kenichiro; Aoki, Akira; Yamaguchi, Yoko; Ohshima, Mitsuhiro; Izumi, Yuichi

    2014-07-01

    In periodontal therapy, the use of low-level diode lasers has recently been considered to improve wound healing of the gingival tissue. However, its effects on human gingival epithelial cells (HGECs) remain unknown. The aim of the present study was to examine whether high-frequency low-level diode laser irradiation stimulates key cell responses in wound healing, proliferation and migration, in primary cultured HGECs in vitro. HGECs were derived from seven independent gingival tissue specimens. Cultured HGECs were exposed to a single session of high-frequency (30 kHz) low-level diode laser irradiation with various irradiation time periods (fluence 5.7-56.7 J/cm(2)). After 20-24 h, cell proliferation was evaluated by WST-8 assay and [(3)H]thymidine incorporation assay, and cell migration was monitored by in vitro wound healing assay. Further, phosphorylation of the mitogen-activated protein kinase (MAPK) pathways after irradiation was investigated by Western blotting. The high-frequency low-level irradiation significantly increased cell proliferation and [(3)H]thymidine incorporation at various irradiation time periods. Migration of the irradiated cells was significantly accelerated compared with the nonirradiated control. Further, the low-level diode laser irradiation induced phosphorylation of MAPK/extracellular signal-regulated protein kinase (ERK) at 5, 15, 60, and 120 min after irradiation. Stress-activated protein kinases/c-Jun N-terminal kinase and p38 MAPK remained un-phosphorylated. The results show that high-frequency low-level diode laser irradiation promotes HGEC proliferation and migration in association with the activation of MAPK/ERK, suggesting that laser irradiation may accelerate gingival wound healing.

  19. Downregulation of VEGFA inhibits proliferation, promotes apoptosis, and suppresses migration and invasion of renal clear cell carcinoma

    PubMed Central

    Zeng, Fan-Chang; Zeng, Ming-Qiang; Huang, Liang; Li, Yong-Lin; Gao, Ben-Min; Chen, Jun-Jie; Xue, Rui-Zhi; Tang, Zheng-Yan

    2016-01-01

    Objective The aim of this study was to investigate the effects of vascular endothelial growth factor A (VEGFA) on cell proliferation, apoptosis, migration, and invasion in renal clear cell carcinoma (RCCC). Methods Between June 2012 and June 2015, RCCC tissues were obtained for the experimental group, and RCCC adjacent tumor-free kidney parenchyma tissues were obtained for the control group. VEGFA mRNA and protein expressions and phosphoinositide 3-kinase, serine/threonine-specific protein kinase (AKT), and phosphorylated-AKT protein expressions were detected. The chemically synthesized specific siRNA using RNA interference technology was used to inhibit VEGFA gene expression in human RCCC 786-O cells. The negative control (NC) group was transfected with NC sequence, and the blank group was transfected with no sequence. Flow cytometry, scratch test, and cell-penetrating experiment were used to detect cell proliferation, apoptosis, migration, and invasion of 786-O cells. Results Positive expression of VEGFA protein was 60.62% in RCCC tissue and 18.34% in adjacent tissue with statistically significant difference (P<0.001). VEGFA protein and mRNA expressions were higher in RCCC tissue than those in adjacent tissue (both P<0.01). VEGF expression in RCCC tissue was associated with Fuhrman grading and American Joint Committee on Cancer staging (both P<0.05). After RCCC 786-O cells transfecting the VEGFA siRNA, the VEGFA mRNA and protein expressions and phosphoinositide 3-kinase and phosphorylated-AKT protein expressions were significantly decreased, cell proliferation was remarkably inhibited, cell apoptotic ratio was obviously increased, and migration distance and invasive cell number were markedly decreased compared to those in the NC group and the blank group (all P<0.05). Conclusion Inhibition of VEGFA inhibited proliferation, promoted apoptosis, and suppressed migration and invasion of RCCC 786-O cells. VEGF has a potential role in diagnosis and therapy of RCCC

  20. MicroRNA-144 affects radiotherapy sensitivity by promoting proliferation, migration and invasion of breast cancer cells.

    PubMed

    Yu, Lei; Yang, Yanming; Hou, Jiguang; Zhai, Chengwei; Song, Yunhao; Zhang, Zhiliang; Qiu, Ling; Jia, Xiaojing

    2015-10-01

    Radiotherapy resistance remains a major obstacle for patients with breast cancer. miRNAs are important regulators in many biological processes including proliferation, apoptosis, invasion and metastasis and response to treatment in different types of tumors. Here, we describe the role of miRNA-144 in the regulation of radiotherapy sensitivity, migration and invasion of breast cancer cells. The cell survival rate of breast cancer cells was measured by WST-1 assay after irradiation. The caspase-3/-7 activity and apoptotic proteins were analyzed by Caspase-Glo3/7 assay and western blot analysis, respectively. The migration and invasion of breast cancer cells were evaluated by BD Transwell migration and Matrigel invasion assays. The EMT markers were detected by western blot analysis. We found that overexpression of miR-144 increased the proliferation rate of MDA-MB-231 cells without radiation. Both MDA-MB‑231 and SKBR3 cells exhibited significantly increased radiation resistance after overexpression of miR-144. Meanwhile, the migration and invasion of both MDA-MB-231 and SKBR3 cells were changed by altered miR-144 expression. In addition, the overexpression of miR-144 inhibited E-cadherin expression and promoted Snail expression. miR-144 activated AKT by downregulation of PTEN in breast cancer cells. Our results strongly suggest that miR-144 acts as an important regulator of tumorigenesis and tumor progression of breast cancer. These results indicate that miR-144 might serve as a potential molecular target for breast cancer treatment.

  1. TGF-β1 promotes the migration and invasion of bladder carcinoma cells by increasing fascin1 expression.

    PubMed

    Zhang, Naiwen; Bi, Xiaojun; Zeng, Yu; Zhu, Yuyan; Zhang, Zhe; Liu, Yang; Wang, Jianfeng; Li, Xuejie; Bi, Jianbin; Kong, Chuize

    2016-08-01

    Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine that is reported to regulate cellular motility and invasive capability during tumor progression. Fascin1, an actin-bundling protein, increases cell motility, migration and adhesion. To investigate the function of TGF-β1 and test whether fascin1 is an important mediator of the tumor response to TGF-β1 in bladder carcinoma cells, real-time RT-PCR and western blot analysis were used to test changes in fascin1 expression after TGF-β1 (10 ng/ml) treatment in T24 and BIU87 cells. Small interfering RNA (siRNA) technique was performed to silence fascin1. Cell viability and biological behavior changes were evaluated by cell growth (MTT), wound-healing and Matrigel invasion assays. In the present study, we found that the mRNA and protein levels of fascin1 in the T24 and BIU87 cells were significantly increased after 10 ng/ml TGF-β1 treatment (p<0.05). The proliferation of T24 cells (p=0.005) was also significantly increased, while no significant change was observed in BIU87 cells (p=0.318). In addition, the migratory and invasive potential of the two cell lines were promoted. Furthermore, we successfully silenced fascin1, and observed that fascin1 siRNA significantly attenuated the migration and invasiveness induced by TGF-β1. The findings suggested that TGF-β1 can promote invasion and migration of T24 and BIU87 bladder carcinoma cells, and the increase in fascin1 expression may be the key point of this impact of TGF-β1.

  2. Soluble THSD7A Is an N-Glycoprotein That Promotes Endothelial Cell Migration and Tube Formation in Angiogenesis

    PubMed Central

    Kuo, Meng-Wei; Wang, Chian-Huei; Wu, Hsiao-Chun; Chang, Shing-Jyh; Chuang, Yung-Jen

    2011-01-01

    Background Thrombospondin type I domain containing 7A (THSD7A) is a novel neural protein that is known to affect endothelial migration and vascular patterning during development. To further understand the role of THSD7A in angiogenesis, we investigated the post-translational modification scheme of THS7DA and to reveal the underlying mechanisms by which this protein regulates blood vessel growth. Methodology/Principal Findings Full-length THSD7A was overexpressed in human embryonic kidney 293T (HEK293T) cells and was found to be membrane associated and N-glycosylated. The soluble form of THSD7A, which is released into the cultured medium, was harvested for further angiogenic assays. We found that soluble THSD7A promotes human umbilical vein endothelial cell (HUVEC) migration and tube formation. HUVEC sprouts and zebrafish subintestinal vessel (SIV) angiogenic assays further revealed that soluble THSD7A increases the number of branching points of new vessels. Interestingly, we found that soluble THSD7A increased the formation of filopodia in HUVEC. The distribution patterns of vinculin and phosphorylated focal adhesion kinase (FAK) were also affected, which implies a role for THSD7A in focal adhesion assembly. Moreover, soluble THSD7A increased FAK phosphorylation in HUVEC, suggesting that THSD7A is involved in regulating cytoskeleton reorganization. Conclusions/Significance Taken together, our results indicate that THSD7A is a membrane-associated N-glycoprotein with a soluble form. Soluble THSD7A promotes endothelial cell migration during angiogenesis via a FAK-dependent mechanism and thus may be a novel neuroangiogenic factor. PMID:22194972

  3. Epigenetic silencing of ITGA2 by MiR-373 promotes cell migration in breast cancer.

    PubMed

    Ding, Wen; Fan, Xiao-Lu; Xu, Xuan; Huang, Jin-Zhou; Xu, Song-Hui; Geng, Qian; Li, Rong; Chen, De; Yan, Guang-Rong

    2015-01-01

    The loss of ITGA2 plays an important role in cancer metastasis in several solid cancers. However, the molecular mechanism of ITGA2 loss in primary cancers remains unclear. In this study, we found that a lower ITGA2 protein level was observed in breast cancers compared to adjacent non-cancerous breast tissues. Interestingly, the reduction degree of ITGA2 at the protein level was far more than that at the mRNA level. We further showed that the translation of ITGA2 mRNA was directly inhibited by miR-373 through binding to ITGA2-3'UTR. Silencing of ITGA2 detached cell-cell interactions, induced the deploymerization of stress fiber F-actin and stimulated cancer cell migration, similar to the effect of miR-373 over-expression. The co-expression of ITGA2, not ITGA2-3'UTR, could abrogate miR-373-induced cancer cell migration because that the expression of ITGA2-3'UTR was inhibited by co-transfected miR-373. ITGA2 protein level was inversely associated with miR-373 level in breast cancers (r = -0.663, P<0.001). 73.33% of breast cancer patients with high miR-373 and low ITGA2 expression exhibited the lymph node-positive metastases. Together, our results show that epigenetic silencing of ITGA2 by miR-373 stimulates breast cancer migration, and miR-373high/ITGA2low may be as a prognosis biomarker for breast cancer patients.

  4. MiR-200c promotes bladder cancer cell migration and invasion by directly targeting RECK

    PubMed Central

    Cheng, Yidong; Zhang, Xiaolei; Li, Peng; Yang, Chengdi; Tang, Jinyuan; Deng, Xiaheng; Yang, Xiao; Tao, Jun; Lu, Qiang; Li, Pengchao

    2016-01-01

    Background Increasing evidence suggests that the dysregulation of certain microRNAs plays an important role in tumorigenesis and metastasis. MiR-200c exhibits a disordered expression in many tumors and presents dual roles in bladder cancer (BC). Therefore, the definite role of miR-200c in BC needs to be investigated further. Materials and methods Quantitative reverse transcription polymerase chain reaction was used to assess miR-200c expression. Cell invasion and migration were evaluated using wound healing and transwell assays. The luciferase reporter assay was used to identify the direct target of miR-200c. The expression of reversion-inducing cysteine-rich protein with kazal motifs (RECK) in BC tissues and adjacent nontumor tissues, as well as in BC cell lines, was detected through quantitative reverse transcription polymerase chain reaction, Western blot assay, and immunohistochemistry. Results The miR-200c expression was significantly upregulated in the BC tissues compared with the adjacent nontumor tissues. The downregulation of miR-200c significantly inhibited cell migration and invasion in the BC cell lines. The luciferase reporter assay showed that RECK was a direct target of miR-200c. The knockdown of RECK in the BC cell lines treated with anti-miR-200c elevated the previously attenuated cell migration and invasion. Conclusion Our findings indicated that miR-200c functions as oncogenes in BC and may provide a novel therapeutic strategy for the treatment of BC. PMID:27574450

  5. Shootin1 acts in concert with KIF20B to promote polarization of migrating neurons.

    PubMed

    Sapir, Tamar; Levy, Talia; Sakakibara, Akira; Rabinkov, Aharon; Miyata, Takaki; Reiner, Orly

    2013-07-17

    Shootin1 has been ascribed a role in regulating polarization of primary hippocampal neurons. To better understand the possible role of Shootin1 in the developing brain, we identified a member of the kinesin superfamily, KIF20B, as a novel Shootin1 interacting protein and a potential mediator of Shootin1 interaction with microtubules. KIF20B/Shootin1 binding was mapped to a 57 aa KIF20B sequence, which was used as a dominant-negative fragment. Direct interaction between that peptide (MBD) and Shootin1 was confirmed by surface plasmon resonance-based technology and the affinity was determined in the 10⁻⁷ m range. The proteins are expressed in the developing brain and formed a complex in vivo based on coimmunoprecipitation experiments and coimmunostaining in primary neurons. In primary hippocampal neurons Kif20b knockdown reduced Shootin1 mobilization to the developing axon, as evidenced by immunostaining and fluorescence recovery after photobleaching analysis, suggesting that Shootin1 is a novel KIF20B cargo. shRNA targeting of Shootin1 reduced PIP3 accumulation in the growth cone, as did Kif20b shRNA. In the developing mouse brain, Kif20b knockdown or expression of the KIF20B minimal binding domain inhibited neuronal migration, and in vivo migration assays suggested that Shootin1/Kif20b acts in the same genetic pathway. Time-lapse imaging of multipolar cells in the subventricular zone revealed that downregulating levels of either Shootin1 or Kif20b hindered the transition from multipolar to bipolar cells. Collectively, our data demonstrate the importance of the Shootin1/KIF20B interaction to the dynamic process of pyramidal neuronal polarization and migration.

  6. Bmi-1 promotes the invasion and migration of colon cancer stem cells through the downregulation of E-cadherin.

    PubMed

    Zhang, Zefeng; Bu, Xiaoling; Chen, Hao; Wang, Qiyi; Sha, Weihong

    2016-10-01

    Metastasis and recurrence are the challenges of cancer therapy. Recently, mounting evidence has suggested that cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) are critical factors in tumor metastasis and recurrence. The oncogene, Bmi-1, promotes the development of hematologic malignancies and many solid tumors. The aim of the present study was to elucidate the mechanisms through which Bmi-1 promotes the invasion and migration of colon CSCs (CCSCs) using the HCT116 colon cancer cell line. Sphere formation medium and magnetic‑activated cell sorting were used to enrich and screen the CCSCs. CD133 and CD44 were regarded as markers of CCSCs and they were found to be co-expressed in the HCT116 colon cancer cell line. Colony formation assay, cell proliferation assay and viability assay using the Cell Counting Kit-8, and transplantation assay using nude mice injected with CCSCs were used to examine the CCSCs. The CD133+CD44+ HCT116 cells exhibited greater cloning efficiency, an enhanced proliferative ability, increased cell viability and stronger tumorigenicity; these cells were used as the CCSCs for subsequent experiments. In addition, the invasive and migratory abilities of the CD133+CD44+ HCT116 cells were markedly decreased when Bmi-1 was silenced by small interfering RNA (siRNA). The results of RT-qPCR and western blot analysis suggested that Bmi-1 had a negative effect on E-cadherin expression. On the whole, our findings suggest that Bmi-1 promotes the invasion and migration of CCSCs through the downregulation of E-cadherin, possibly by inducing EMT. Our findings thus indicate that Bmi-1 may be a novel therapeutic target for the treatment of colon cancer. PMID:27600678

  7. Bmi-1 promotes the invasion and migration of colon cancer stem cells through the downregulation of E-cadherin

    PubMed Central

    Zhang, Zefeng; Bu, Xiaoling; Chen, Hao; Wang, Qiyi; Sha, Weihong

    2016-01-01

    Metastasis and recurrence are the challenges of cancer therapy. Recently, mounting evidence has suggested that cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) are critical factors in tumor metastasis and recurrence. The oncogene, Bmi-1, promotes the development of hematologic malignancies and many solid tumors. The aim of the present study was to elucidate the mechanisms through which Bmi-1 promotes the invasion and migration of colon CSCs (CCSCs) using the HCT116 colon cancer cell line. Sphere formation medium and magnetic-activated cell sorting were used to enrich and screen the CCSCs. CD133 and CD44 were regarded as markers of CCSCs and they were found to be co-expressed in the HCT116 colon cancer cell line. Colony formation assay, cell proliferation assay and viability assay using the Cell Counting Kit-8, and transplantation assay using nude mice injected with CCSCs were used to examine the CCSCs. The CD133+CD44+ HCT116 cells exhibited greater cloning efficiency, an enhanced proliferative ability, increased cell viability and stronger tumorigenicity; these cells were used as the CCSCs for subsequent experiments. In addition, the invasive and migratory abilities of the CD133+CD44+ HCT116 cells were markedly decreased when Bmi-1 was silenced by small interfering RNA (siRNA). The results of RT-qPCR and western blot analysis suggested that Bmi-1 had a negative effect on E-cadherin expression. On the whole, our findings suggest that Bmi-1 promotes the invasion and migration of CCSCs through the downregulation of E-cadherin, possibly by inducing EMT. Our findings thus indicate that Bmi-1 may be a novel therapeutic target for the treatment of colon cancer. PMID:27600678

  8. Activated protein C promotes breast cancer cell migration through interactions with EPCR and PAR-1

    SciTech Connect

    Beaulieu, Lea M.; Church, Frank C. . E-mail: fchurch@email.unc.edu

    2007-02-15

    Activated protein C (APC) is a serine protease that regulates thrombin (IIa) production through inactivation of blood coagulation factors Va and VIIIa. APC also has non-hemostatic functions related to inflammation, proliferation, and apoptosis through various mechanisms. Using two breast cancer cell lines, MDA-MB-231 and MDA-MB-435, we investigated the role of APC in cell chemotaxis and invasion. Treatment of cells with increasing APC concentrations (1-50 {mu}g/ml) increased invasion and chemotaxis in a concentration-dependent manner. Only the active form of APC increased invasion and chemotaxis of the MDA-MB-231 cells when compared to 3 inactive APC derivatives. Using a modified 'checkerboard' analysis, APC was shown to only affect migration when plated with the cells; therefore, APC is not a chemoattractant. Blocking antibodies to endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR-1) attenuated the effects of APC on chemotaxis in the MDA-MB-231 cells. Finally, treatment of the MDA-MB-231 cells with the proliferation inhibitor, Na butyrate, showed that APC did not increase migration by increasing cell number. Therefore, APC increases invasion and chemotaxis of cells by binding to the cell surface and activating specific signaling pathways through EPCR and PAR-1.

  9. Acid-sensing ion channels promote the inflammation and migration of cultured rat microglia.

    PubMed

    Yu, Xiao-Wei; Hu, Zhuang-Li; Ni, Ming; Fang, Peng; Zhang, Pei-Wei; Shu, Qing; Fan, Hua; Zhou, Hai-Yun; Ni, Lan; Zhu, Ling-Qiang; Chen, Jian-Guo; Wang, Fang

    2015-03-01

    Microglia, the major immune cells in central nervous system, act as the surveillance and scavenger of immune defense and inflammatory response. Previous studies suggest that there might be close relationship between acid-sensing ion channels (ASICs) and inflammation, however, the exact role of ASICs in microglia during inflammation remains elusive. In the present study, we identified the existence of ASICs in the primary cultured rat microglia and explored their functions. By using reverse transcriptase polymerase chain reaction (RT-PCR), quantitative real-time PCR (qPCR), western blotting, and immunofluorescence experiments, we demonstrated that ASIC1, ASIC2a, and ASIC3 were existed in cultured and in situ rat microglia. After lipopolysaccharide (LPS) stimulation, the expressions of microglial ASIC1 and ASIC2a were upregulated. Meanwhile, ASIC-like currents and acid-induced elevation of intracellular calcium were increased, which could be inhibited by the nonspecific ASICs antagonist amiloride and specific homomeric ASIC1a blocker PcTx1. In addition, both inhibitors reduced the expression of inflammatory cytokines, including inducible nitric oxide synthase and cyclooxygenase 2 stimulated by LPS. Furthermore, we also observed significant increase in the expression of ASIC1 and ASIC2a in scrape-stimulated microglial migration. Amiloride and PcTx1 prevented the migration by inhibiting ERK phosphorylation. Taken together, these results suggest that ASICs participate in neuroinflammatory response, which will provide a novel therapeutic strategy for controlling the inflammation-relevant neuronal diseases.

  10. Vegfa signaling promotes zebrafish intestinal vasculature development through endothelial cell migration from the posterior cardinal vein.

    PubMed

    Koenig, Andrew L; Baltrunaite, Kristina; Bower, Neil I; Rossi, Andrea; Stainier, Didier Y R; Hogan, Benjamin M; Sumanas, Saulius

    2016-03-01

    The mechanisms underlying organ vascularization are not well understood. The zebrafish intestinal vasculature forms early, is easily imaged using transgenic lines and in-situ hybridization, and develops in a stereotypical pattern thus making it an excellent model for investigating mechanisms of organ specific vascularization. Here, we demonstrate that the sub-intestinal vein (SIV) and supra-intestinal artery (SIA) form by a novel mechanism from angioblasts that migrate out of the posterior cardinal vein and coalesce to form the intestinal vasculature in an anterior to posterior wave with the SIA forming after the SIV. We show that vascular endothelial growth factor aa (vegfaa) is expressed in the endoderm at the site where intestinal vessels form and therefore likely provides a guidance signal. Vegfa/Vegfr2 signaling is required for early intestinal vasculature development with mutation in vegfaa or loss of Vegfr2 homologs causing nearly complete inhibition of the formation of the intestinal vasculature. Vegfc and Vegfr3 function, however, are dispensable for intestinal vascularization. Interestingly, ubiquitous overexpression of Vegfc resulted in an overgrowth of the SIV, suggesting that Vegfc is sufficient to induce SIV development. These results argue that Vegfa signaling directs endothelial cells to migrate out of existing vasculature and coalesce to form the intestinal vessels. It is likely that a similar mechanism is utilized during vascularization of other organs.

  11. Galectin-3 regulates intracellular trafficking of epidermal growth factor receptor through Alix and promotes keratinocyte migration

    PubMed Central

    Liu, Wei; Hsu, Daniel K.; Chen, Huan-Yuan; Yang, Ri-Yao; Carraway, Kermit L.; Isseroff, Roslyn R.; Liu, Fu-Tong

    2012-01-01

    The epidermal growth factor receptor (EGFR)-mediated signaling pathways are important in a variety of cellular processes, including cell migration and wound re-epithelialization. Intracellular trafficking of EGFR is critical for maintaining EGFR surface expression. Galectin-3, a member of an animal lectin family, has been implicated in a number of physiological and pathological processes. Through studies of galectin-3-deficient mice and cells isolated from these mice, we demonstrated that absence of galectin-3 impairs keratinocyte migration and skin wound re-epithelialization. We have linked this pro-migratory function to a crucial role of cytosolic galectin-3 in controlling intracellular trafficking and cell surface expression of EGFR after EGF stimulation. Without galectin-3, the surface levels of EGFR are dramatically reduced and the receptor accumulates diffusely in the cytoplasm. This is associated with reduced rates of both endocytosis and recycling of the receptor. We have provided evidence that this novel function of galectin-3 may be mediated through interaction with its binding partner Alix, which is a protein component of the endosomal sorting complex required for transport (ESCRT) machinery. Our results suggest that galectin-3 is potentially a critical regulator of a number of important cellular responses through its intracellular control of trafficking of cell surface receptors. PMID:22785133

  12. Rebalancing brain drain: exploring resource reallocation to address health worker migration and promote global health.

    PubMed

    Mackey, Timothy Ken; Liang, Bryan Albert

    2012-09-01

    Global public health is threatened by an imbalance in health worker migration from resource-poor countries to developed countries. This "brain drain" results in health workforce shortages, health system weakening, and economic loss and waste, threatening the well-being of vulnerable populations and effectiveness of global health interventions. Current structural imbalances in resource allocation and global incentive structures have resulted in 57 countries identified by WHO as having a "critical shortage" of health workers. Yet current efforts to strengthen domestic health systems have fallen short in addressing this issue. Instead, global solutions should focus on sustainable forms of equitable resource sharing. This can be accomplished by adoption of mandatory global resource and staff-sharing programs in conjunction with implementation of state-based health services corps.

  13. The CXCL10/CXCR3 axis promotes cardiac microvascular endothelial cell migration via the p38/FAK pathway in a proliferation-independent manner.

    PubMed

    Xia, Jing-Bo; Mao, Cheng-Zhou; Chen, Zhuo-Ying; Liu, Guang-Hui; Wu, Hai-Yan; Zhou, Deng-Cheng; Park, Kyu-Sang; Zhao, Hui; Kim, Soo-Ki; Cai, Dong-Qing; Qi, Xu-Feng

    2016-04-01

    CXCL10 is a chemokine with potent chemotactic activity for immune and non-immune cells expressing its receptor CXCR3. Previous studies have demonstrated that CXCL10 is involved in myocardial infarction. However, the role of CXCL10 in cardiac microvascular endothelial cell (CMEC) regulation and related mechanisms remains unclear. In this study, we investigated the effects of CXCL10 on the CMEC migration and explored its potential molecular mechanism by wound healing, cell proliferation and viability analysis. Furthermore, migration-related signaling pathways, including FAK, Erk, p38 and Smad, were examined by Western blotting. We found that CXCL10 significantly promotes CMEC migration under normal conditions and during hypoxia/ischemia. However, no significant differences in CMEC proliferation and viability were observed with or without CXCL10 treatment. CXCL10-mediated CMEC migration was greatly blocked by treatment with an anti-CXCR3 antibody. Although CXCL10 treatment promoted phosphorylation and activation of the FAK, Erk, and p38 pathways during hypoxia/ischemia, CXCL10-mediated CMEC migration was significantly blocked by p38 and FAK inhibitors, but not by an Erk inhibitor. Furthermore, CXCL10-mediated FAK activation was suppressed by the p38 inhibitor. These findings indicated that the CXCL10/CXCR3 pathway promotes the migration of CMECs under normal conditions and during hypoxia/ischemia in a proliferation-independent manner, at least in part, through regulation of the p38/FAK pathways.

  14. High glucose promotes the migration of retinal pigment epithelial cells through increased oxidative stress and PEDF expression.

    PubMed

    Farnoodian, Mitra; Halbach, Caroline; Slinger, Cassidy; Pattnaik, Bikash R; Sorenson, Christine M; Sheibani, Nader

    2016-09-01

    Defects in the outer blood-retinal barrier have significant impact on the pathogenesis of diabetic retinopathy and macular edema. However, the detailed mechanisms involved remain largely unknown. This is, in part, attributed to the lack of suitable animal and cell culture models, including those of mouse origin. We recently reported a method for the culture of retinal pigment epithelial (RPE) cells from wild-type and transgenic mice. The RPE cells are responsible for maintaining the integrity of the outer blood-retinal barrier whose dysfunction during diabetes has a significant impact on vision. Here we determined the impact of high glucose on the function of RPE cells. We showed that high glucose conditions resulted in enhanced migration and increased the level of oxidative stress in RPE cells, but minimally impacted their rate of proliferation and apoptosis. High glucose also minimally affected the cell-matrix and cell-cell interactions of RPE cells. However, the expression of integrins and extracellular matrix proteins including pigment epithelium-derived factor (PEDF) were altered under high glucose conditions. Incubation of RPE cells with the antioxidant N-acetylcysteine under high glucose conditions restored normal migration and PEDF expression. These cells also exhibited increased nuclear localization of the antioxidant transcription factor Nrf2 and ZO-1, reduced levels of β-catenin and phagocytic activity, and minimal effect on production of vascular endothelial growth factor, inflammatory cytokines, and Akt, MAPK, and Src signaling pathways. Thus high glucose conditions promote RPE cell migration through increased oxidative stress and expression of PEDF without a significant effect on the rate of proliferation and apoptosis. PMID:27440660

  15. PREX2 promotes the proliferation, invasion and migration of pancreatic cancer cells by modulating the PI3K signaling pathway

    PubMed Central

    Yang, Jianyi; Gong, Xuejun; Ouyang, Lu; He, Wen; Xiao, Rou; Tan, Li

    2016-01-01

    Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchanger factor 2 (PREX2) is a novel regulator of the small guanosine triphosphatase Rac, and has been observed to be implicated in human cancer by inhibiting the activity of phosphatase and tensin homolog (PTEN), thus upregulating the activity of the phosphoinositide 3-kinase (PI3K) signaling pathway. However, the exact role of PREX2 in pancreatic cancer has not been reported to date. In the present study, the expression levels of PREX2 were observed to be frequently increased in pancreatic cancer specimens compared with those in their matched adjacent normal tissues. In addition, PREX2 expression was also frequently upregulated in several pancreatic cancer cell lines, including AsPC-1, BxPC-3, PANC-1 and CFAPC-1, compared with that in the normal pancreatic epithelial cell line HPC-Y5. Overexpression of PREX2 significantly promoted the proliferation, invasion and migration of pancreatic cancer PANC-1 cells, while small interfering RNA-induced knockdown of PREX2 expression significantly inhibited the proliferation, invasion and migration of these cells. Investigation of the molecular mechanism revealed that the overexpression of PREX2 upregulated the phosphorylation levels of PTEN, indicating that the activity of PTEN was reduced, which further increased the phosphorylation levels of AKT, which indicated that the activity of the PI3K signaling pathway was upregulated. By contrast, knockdown of PREX2 upregulated the activity of PTEN and inhibited the activity of the PI3K signaling pathway. In conclusion, the present study demonstrated that PREX2 regulates the proliferation, invasion and migration of pancreatic cancer cells, probably at least via modulation of the activity of PTEN and the PI3K signaling pathway. PMID:27446408

  16. Tenascin promotes cerebellar granule cell migration and neurite outgrowth by different domains in the fibronectin type III repeats

    PubMed Central

    1992-01-01

    The extracellular matrix molecule tenascin has been implicated in neuron-glia recognition in the developing central and peripheral nervous system and in regeneration. In this study, its role in Bergmann glial process-mediated neuronal migration was assayed in vitro using tissue explants of the early postnatal mouse cerebellar cortex. Of the five mAbs reacting with nonoverlapping epitopes on tenascin, mAbs J1/tn1, J1/tn4, and J1/tn5, but not mAbs J1/tn2 and J1/tn3 inhibited granule cell migration. Localization of the immunoreactive domains by EM of rotary shadowed tenascin molecules revealed that the mAbs J1/tn4 and J1/tn5, like the previously described J1/tn1 antibody, bound between the third and fifth fibronectin type III homologous repeats and mAb J1/tn3 bound between the third and fifth EGF-like repeats. mAb J1/tn2 had previously been found to react between fibronectin type III homologous repeats 10 and 11 of the mouse molecule (Lochter, A., L. Vaughan, A. Kaplony, A. Prochiantz, M. Schachner, and A. Faissner. 1991. J. Cell Biol. 113:1159-1171). When postnatal granule cell neurons were cultured on tenascin adsorbed to polyornithine, both the percentage of neurite-bearing cells and the length of outgrowing neurites were increased when compared to neurons growing on polyornithine alone. This neurite outgrowth promoting effect of tenascin was abolished only by mAb J1/tn2 or tenascin added to the culture medium in soluble form. The other antibodies did not modify the stimulatory or inhibitory effects of the molecule. These observations indicate that tenascin influences neurite outgrowth and migration of cerebellar granule cells by different domains in the fibronectin type III homologous repeats. PMID:1371773

  17. The promoting effect of pentadecapeptide BPC 157 on tendon healing involves tendon outgrowth, cell survival, and cell migration.

    PubMed

    Chang, Chung-Hsun; Tsai, Wen-Chung; Lin, Miao-Sui; Hsu, Ya-Hui; Pang, Jong-Hwei Su

    2011-03-01

    Pentadecapeptide BPC 157, composed of 15 amino acids, is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice. Experimentally it has been demonstrated to accelerate the healing of many different wounds, including transected rat Achilles tendon. This study was designed to investigate the potential mechanism of BPC 157 to enhance healing of injured tendon. The outgrowth of tendon fibroblasts from tendon explants cultured with or without BPC 157 was examined. Results showed that BPC 157 significantly accelerated the outgrowth of tendon explants. Cell proliferation of cultured tendon fibroblasts derived from rat Achilles tendon was not directly affected by BPC 157 as evaluated by MTT assay. However, the survival of BPC 157-treated cells was significantly increased under the H(2)O(2) stress. BPC 157 markedly increased the in vitro migration of tendon fibroblasts in a dose-dependent manner as revealed by transwell filter migration assay. BPC 157 also dose dependently accelerated the spreading of tendon fibroblasts on culture dishes. The F-actin formation as detected by FITC-phalloidin staining was induced in BPC 157-treated fibroblasts. The protein expression and activation of FAK and paxillin were determined by Western blot analysis, and the phosphorylation levels of both FAK and paxillin were dose dependently increased by BPC 157 while the total amounts of protein was unaltered. In conclusion, BPC 157 promotes the ex vivo outgrowth of tendon fibroblasts from tendon explants, cell survival under stress, and the in vitro migration of tendon fibroblasts, which is likely mediated by the activation of the FAK-paxillin pathway. PMID:21030672

  18. ITF promotes migration of intestinal epithelial cells through crosstalk between the ERK and JAK/STAT3 pathways

    PubMed Central

    Le, Juan; Zhang, Duan Y.; Zhao, Yong; Qiu, Wei; Wang, Peng; Sun, Yong

    2016-01-01

    Intestinal trefoil factor (ITF), a member of the trefoil factor family, is a “Super-protective factor” for intestinal mucosal protection. This study was designed to explore the mechanism by which ITF promotes intestinal epithelial cell migration. Intestinal epithelial cells were treated with the human ITF (hITF). Phospho-ERK, phospho-STAT3 Tyr705, and phospho-STAT3 Ser727 levels were detected at different time points by western blot. To assess the potential crosstalk between the ERK and JAK/STAT3 pathways, HT-29 cells were treated with the MEK-inhibitor, U0126, and phosphor-STAT3 levels were evaluated. Conversely, cells were treated with the JAK-inhibitor, AG490, and ERK-activity was evaluated. Transwell assay was performed to investigate the effect of the crosstalk on the cell motility. MMP-2 and MMP-9 transcription was analyzed by quantitative real-time PCR. E-cadherin degradation was detected by immunofluorescence. Our results indicate that hITF simultaneously activated the ERK and JAK/STAT3 pathways and a crosstalk was detected between the two pathways. hITF increased cell migration. This effect was abolished by U0126 and AG490 treatment. hITF increased MMP2 and MMP9 mRNA levels and E-cadherin degradation and U0126 and AG490 abolished this effect of hITF. In conclusion, the hITF-induced crosstalk between the ERK and JAK/STAT3 pathways is associated with intestinal epithelial cell migration. PMID:27616044

  19. Upregulation of the long noncoding RNA TUG1 promotes proliferation and migration of esophageal squamous cell carcinoma.

    PubMed

    Xu, Youtao; Wang, Jie; Qiu, Mantang; Xu, Lei; Li, Ming; Jiang, Feng; Yin, Rong; Xu, Lin

    2015-03-01

    Esophageal squamous cell carcinoma (ESCC) is one of the prevalent and deadly cancers worldwide, especially in Eastern Asia. The prognosis of ESCC remains poor; thus, it is still necessary to further dissect the underlying mechanisms and explore therapeutic targets of ESCC. Recent studies show that long noncoding RNAs (lncRNAs) have critical roles in diverse biological processes, including tumorigenesis. Some lncRNAs, such as HOTAIR and POU3F3, were reported to play important roles in ESCC. Here, we characterized the expression profile of taurine-upregulated gene 1 (TUG1), a lncRNA recruiting and binding to polycomb repressive complex 2 (PRC2), in ESCC. In a cohort of 62 patients, TUG1 was significantly overexpressed in ESCC tissues compared with paired adjacent normal tissues, and high expression level of TUG1 was associated with family history and upper segment of esophageal cancer (p < 0.05). Further, in vitro silencing TUG1 via siRNA inhibited the proliferation and migration of ESCC cells and blocked the progression of cell cycle. Therefore, our study indicates that TUG1 promotes proliferation and migration of ESCC cells and is a potential oncogene of ESCC.

  20. IGK with conserved IGKV/IGKJ repertoire is expressed in acute myeloid leukemia and promotes leukemic cell migration

    PubMed Central

    Sun, Xiaoping; He, Zhiqiao; Hu, Fanlei; Chen, Lei; Bueso-Ramos, Carlos E.

    2015-01-01

    We have previously reported that immunoglobulin heavy chain genes were expressed in myeloblasts and mature myeloid cells. In this study, we further demonstrated that rearranged Ig κ light chain was also frequently expressed in acute myeloid leukemia cell lines (6/6), primary myeloblasts from patients with acute myeloid leukemia (17/18), and mature monocytes (11/12) and neutrophils (3/12) from patients with non-hematopoietic neoplasms, but not or only rarely expressed in mature neutrophils (0/8) or monocytes (1/8) from healthy individuals. Interestingly, myeloblasts and mature monocytes/neutrophils shared several restricted IGKV and IGKJ gene usages but with different expression frequency. Surprisingly, almost all of the acute myeloid leukemia-derived IGKV showed somatic hypermutation; in contrast, mature myeloid cells-derived IGKV rarely had somatic hypermutation. More importantly, although IGK expression appeared not to affect cell proliferation, reduced IGK expression led to a decrease in cell migration in acute myeloid leukemia cell lines HL-60 and NB4, whereas increased IGK expression promoted their motility. In summary, IGK is expressed in myeloblasts and mature myeloid cells from patients with non-hematopoietic neoplasms, and is involved in cell migration. These results suggest that myeloid cells-derived IgK may have a role in leukemogenesis and may serve as a novel tumor marker for monitoring minimal residual disease and developing target therapy. PMID:26429876

  1. Notch activation mediates angiotensin II-induced vascular remodeling by promoting the proliferation and migration of vascular smooth muscle cells.

    PubMed

    Ozasa, Yukako; Akazawa, Hiroshi; Qin, Yingjie; Tateno, Kaoru; Ito, Kaoru; Kudo-Sakamoto, Yoko; Yano, Masamichi; Yabumoto, Chizuru; Naito, Atsuhiko T; Oka, Toru; Lee, Jong-Kook; Minamino, Tohru; Nagai, Toshio; Kobayashi, Yoshio; Komuro, Issei

    2013-10-01

    Notch signaling is involved in an intercellular communication mechanism that is essential for coordinated cell fate determination and tissue morphogenesis. The biological effects of Notch signaling are context-dependent. We investigated the functional and hierarchical relationship between angiotensin (Ang) II receptor signaling and Notch signaling in vascular smooth muscle cells (VSMCs). A fluorogenic substrate assay revealed directly that the enzymatic activity of γ-secretase was enhanced after 10 min of Ang II stimulation in HEK293 cells expressing Ang II type 1 receptor. Notch cleavage by γ-secretase was consistently induced and peaked at 10 min after Ang II stimulation, and the Ang II-stimulated increase in Notch intracellular domain production was significantly suppressed by treatment with the γ-secretase inhibitor DAPT. Treatment with DAPT also significantly reduced the Ang II-stimulated proliferation and migration of human aortic VSMCs, as revealed by BrdU incorporation and the Boyden chamber assay, respectively. Systemic administration of the γ-secretase inhibitor dibenzazepine reduced Ang II-induced medial thickening and perivascular fibrosis in the aortas of wild-type mice. These findings suggest that the hierarchical Ang II receptor-Notch signaling pathway promotes the proliferation and migration of VSMCs, and thereby contributes to the progression of vascular remodeling. PMID:23719127

  2. Androgen receptor (AR) promotes male bladder cancer cell proliferation and migration via regulating CD24 and VEGF.

    PubMed

    Ding, Guoqing; Yu, Shicheng; Cheng, Sheng; Li, Gonghui; Yu, Yanlan

    2016-01-01

    Increasing evidence has proved the pivotal roles of androgen receptor in various diseases, including prostate cancer and bladder cancer. The CD24 has been proved to be correlated to bladder cancer metastasis and tumorigenesis in recent study. This study was aimed to investigate the roles of AR in bladder cell proliferation and metastasis and to explore its potential mechanism. Expressions of AR in two kinds of bladder tumor cells (T24 and UM-UC-3) were analyzed using the CRISPR Activation Plasmid transfection or siRNA-mediated gene. The effects of AR on tumor cell proliferation and migration were also analyzed. Moreover, the effects of CD24 and influence of AR on cell proliferation and metastasis-related protein were also analyzed. The results showed that AR was significantly down-regulated in T24 cells but was significantly overexpressed in UM-UC-3 cells. The up-regulated T24 promotes cell proliferation, but this enhance effect was blocked by silencing CD24. Additionally, the AR overexpression significantly increased the VEGF and CD24 expression. Besides, the migrated bladder cells was increased by the up-regulated AR, but was decreased by silencing CD24 or silencing VEGF. Taken together, our study suggested that the up-regulated AR enhances the male bladder tumor cell proliferation and metastasis via modulating the CD24 and VEGF. This study may provide theoretical basis for the possibility of AR to be a therapeutic target for bladder cancer.

  3. Light-emitting conjugated polymers with microporous network architecture: interweaving scaffold promotes electronic conjugation, facilitates exciton migration, and improves luminescence.

    PubMed

    Xu, Yanhong; Chen, Long; Guo, Zhaoqi; Nagai, Atsushi; Jiang, Donglin

    2011-11-01

    Herein we report a strategy for the design of highly luminescent conjugated polymers by restricting rotation of the polymer building blocks through a microporous network architecture. We demonstrate this concept using tetraphenylethene (TPE) as a building block to construct a light-emitting conjugated microporous polymer. The interlocked network successfully restricted the rotation of the phenyl units, which are the major cause of fluorescence deactivation in TPE, thus providing intrinsic luminescence activity for the polymers. We show positive "CMP effects" that the network promotes π-conjugation, facilitates exciton migration, and improves luminescence activity. Although the monomer and linear polymer analogue in solvents are nonemissive, the network polymers are highly luminescent in various solvents and the solid state. Because emission losses due to rotation are ubiquitous among small chromophores, this strategy can be generalized for the de novo design of light-emitting materials by integrating the chromophores into an interlocked network architecture.

  4. Loss of p53 promotes RhoA-ROCK-dependent cell migration and invasion in 3D matrices.

    PubMed

    Gadea, Gilles; de Toledo, Marion; Anguille, Christelle; Roux, Pierre

    2007-07-01

    In addition to its role in controlling cell cycle progression, the tumor suppressor protein p53 can also affect other cellular functions such as cell migration. In this study, we show that p53 deficiency in mouse embryonic fibroblasts cultured in three-dimensional matrices induces a switch from an elongated spindle morphology to a markedly spherical and flexible one associated with highly dynamic membrane blebs. These rounded, motile cells exhibit amoeboid-like movement and have considerably increased invasive properties. The morphological transition requires the RhoA-ROCK (Rho-associated coil-containing protein kinase) pathway and is prevented by RhoE. A similar p53-mediated transition is observed in melanoma A375P cancer cells. Our data suggest that genetic alterations of p53 in tumors are sufficient to promote motility and invasion, thereby contributing to metastasis.

  5. Body protective compound-157 enhances alkali-burn wound healing in vivo and promotes proliferation, migration, and angiogenesis in vitro.

    PubMed

    Huang, Tonglie; Zhang, Kuo; Sun, Lijuan; Xue, Xiaochang; Zhang, Cun; Shu, Zhen; Mu, Nan; Gu, Jintao; Zhang, Wangqian; Wang, Yukun; Zhang, Yingqi; Zhang, Wei

    2015-01-01

    Chemical burns take up a high proportion of burns admissions and can penetrate deep into tissues. Various reagents have been applied in the treatment of skin chemical burns; however, no optimal reagent for skin chemical burns currently exists. The present study investigated the effect of topical body protective compound (BPC)-157 treatment on skin wound healing, using an alkali burn rat model. Topical treatment with BPC-157 was shown to accelerate wound closure following an alkali burn. Histological examination of skin sections with hematoxylin-eosin and Masson staining showed better granulation tissue formation, reepithelialization, dermal remodeling, and a higher extent of collagen deposition when compared to the model control group on the 18th day postwounding. BPC-157 could promote vascular endothelial growth factor expression in wounded skin tissues. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and cell cycle analysis demonstrated that BPC-157 enhanced the proliferation of human umbilical vein endothelial cells (HUVECs). Transwell assay and wound healing assay showed that BPC-157 significantly promoted migration of HUVECs. We also observed that BPC-157 upregulated the expression of VEGF-a and accelerated vascular tube formation in vitro. Moreover, further studies suggested that BPC-157 regulated the phosphorylation level of extracellular signal-regulated kinases 1 and 2 (ERK1/2) as well as its downstream targets, including c-Fos, c-Jun, and Egr-1, which are key molecules involved in cell growth, migration, and angiogenesis. Altogether, our results indicated that BPC-157 treatment may accelerate wound healing in a model of alkali burn-induced skin injury. The therapeutic mechanism may be associated with accelerated granulation tissue formation, reepithelialization, dermal remodeling, and collagen deposition through ERK1/2 signaling pathway. PMID:25995620

  6. Body protective compound-157 enhances alkali-burn wound healing in vivo and promotes proliferation, migration, and angiogenesis in vitro

    PubMed Central

    Huang, Tonglie; Zhang, Kuo; Sun, Lijuan; Xue, Xiaochang; Zhang, Cun; Shu, Zhen; Mu, Nan; Gu, Jintao; Zhang, Wangqian; Wang, Yukun; Zhang, Yingqi; Zhang, Wei

    2015-01-01

    Chemical burns take up a high proportion of burns admissions and can penetrate deep into tissues. Various reagents have been applied in the treatment of skin chemical burns; however, no optimal reagent for skin chemical burns currently exists. The present study investigated the effect of topical body protective compound (BPC)-157 treatment on skin wound healing, using an alkali burn rat model. Topical treatment with BPC-157 was shown to accelerate wound closure following an alkali burn. Histological examination of skin sections with hematoxylin–eosin and Masson staining showed better granulation tissue formation, reepithelialization, dermal remodeling, and a higher extent of collagen deposition when compared to the model control group on the 18th day postwounding. BPC-157 could promote vascular endothelial growth factor expression in wounded skin tissues. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and cell cycle analysis demonstrated that BPC-157 enhanced the proliferation of human umbilical vein endothelial cells (HUVECs). Transwell assay and wound healing assay showed that BPC-157 significantly promoted migration of HUVECs. We also observed that BPC-157 upregulated the expression of VEGF-a and accelerated vascular tube formation in vitro. Moreover, further studies suggested that BPC-157 regulated the phosphorylation level of extracellular signal-regulated kinases 1 and 2 (ERK1/2) as well as its downstream targets, including c-Fos, c-Jun, and Egr-1, which are key molecules involved in cell growth, migration, and angiogenesis. Altogether, our results indicated that BPC-157 treatment may accelerate wound healing in a model of alkali burn-induced skin injury. The therapeutic mechanism may be associated with accelerated granulation tissue formation, reepithelialization, dermal remodeling, and collagen deposition through ERK1/2 signaling pathway. PMID:25995620

  7. The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration.

    PubMed

    Mantuano, Elisabetta; Lam, Michael S; Shibayama, Masataka; Campana, W Marie; Gonias, Steven L

    2015-09-15

    NMDA receptors (NMDA-Rs) are ionotropic glutamate receptors, which associate with LDL-receptor-related protein-1 (LRP1) to trigger cell signaling in response to protein ligands in neurons. Here, we demonstrate for the first time that the NMDA-R is expressed by rat Schwann cells and functions independently and with LRP1 to regulate Schwann cell physiology. The NR1 (encoded by GRIN1) and NR2b (encoded by GRIN2B) NMDA-R subunits were expressed by cultured Schwann cells and upregulated in sciatic nerves following crush injury. The ability of LRP1 ligands to activate ERK1/2 (also known as MAPK3 and MAPK1, respectively) and promote Schwann cell migration required the NMDA-R. NR1 gene silencing compromised Schwann cell survival. Injection of the LRP1 ligands tissue-type plasminogen activator (tPA, also known as PLAT) or MMP9-PEX into crush-injured sciatic nerves activated ERK1/2 in Schwann cells in vivo, and the response was blocked by systemic treatment with the NMDA-R inhibitor MK801. tPA was unique among the LRP1 ligands examined because tPA activated cell signaling and promoted Schwann cell migration by interacting with the NMDA-R independently of LRP1, albeit with delayed kinetics. These results define the NMDA-R as a Schwann cell signaling receptor for protein ligands and a major regulator of Schwann cell physiology, which may be particularly important in peripheral nervous system (PNS) injury. PMID:26272917

  8. The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration

    PubMed Central

    Mantuano, Elisabetta; Lam, Michael S.; Shibayama, Masataka; Campana, W. Marie; Gonias, Steven L.

    2015-01-01

    ABSTRACT NMDA receptors (NMDA-Rs) are ionotropic glutamate receptors, which associate with LDL-receptor-related protein-1 (LRP1) to trigger cell signaling in response to protein ligands in neurons. Here, we demonstrate for the first time that the NMDA-R is expressed by rat Schwann cells and functions independently and with LRP1 to regulate Schwann cell physiology. The NR1 (encoded by GRIN1) and NR2b (encoded by GRIN2B) NMDA-R subunits were expressed by cultured Schwann cells and upregulated in sciatic nerves following crush injury. The ability of LRP1 ligands to activate ERK1/2 (also known as MAPK3 and MAPK1, respectively) and promote Schwann cell migration required the NMDA-R. NR1 gene silencing compromised Schwann cell survival. Injection of the LRP1 ligands tissue-type plasminogen activator (tPA, also known as PLAT) or MMP9-PEX into crush-injured sciatic nerves activated ERK1/2 in Schwann cells in vivo, and the response was blocked by systemic treatment with the NMDA-R inhibitor MK801. tPA was unique among the LRP1 ligands examined because tPA activated cell signaling and promoted Schwann cell migration by interacting with the NMDA-R independently of LRP1, albeit with delayed kinetics. These results define the NMDA-R as a Schwann cell signaling receptor for protein ligands and a major regulator of Schwann cell physiology, which may be particularly important in peripheral nervous system (PNS) injury. PMID:26272917

  9. The Proprotein Convertase Furin Contributes to Rhabdomyosarcoma Malignancy by Promoting Vascularization, Migration and Invasion.

    PubMed

    Jaaks, Patricia; D'Alessandro, Valentina; Grob, Nicole; Büel, Sina; Hajdin, Katarina; Schäfer, Beat W; Bernasconi, Michele

    2016-01-01

    The proprotein convertase (PC) furin cleaves precursor proteins, an important step in the activation of many cancer-associated proteins. Substrates of furin and furin-like PCs play a role in proliferation, metastasis and invasion. Some of them are involved in the progression of the pediatric soft tissue sarcoma rhabdomyosarcoma (RMS). In this study, we show that PCs, and in particular furin, are expressed in RMS cell lines. To investigate the functional role of furin, we generated RMS cell lines with modulated furin activity. Silencing or stable inhibition of furin delayed tumor growth in Rh30 and RD xenografts in vivo, and was correlated with lower microvessel density. Reduced furin activity also decreased migration and invasion abilities in vitro, and inhibition of furin in RMS cells diminished processing of IGF1R, VEGF-C, PDGF-B and MT1-MMP, leading to lower levels of mature proteins. Furthermore, we found that furin activity is required for proper IGF signaling in RMS cells, as furin silencing resulted in reduced phosphorylation of Akt upon IGF1 stimulation. Taken together, our results suggest that furin plays an important role in the malignant phenotype of RMS cells by activating proteins involved in tumor growth and vascularization, metastasis and invasion. PMID:27548722

  10. TNFα promotes CAR-dependent migration of leukocytes across epithelial monolayers

    PubMed Central

    Morton, Penny E.; Hicks, Alexander; Ortiz-Zapater, Elena; Raghavan, Swetavalli; Pike, Rosemary; Noble, Alistair; Woodfin, Abigail; Jenkins, Gisli; Rayner, Emma; Santis, George; Parsons, Maddy

    2016-01-01

    Trans-epithelial migration (TEpM) of leukocytes during inflammation requires engagement with receptors expressed on the basolateral surface of the epithelium. One such receptor is Coxsackie and Adenovirus Receptor (CAR) that binds to Junctional Adhesion Molecule-like (JAM-L) expressed on leukocytes. Here we provide the first evidence that efficient TEpM of monocyte-derived THP-1 cells requires and is controlled by phosphorylation of CAR. We show that TNFα acts in a paracrine manner on epithelial cells via a TNFR1-PI3K-PKCδ pathway leading to CAR phosphorylation and subsequent transmigration across cell junctions. Moreover, we show that CAR is hyper-phosphorylated in vivo in acute and chronic lung inflammation models and this response is required to facilitate immune cell recruitment. This represents a novel mechanism of feedback between leukocytes and epithelial cells during TEpM and may be important in controlling responses to pro-inflammatory cytokines in pathological settings. PMID:27193388

  11. The widely expressed extracellular matrix protein SMOC-2 promotes keratinocyte attachment and migration

    SciTech Connect

    Maier, Silke; Paulsson, Mats; Hartmann, Ursula

    2008-08-01

    SMOC-2 is a recently discovered member of the BM-40/SPARC/osteonectin family of extracellular multidomain proteins of so far unknown function. While we have shown earlier that the homologous protein SMOC-1 is associated with basement membranes, in this study we demonstrate that, in the mouse, SMOC-2 could be detected in a large number of non-basement membrane localizations, often showing a diffuse tissue distribution. A more distinct expression pattern was seen in skin where SMOC-2 is mainly present in the basal layers of the epidermis. Functionally, recombinant SMOC-2 stimulated attachment of primary epidermal cells as well as several epidermal-derived cell lines but had no effect on the attachment of non-epidermal cells. Inhibition experiments using blocking antibodies against individual integrin subunits allowed the identification of {alpha}v{beta}6 and {alpha}v{beta}1 integrins as important cellular receptors for SMOC-2. Cell attachment as well as the formation of focal adhesions could be attributed to the extracellular calcium-binding domain. The calcium-binding domain also stimulated migration, but not proliferation of keratinocyte-like HaCaT cells. We conclude that SMOC-2, like other members of the BM40/SPARC family, acts as a regulator of cell-matrix interactions.

  12. The Proprotein Convertase Furin Contributes to Rhabdomyosarcoma Malignancy by Promoting Vascularization, Migration and Invasion

    PubMed Central

    Jaaks, Patricia; D’Alessandro, Valentina; Grob, Nicole; Büel, Sina; Hajdin, Katarina; Schäfer, Beat W.; Bernasconi, Michele

    2016-01-01

    The proprotein convertase (PC) furin cleaves precursor proteins, an important step in the activation of many cancer-associated proteins. Substrates of furin and furin-like PCs play a role in proliferation, metastasis and invasion. Some of them are involved in the progression of the pediatric soft tissue sarcoma rhabdomyosarcoma (RMS). In this study, we show that PCs, and in particular furin, are expressed in RMS cell lines. To investigate the functional role of furin, we generated RMS cell lines with modulated furin activity. Silencing or stable inhibition of furin delayed tumor growth in Rh30 and RD xenografts in vivo, and was correlated with lower microvessel density. Reduced furin activity also decreased migration and invasion abilities in vitro, and inhibition of furin in RMS cells diminished processing of IGF1R, VEGF-C, PDGF-B and MT1-MMP, leading to lower levels of mature proteins. Furthermore, we found that furin activity is required for proper IGF signaling in RMS cells, as furin silencing resulted in reduced phosphorylation of Akt upon IGF1 stimulation. Taken together, our results suggest that furin plays an important role in the malignant phenotype of RMS cells by activating proteins involved in tumor growth and vascularization, metastasis and invasion. PMID:27548722

  13. TNFα promotes CAR-dependent migration of leukocytes across epithelial monolayers.

    PubMed

    Morton, Penny E; Hicks, Alexander; Ortiz-Zapater, Elena; Raghavan, Swetavalli; Pike, Rosemary; Noble, Alistair; Woodfin, Abigail; Jenkins, Gisli; Rayner, Emma; Santis, George; Parsons, Maddy

    2016-01-01

    Trans-epithelial migration (TEpM) of leukocytes during inflammation requires engagement with receptors expressed on the basolateral surface of the epithelium. One such receptor is Coxsackie and Adenovirus Receptor (CAR) that binds to Junctional Adhesion Molecule-like (JAM-L) expressed on leukocytes. Here we provide the first evidence that efficient TEpM of monocyte-derived THP-1 cells requires and is controlled by phosphorylation of CAR. We show that TNFα acts in a paracrine manner on epithelial cells via a TNFR1-PI3K-PKCδ pathway leading to CAR phosphorylation and subsequent transmigration across cell junctions. Moreover, we show that CAR is hyper-phosphorylated in vivo in acute and chronic lung inflammation models and this response is required to facilitate immune cell recruitment. This represents a novel mechanism of feedback between leukocytes and epithelial cells during TEpM and may be important in controlling responses to pro-inflammatory cytokines in pathological settings. PMID:27193388

  14. S100A8 promotes migration and infiltration of inflammatory cells in acute anterior uveitis

    PubMed Central

    Wang, Yuqin; Zhang, Zuhui; Zhang, Laihe; Li, Xinxin; Lu, Rui; Xu, Peipei; Zhang, Xuhong; Dai, Mali; Dai, Xiaodan; Qu, Jia; Lu, Fan; Chi, Zailong

    2016-01-01

    Uveitis, the pathologic condition of inflammation of the uvea, frequently leads to severe vision loss and blindness. S100A8 is a calcium-binding protein which mainly expresses in granulocytes and monocytes and plays a prominent role in the regulation of inflammatory processes and immune response. Here, we determined the role of S100A8-positive cells in acute anterior uveitis (AAU) and keratitis. In rat models of endotoxin (lipopolisaccharide, LPS) -induced uveitis (EIU) and keratitis, S100A8-positive granulocytes and monocytes increased significantly in the iris-ciliary body and cornea as well as in the blood. Interestingly, Glucocorticoids slightly increased S100A8 levels in leukocytes, but reduced its presence significantly in the iris-ciliary body after LPS injection. Moreover, inhibition of NF-kB activation remarkably suppressed both progression of AAU and total S100A8 levels in leukocytes and the iris-ciliary body after LPS administration. Additionally, S100A8 protein level was also found to be elevated in the serum of AAU patients parallel with the progression of AAU through the designated clinical stages. Thus, S100A8 plays a pivotal role in the processes of AAU through involvement in migration and infiltration of S100A8-positive cells. Our findings suggest that serum levels of S100A8 protein can be used to monitor inflammatory activity in AAU. PMID:27786310

  15. A novel signaling pathway of tissue kallikrein in promoting keratinocyte migration: Activation of proteinase-activated receptor 1 and epidermal growth factor receptor

    SciTech Connect

    Gao, Lin; Chao, Lee; Chao, Julie

    2010-02-01

    Biological functions of tissue kallikrein (TK, KLK1) are mainly mediated by kinin generation and subsequent kinin B2 receptor activation. In this study, we investigated the potential role of TK and its signaling pathways in cultured human keratinocyte migration and in a rat skin wound healing model. Herein, we show that TK promoted cell migration and proliferation in a concentration- and time-dependent manner. Inactive TK or kinin had no significant effect on cell migration. Interestingly, cell migration induced by active TK was not blocked by icatibant or L-NAME, indicating an event independent of kinin B2 receptor and nitric oxide formation. TK's stimulatory effect on cell migration was inhibited by small interfering RNA for proteinase-activated receptor 1 (PAR{sub 1}), and by PAR{sub 1} inhibitor. TK-induced migration was associated with increased phosphorylation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK), which was blocked by inhibition of protein kinase C (PKC), Src, EGFR and ERK. TK-induced cell migration and EGFR phosphorylation were blocked by metalloproteinase (MMP) inhibitor, heparin, and antibodies against EGFR external domain, heparin-binding EGF-like growth factor (HB-EGF) and amphiregulin (AR). Local application of TK promoted skin wound healing in rats, whereas icatibant and EGFR inhibitor blocked TK's effect. Skin wound healing was further delayed by aprotinin and neutralizing TK antibody. This study demonstrates a novel role of TK in skin wound healing and uncovers new signaling pathways mediated by TK in promoting keratinocyte migration through activation of the PAR{sub 1}-PKC-Src-MMP pathway and HB-EGF/AR shedding-dependent EGFR transactivation.

  16. HB-EGF-Promoted Airway Smooth Muscle Cells and Their Progenitor Migration Contribute to Airway Smooth Muscle Remodeling in Asthmatic Mouse.

    PubMed

    Wang, Qing; Li, Hequan; Yao, Yinan; Lu, Guohua; Wang, Yuehong; Xia, Dajing; Zhou, Jianying

    2016-03-01

    The airway smooth muscle (ASM) cells' proliferation, migration, and their progenitor's migration are currently regarded as causative factors for ASM remodeling in asthma. Heparin-binding epidermal growth factor (HB-EGF), a potent mitogen and chemotactic factor, could promote ASM cell proliferation through MAPK pathways. In this study, we obtained primary ASM cells and their progenitors from C57BL/6 mice and went on to explore the role of HB-EGF in these cells migration and the underlying mechanisms. We found that recombinant HB-EGF (rHB-EGF) intratracheal instillation accelerated ASM layer thickening in an OVA-induced asthmatic mouse. Modified Boyden chamber assay revealed that rHB-EGF facilitate ASM cell migration in a dose-dependent manner and ASM cells from asthmatic mice had a greater migration ability than that from normal counterparts. rHB-EGF could stimulate the phosphorylation of ERK1/2 and p38 in ASM cells but further migration assay showed that only epidermal growth factor receptor inhibitor (AG1478) or p38 inhibitor (SB203580), but not ERK1/2 inhibitor (PD98059), could inhibit rHB-EGF-mediated ASM cells migration. Actin cytoskeleton experiments exhibited that rHB-EGF could cause actin stress fibers disassembly and focal adhesions formation of ASM cells through the activation of p38. Finally, airway instillation of rHB-EGF promoted the recruitment of bone marrow-derived smooth muscle progenitor cells, which were transferred via caudal vein, migrating into the airway from the circulation. These observations demonstrated that ASM remodeling in asthma might have resulted from HB-EGF-mediated ASM cells and their progenitor cells migration, via p38 MAPK-dependent actin cytoskeleton remodeling.

  17. BCAT1 promotes tumor cell migration and invasion in hepatocellular carcinoma

    PubMed Central

    Xu, Meng; Liu, Qingquan; Jia, Yuli; Tu, Kangsheng; Yao, Yingmin; Liu, Qingguang; Guo, Cheng

    2016-01-01

    Branched-chain amino acid transaminase 1 (BCAT1) has been associated with numerous types of tumors; however, few previous studies have evaluated the expression and role of BCAT1 in hepatocellular carcinoma (HCC). In the present study, the expression of BCAT1 was detected by reverse transcription-quantitative polymerase chain reaction and immunoblotting in six HCC cell lines and 74 pairs of HCC and adjacent non-cancerous liver tissues. In addition, the correlation between the expression levels of c-Myc and BCAT1 was analyzed using immunohistochemistry. Furthermore, RNA silencing was performed using c-Myc-specific or BCAT1-specific small interfering RNA, after which wound healing and Transwell cell invasion assays were performed. Finally, the clinicopathological characteristics of BCAT1 in patients with HCC were analyzed. It was shown that the expression of BCAT1 was significantly higher in HCC tissues compared with adjacent non-tumor tissues (P<0.001), and in HCC cell lines compared within the L-02 hepatic cell line (P<0.001). In addition, immunohistochemical analyses indicated that the expression of BCAT1 was positively correlated with c-Myc (r=0.706, P<0.001). BCAT1 expression was shown to be downregulated in c-Myc-knockdown cells, and silencing of BCAT1 expression reduced the invasion and migration of HCC cells. Furthermore, a clinical analysis indicated that BCAT1 expression in HCC tissues was significantly associated with the tumor-node-metastasis stage, tumor number and tumor differentiation (all P<0.05), and that BCAT1 was able to predict the 5-year survival and disease-free survival rates of patients with HCC (both P<0.001). The results of the present study suggested that BCAT1 expression is upregulated in patients with HCC, and that BCAT1 may serve as a potential molecular target for the diagnosis and treatment of HCC.

  18. TNF-{alpha} promotes human retinal pigment epithelial (RPE) cell migration by inducing matrix metallopeptidase 9 (MMP-9) expression through activation of Akt/mTORC1 signaling

    SciTech Connect

    Wang, Cheng-hu; Cao, Guo-Fan; Jiang, Qin; Yao, Jin

    2012-08-17

    Highlights: Black-Right-Pointing-Pointer TNF-{alpha} induces MMP-9 expression and secretion to promote RPE cell migration. Black-Right-Pointing-Pointer MAPK activation is not critical for TNF-{alpha}-induced MMP-9 expression. Black-Right-Pointing-Pointer Akt and mTORC1 signaling mediate TNF-{alpha}-induced MMP-9 expression. Black-Right-Pointing-Pointer SIN1 knockdown showed no significant effect on MMP-9 expression by TNF-{alpha}. -- Abstract: Tumor necrosis factor-alpha (TNF-{alpha}) promotes in vitro retinal pigment epithelial (RPE) cell migration to initiate proliferative vitreoretinopathy (PVR). Here we report that TNF-{alpha} promotes human RPE cell migration by inducing matrix metallopeptidase 9 (MMP-9) expression. Inhibition of MMP-9 by its inhibitor or its neutralizing antibody inhibited TNF-{alpha}-induced in vitro RPE cell migration. Reversely, exogenously-added active MMP-9 promoted RPE cell migration. Suppression Akt/mTOR complex 1(mTORC1) activation by LY 294002 and rapamycin inhibited TNF-{alpha}-mediated MMP-9 expression. To introduce a constitutively active Akt (CA-Akt) in cultured RPE cells increased MMP-9 expression, and to block mTORC1 activation by rapamycin inhibited its effect. RNA interference (RNAi)-mediated silencing of SIN1, a key component of mTOR complex 2 (mTORC2), had no effect on MMP-9 expression or secretion. In conclusion, this study suggest that TNF-{alpha} promotes RPE cell migration by inducing MMP-9 expression through activation of Akt/ mTORC1, but not mTORC2 signaling.

  19. Macrophage Migration Inhibitory Factor promotes tumor growth and metastasis by inducing Myeloid Derived Suppressor Cells in the tumor microenvironment

    PubMed Central

    Simpson, Kendra D.; Templeton, Dennis J.; Cross, Janet V.

    2012-01-01

    The Macrophage Migration Inhibitory Factor (MIF), an inflammatory cytokine, is overexpressed in many solid tumors and is associated with poor prognosis. We previously identified inhibitors of MIF within a class of natural products with demonstrated anti-cancer activities. We therefore sought to determine how MIF contributes to tumor growth and progression. We show here that, in murine tumors including the 4T1 model of aggressive, spontaneously metastatic breast cancer in immunologically intact mice, tumor-derived MIF promotes tumor growth and pulmonary metastasis through control of inflammatory cells within the tumor. Specifically, MIF increases the prevalence of a highly immune suppressive subpopulation of myeloid derived suppressor cells (MDSCs) within the tumor. In vitro, MIF promotes differentiation of myeloid cells into the same population of MDSCs. Pharmacologic inhibition of MIF reduces MDSC accumulation in the tumor similar to MIF depletion, and blocks the MIF-dependent in vitro differentiation of MDSCs. Our results demonstrate that MIF is a therapeutically targetable mechanism for control of tumor growth and metastasis through regulation of the host immune response, and support the potential utility of MIF inhibitors, either alone or in combination with standard tumor-targeting therapeutic or immunotherapy approaches. PMID:23125418

  20. Merkel Cell Polyomavirus Small T Antigen Mediates Microtubule Destabilization To Promote Cell Motility and Migration

    PubMed Central

    Knight, Laura M.; Stakaityte, Gabriele; Wood, Jennifer, J.; Abdul-Sada, Hussein; Griffiths, David A.; Howell, Gareth J.; Wheat, Rachel; Blair, G. Eric; Steven, Neil M.; Macdonald, Andrew; Blackbourn, David J.

    2014-01-01

    ABSTRACT Merkel cell carcinoma (MCC) is an aggressive skin cancer of neuroendocrine origin with a high propensity for recurrence and metastasis. Merkel cell polyomavirus (MCPyV) causes the majority of MCC cases due to the expression of the MCPyV small and large tumor antigens (ST and LT, respectively). Although a number of molecular mechanisms have been attributed to MCPyV tumor antigen-mediated cellular transformation or replication, to date, no studies have investigated any potential link between MCPyV T antigen expression and the highly metastatic nature of MCC. Here we use a quantitative proteomic approach to show that MCPyV ST promotes differential expression of cellular proteins implicated in microtubule-associated cytoskeletal organization and dynamics. Intriguingly, we demonstrate that MCPyV ST expression promotes microtubule destabilization, leading to a motile and migratory phenotype. We further highlight the essential role of the microtubule-associated protein stathmin in MCPyV ST-mediated microtubule destabilization and cell motility and implicate the cellular phosphatase catalytic subunit protein phosphatase 4C (PP4C) in the regulation of this process. These findings suggest a possible molecular mechanism for the highly metastatic phenotype associated with MCC. IMPORTANCE Merkel cell polyomavirus (MCPyV) causes the majority of cases of Merkel cell carcinoma (MCC), an aggressive skin cancer with a high metastatic potential. However, the molecular mechanisms leading to virally induced cancer development have yet to be fully elucidated. In particular, no studies have investigated any potential link between the virus and the highly metastatic nature of MCC. We demonstrate that the MCPyV small tumor antigen (ST) promotes the destabilization of the host cell microtubule network, which leads to a more motile and migratory cell phenotype. We further show that MCPyV ST induces this process by regulating the phosphorylation status of the cellular microtubule

  1. Increased cellular apoptosis susceptibility (CSE1L/CAS) protein expression promotes protrusion extension and enhances migration of MCF-7 breast cancer cells

    SciTech Connect

    Tai, Cheng-Jeng; Shen, Shing-Chuan; Lee, Woan-Ruoh; Liao, Ching-Fong; Deng, Win-Ping; Chiou, Hung-Yi; Hsieh, Cheng-I; Tung, Jai-Nien; Chen, Ching-Shyang; Chiou, Jeng-Fong; Li, Li-Tzu; Lin, Chuang-Yu; Hsu, Chung-Huei; Jiang, Ming-Chung

    2010-10-15

    Microtubules are part of cell structures that play a role in regulating the migration of cancer cells. The cellular apoptosis susceptibility (CSE1L/CAS) protein is a microtubule-associated protein that is highly expressed in cancer. We report here that CSE1L regulates the association of {alpha}-tubulin with {beta}-tubulin and promotes the migration of MCF-7 breast cancer cells. CSE1L was associated with {alpha}-tubulin and {beta}-tubulin in GST (glutathione S-transferase) pull-down and immunoprecipitation assays. CSE1L-GFP (green fluorescence protein) fusion protein experiments showed that the N-terminal of CSE1L interacted with microtubules. Increased CSE1L expression resulted in decreased tyrosine phosphorylation of {alpha}-tubulin and {beta}-tubulin, increased {alpha}-tubulin and {beta}-tubulin association, and enhanced assembly of microtubules. Cell protrusions or pseudopodia are temporary extensions of the plasma membrane and are implicated in cancer cell migration and invasion. Increased CSE1L expression increased the extension of MCF-7 cell protrusions. In vitro migration assay showed that enhanced CSE1L expression increased the migration of MCF-7 cells. Our results indicate that CSE1L plays a role in regulating the extension of cell protrusions and promotes the migration of cancer cells.

  2. miR-148b-3p promotes migration of Schwann cells by targeting cullin-associated and neddylation-dissociated 1

    PubMed Central

    Qian, Tian-mei; Zhao, Li-li; Wang, Jing; Li, Ping; Qin, Jing; Liu, Yi-sheng; Yu, Bin; Ding, Fei; Gu, Xiao-song; Zhou, Song-lin

    2016-01-01

    MicroRNAs (miRNAs) are small, non-coding RNAs that negatively adjust gene expression in multifarious biological processes. However, the regulatory effects of miRNAs on Schwann cells remain poorly understood. Previous microarray analysis results have shown that miRNA expression is altered following sciatic nerve transaction, thereby affecting proliferation and migration of Schwann cells. This study investigated whether miR-148b-3p could regulate migration of Schwann cells by directly targeting cullin-associated and neddylation-dissociated 1 (Cand1). Up-regulated expression of miR-148b-3p promoted Schwann cell migration, whereas silencing of miR-148b-3p inhibited Schwann cell migration in vitro. Further experiments confirmed that Cand1 was a direct target of miR-148b-3p, and Cand1 knockdown reversed suppression of the miR-148b-3p inhibitor on Schwann cell migration. These results suggested that miR-148b-3p promoted migration of Schwann cells by directly targeting Cand1 in vitro. PMID:27482232

  3. Hypoxia-Induced Upregulation of miR-132 Promotes Schwann Cell Migration After Sciatic Nerve Injury by Targeting PRKAG3.

    PubMed

    Yao, Chun; Shi, Xiangxiang; Zhang, Zhanhu; Zhou, Songlin; Qian, Tianmei; Wang, Yaxian; Ding, Fei; Gu, Xiaosong; Yu, Bin

    2016-10-01

    Following peripheral nerve injury, hypoxia is formed as a result of defects in blood supply at the injury site. Despite accumulating evidence on the effects of microRNAs (miRNAs) on phenotype modulation of Schwann cells (SCs) after peripheral nerve injury, the impact of hypoxia on SC behaviors through miRNAs during peripheral nerve regeneration has not been estimated. In this study, we confirmed our previous microarray data on the upregulation of miR-132 after sciatic nerve injury in rats and observed that overexpression of miR-132 significantly promoted cell migration of primary cultured SCs. Interestingly, hypoxia-increased expression of miR-132 also enhanced SC migration while inhibition of miR-132 suppressed hypoxia-induced increase in SC migration. miR-132 downregulated PRKAG3 through binding to its 3'-UTR, and PRKAG3 knockdown compromised the reducing effect of miR-132 inhibition on SC migration under normal or hypoxia condition. Moreover, in vivo injection of miR-132 agomir into rats with sciatic nerve transection accelerated SC migration from the proximal to distal stump. Overall, our results suggest that the hypoxia-induced upregulation of miR-132 could promote SC migration and facilitate peripheral nerve regeneration.

  4. TLR4 induces CREB-mediated IL-6 production via upregulation of F-spondin to promote vascular smooth muscle cell migration.

    PubMed

    Lee, Guan-Lin; Wu, Jing-Yiing; Yeh, Chang-Ching; Kuo, Cheng-Chin

    2016-05-13

    Toll-like receptor 4 (TLR4) is important in promoting inflammation and vascular smooth muscle cell (VSMC) migration, both of which contribute to atherosclerosis development and progression. But the mechanism underlying the regulation of TLR4 in VSMC migration remains unclear. Stimulation of VSMCs with LPS increased the cellular level of F-spondin which is associated with the regulation of proinflammatory cytokine production. The LPS-induced F-spondin expression depended on TLR4-mediated PI3K/Akt pathway. Suppression of F-spondin level by siRNA inhibited not only F-spondin expression but also LPS-induced phosphorylation of cAMP response element binding protein (CREB) and IL-6 expression, VSMC migration and proliferation as well as MMP9 expression. Moreover, suppression of CREB level by siRNA inhibited TLR4-induced IL-6 production and VSMC migration. Inhibition of F-spondin siRNA on LPS-induced migration was restored by addition of exogenous recombinant mouse IL-6. We conclude that upon ligand binding, TLR4 activates PI3K/Akt signaling to induce F-spondin expression, subsequently control CREB-mediated IL-6 production to promote VSMC migration. These findings provide vital insights into the essential role of F-spondin in VSMC function and will be valuable for developing new therapeutic strategies against atherosclerosis.

  5. E6/E7 oncoproteins of high risk HPV-16 upregulate MT1-MMP, MMP-2 and MMP-9 and promote the migration of cervical cancer cells

    PubMed Central

    Zhu, Dingjun; Ye, Mei; Zhang, Wei

    2015-01-01

    Background: E6 and E7 of high risk human papillomavirus 16 (HPV16) were reported to correlate with the cervical cancer (CC). And the presence of matrix metalloproteinases (MMPs) has also been indicated to be associated with CC. Methods: The present study investigated the expression of MMPs (MT1-MMP, MMP-2 and MMP-9) in CC cells with HPV16-E6/E7 oncoprotein(s) negative or positive, and then determined the regulation of HPV16-E6/E7 oncoproteins on the expression of MMPs (MT1-MMP, MMP-2 and MMP-9) and the migration of cervical cancer Caski and SiHa cells with RNAi technology. Results: It was demonstrated that the overexpression or the knockdown of HPV16-E6/E7 promoted or reduced MT1-MMP, MMP-2 and MMP-9 in CC cells. And the HPV16-E6, -E7 or -E6E7 influenced the migration of CC cells. The overexpression or the knockdown of them promoted or inhibited the migration of C33A or Caski/SiHa cells. Moreover, the chemical inhibition of MMP-2 or MMP-9 significantly reduced the migration of CC Caski or SiHa cells. Conclusions: Our results demonstrated that the E6-HPV16 or E7-HPV16 promoted the activity of MMP-2/9, and contributed to the migration of cervical cells. PMID:26191191

  6. The apoptotic members CD95, BclxL, and Bcl-2 cooperate to promote cell migration by inducing Ca(2+) flux from the endoplasmic reticulum to mitochondria.

    PubMed

    Fouqué, A; Lepvrier, E; Debure, L; Gouriou, Y; Malleter, M; Delcroix, V; Ovize, M; Ducret, T; Li, C; Hammadi, M; Vacher, P; Legembre, P

    2016-10-01

    Metalloprotease-processed CD95L (cl-CD95L) is a soluble cytokine that implements a PI3K/Ca(2+) signaling pathway in triple-negative breast cancer (TNBC) cells. Accordingly, high levels of cl-CD95L in TNBC women correlate with poor prognosis, and administration of this ligand in an orthotopic xenograft mouse model accelerates the metastatic dissemination of TNBC cells. The molecular mechanism underlying CD95-mediated cell migration remains unknown. Here, we present genetic and pharmacologic evidence that the anti-apoptotic molecules BclxL and Bcl-2 and the pro-apoptotic factors BAD and BID cooperate to promote migration of TNBC cells stimulated with cl-CD95L. BclxL was distributed in both endoplasmic reticulum (ER) and mitochondrion membranes. The mitochondrion-localized isoform promoted cell migration by interacting with voltage-dependent anion channel 1 to orchestrate Ca(2+) transfer from the ER to mitochondria in a BH3-dependent manner. Mitochondrial Ca(2+) uniporter contributed to this flux, which favored ATP production and cell migration. In conclusion, this study reveals a novel molecular mechanism controlled by BclxL to promote cancer cell migration and supports the use of BH3 mimetics as therapeutic options not only to kill tumor cells but also to prevent metastatic dissemination in TNBCs.

  7. The apoptotic members CD95, BclxL, and Bcl-2 cooperate to promote cell migration by inducing Ca2+ flux from the endoplasmic reticulum to mitochondria

    PubMed Central

    Fouqué, A; Lepvrier, E; Debure, L; Gouriou, Y; Malleter, M; Delcroix, V; Ovize, M; Ducret, T; Li, C; Hammadi, M; Vacher, P; Legembre, P

    2016-01-01

    Metalloprotease-processed CD95L (cl-CD95L) is a soluble cytokine that implements a PI3K/Ca2+ signaling pathway in triple-negative breast cancer (TNBC) cells. Accordingly, high levels of cl-CD95L in TNBC women correlate with poor prognosis, and administration of this ligand in an orthotopic xenograft mouse model accelerates the metastatic dissemination of TNBC cells. The molecular mechanism underlying CD95-mediated cell migration remains unknown. Here, we present genetic and pharmacologic evidence that the anti-apoptotic molecules BclxL and Bcl-2 and the pro-apoptotic factors BAD and BID cooperate to promote migration of TNBC cells stimulated with cl-CD95L. BclxL was distributed in both endoplasmic reticulum (ER) and mitochondrion membranes. The mitochondrion-localized isoform promoted cell migration by interacting with voltage-dependent anion channel 1 to orchestrate Ca2+ transfer from the ER to mitochondria in a BH3-dependent manner. Mitochondrial Ca2+ uniporter contributed to this flux, which favored ATP production and cell migration. In conclusion, this study reveals a novel molecular mechanism controlled by BclxL to promote cancer cell migration and supports the use of BH3 mimetics as therapeutic options not only to kill tumor cells but also to prevent metastatic dissemination in TNBCs. PMID:27367565

  8. Leptin promotes human endometriotic cell migration and invasion by up-regulating MMP-2 through the JAK2/STAT3 signaling pathway.

    PubMed

    Ahn, Ji-Hye; Choi, Youn Seok; Choi, Jung-Hye

    2015-10-01

    Despite evidence that leptin may play a role in the pathogenesis of endometriosis, the specific function of leptin in the migration and invasion of endometriotic cells is not well characterized. In this study, we investigated the effect of leptin on the migration, invasion and matrix metalloproteinase (MMP) expression levels of human endometriotic cells. We found that leptin stimulated the migration and invasion of endometriotic cells (11Z, 12Z and 22B) in a dose-dependent manner. Leptin receptor (ObR) siRNA significantly inhibited the migration and invasion induced by leptin in 11Z and 12Z cells. Leptin-induced migration and invasion were significantly attenuated by pretreatment with SB-3CT, a specific gelatinase (MMP-2 and MMP-9) inhibitor. In addition, leptin-induced increases in the mRNA and protein expression and enzyme activity of MMP-2 in 11Z and 12Z cells. Selectively inhibiting MMP-2 using siRNA and an inhibitor (GM6003), impaired the ability of leptin to stimulate the migration and invasion of endometriotic cells, suggesting that MMP-2 plays an essential role in leptin-induced migration and invasion. Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) inhibitor (AG490) significantly inhibited the migration, invasion and MMP-2 expression induced by leptin in endometriotic cells. Furthermore, the Extracellular signal-Regulated Kinase inhibitor PD98059 neutralized the migration and invasion promoting effects of leptin. Taken together, these results suggest that leptin may contribute to the migration and invasion abilities of endometriotic cells via the up-regulation of MMP-2 through an ObR-dependent JAK2/STAT3 signaling pathway.

  9. Neuregulin 1-activated ERBB4 interacts with YAP to induce Hippo pathway targetgenes and promote cell migration

    PubMed Central

    Haskins, Jonathan W.; Nguyen, Don X.; Stern, David F.

    2015-01-01

    The receptor tyrosine kinase ERBB4, a member of the epidermal growth factor receptor (EGFR) family, is unusual in that when phosphorylated, ERBB4 can undergo intramembrane proteolysis, releasing a soluble intracellular domain (ICD) that activates transcription in the nucleus. We found that ERBB4 activated the transcriptional coactivator YAP, which promotes organ and tissue growth and is inhibited by the tumor-suppressor Hippo pathway. Overexpressing ERBB4 in cultured mammary epithelial cells or adding the ERBB4 ligand neuregulin 1 (NRG1) to breast cancer cell cultures promoted the expression of genes regulated by YAP, such as CTGF. Knocking down YAP or ERBB4 prevented the induction of CTGF expression by NRG1, as did preventing ERBB4 cleavage by treating cells with the pan-EGFR inhibitors lapatinib or erlotinib. A PPxY motif in the ERBB4 ICD enabled its interaction with WW domains in YAP, similar to the mode of interaction between YAP and the kinase LATS1, which inhibits the transcriptional activity of YAP. The ERBB4 ICD coimmunoprecipitated with YAP and TEAD1, a YAP coactivator, suggesting that the ERBB4 ICD may functionally interact with YAP and TEAD to promote transcriptional activity. NRG1 stimulated YAP activity to an extent comparable to that of EGF or LPA (lysophosphatidic acid), known activators of YAP. NRG1 stimulated YAP-dependent cell migration in breast cancer cell lines. These observations connect the unusual nuclear function of a growth factor receptor with a mechanosensory pathway and suggest that NRG1-ERBB4-YAP signaling may underlie the aggressive behavior of tumor cells. PMID:25492965

  10. hGAAP promotes cell adhesion and migration via the stimulation of store-operated Ca2+ entry and calpain 2

    PubMed Central

    Saraiva, Nuno; Prole, David L.; Carrara, Guia; Johnson, Benjamin F.; Taylor, Colin W.

    2013-01-01

    Golgi antiapoptotic proteins (GAAPs) are highly conserved Golgi membrane proteins that inhibit apoptosis and promote Ca2+ release from intracellular stores. Given the role of Ca2+ in controlling cell adhesion and motility, we hypothesized that human GAAP (hGAAP) might influence these events. In this paper, we present evidence that hGAAP increased cell adhesion, spreading, and migration in a manner that depended on the C-terminal domain of hGAAP. We show that hGAAP increased store-operated Ca2+ entry and thereby the activity of calpain at newly forming protrusions. These hGAAP-dependent effects regulated focal adhesion dynamics and cell migration. Indeed, inhibition or knockdown of calpain 2 abrogated the effects of hGAAP on cell spreading and migration. Our data reveal that hGAAP is a novel regulator of focal adhesion dynamics, cell adhesion, and migration by controlling localized Ca2+-dependent activation of calpain. PMID:23940116

  11. MiR-625-3p promotes cell migration and invasion via inhibition of SCAI in colorectal carcinoma cells

    PubMed Central

    Wang, Qizhi; Zhang, Pei; Li, Dapeng; Wang, Qiangwu; Wang, Jianchao; Li, Huabin; Liu, Hao; Wang, Zhiwei

    2015-01-01

    MicroRNAs (miRNAs) play a critical role in controlling tumor invasion and metastasis via regulating the expression of a variety of targets, which act as oncogenes or tumor suppressor genes. Abnormally expressed miR-625-3p has been observed in several types of human cancers. However, the molecular mechanisms of miR-625-3p-mediated tumorigenesis are largely elusive. Therefore, the aim of this study was to evaluate the biological function and molecular insight on miR-625-3p-induced oncogenesis in colorectal carcinoma (CRC). The effects of miR-625-3p in cell migration and invasion were analyzed by wound healing assay and transwell assay, respectively. In addition, the expression of miR-625-3p and its targets was detected in five human CRC cell lines. In the present study, we found that overexpression of miR-625-3p promoted migration and invasion in SW480 cells, whereas downregulation of miR-625-3p inhibited cell motility in SW620 cells. More importantly, we observed potential binding sites for miR-625-3p in the 3′-untranslated region of suppressor of cancer cell invasion (SCAI). Notably, we identified that overexpression of miR-625-3p inhibited the expression of SCAI, while depletion of miR-625-3p increased SCAI level, suggesting that SCAI could be a target of miR-625-3p. Additionally, we revealed that miR-625-3p exerts its oncogenic functions through regulation of SCAI/E-cadherin/MMP-9 pathways. Our findings indicate the pivotal role of miR-625-3p in invasion that warrants further exploration whether targeting miR-625-3p could be a promising approach for the treatment of CRC. PMID:26314959

  12. Ephexin4-mediated promotion of cell migration and anoikis resistance is regulated by serine 897 phosphorylation of EphA2☆

    PubMed Central

    Kawai, Hiromu; Kobayashi, Masakazu; Hiramoto-Yamaki, Nao; Harada, Kohei; Negishi, Manabu; Katoh, Hironori

    2013-01-01

    EphA2 is activated through phosphorylation on serine 897 (S897) by Akt to promote cancer cell motility and invasion, independently of stimulation by ephrin, its ligand. Here we show that S897 phosphorylation of EphA2 strengthens the interaction between EphA2 and Ephexin4, a guanine nucleotide exchange factor for the small GTPase RhoG. S897A mutation of EphA2 abolished the EphA2/Ephexin4-mediated RhoG activation, promotion of cell migration, and resistance to anoikis. Our results suggest that S897-phosphorylated EphA2 recruits Ephexin4 to promote cell migration and anoikis resistance, providing a molecular link between S897 phosphorylation of EphA2 and tumor progression. PMID:23772378

  13. Ciliary Neurotrophic Factor Promotes the Migration of Corneal Epithelial Stem/progenitor Cells by Up-regulation of MMPs through the Phosphorylation of Akt

    PubMed Central

    Chen, Jialin; Chen, Peng; Backman, Ludvig J.; Zhou, Qingjun; Danielson, Patrik

    2016-01-01

    The migration of limbal epithelial stem cells is important for the homeostasis and regeneration of corneal epithelium. Ciliary neurotrophic factor (CNTF) has been found to promote corneal epithelial wound healing by activating corneal epithelial stem/progenitor cells. However, the possible effect of CNTF on the migration of corneal epithelial stem/progenitor cells is not clear. This study found the expression of CNTF in mouse corneal epithelial stem/progenitor cells (TKE2) to be up-regulated after injury, on both gene and protein level. CNTF promoted migration of TKE2 in a dose-dependent manner and the peak was seen at 10 ng/ml. The phosphorylation level of Akt (p-Akt), and the expression of MMP3 and MMP14, were up-regulated after CNTF treatment both in vitro and in vivo. Akt and MMP3 inhibitor treatment delayed the migration effect by CNTF. Finally, a decreased expression of MMP3 and MMP14 was observed when Akt inhibitor was applied both in vitro and in vivo. This study provides new insights into the role of CNTF on the migration of corneal epithelial stem/progenitor cells and its inherent mechanism of Up-regulation of matrix metalloproteinases through the Akt signalling pathway. PMID:27174608

  14. Boron promotes streptozotocin-induced diabetic wound healing: roles in cell proliferation and migration, growth factor expression, and inflammation.

    PubMed

    Demirci, Selami; Doğan, Ayşegül; Aydın, Safa; Dülger, Esra Çikler; Şahin, Fikrettin

    2016-06-01

    Acute wounds do not generally require professional treatment modalities and heal in a predictable fashion, but chronic wounds are mainly accompanied with infection and prolonged inflammation, leading to healing impairments and continuous tissue degradation. Although a vast amount of products have been introduced in the market, claiming to provide a better optimization of local and systemic conditions of patients, they do not meet the expectations due to being expensive and not easily accessible, requiring wound care facilities, having patient-specific response, low efficiency, and severe side-effects. In this sense, developing new, safe, self-applicable, effective, and cheap wound care products with broad-range antimicrobial activity is still an attractive area of international research. In the present work, boron derivatives [boric acid and sodium pentaborate pentahydrate (NaB)] were evaluated for their antimicrobial activity, proliferation, migratory, angiogenesis, gene, and growth factor expression promoting effects on dermal cells in vitro. In addition, boron-containing hydrogel formulation was examined for its wound healing promoting potential using full-thickness wound model in streptozotocin-induced diabetic rats. The results revealed that while both boron compounds significantly increased proliferation, migration, vital growth factor, and gene expression levels of dermal cells along with displaying remarkable antimicrobial effects against bacteria, yeast, and fungi, NaB displayed greater antimicrobial properties as well as gene and growth factor expression inductive effects. Animal studies proved that NaB-containing gel formulation enhanced wound healing rate of diabetic animals and histopathological scores. Overall data suggest a potential promising therapeutic option for the management of chronic wounds but further studies are highly warranted to determine signaling pathways and target metabolisms in which boron is involved to elucidate the limitations

  15. Boron promotes streptozotocin-induced diabetic wound healing: roles in cell proliferation and migration, growth factor expression, and inflammation.

    PubMed

    Demirci, Selami; Doğan, Ayşegül; Aydın, Safa; Dülger, Esra Çikler; Şahin, Fikrettin

    2016-06-01

    Acute wounds do not generally require professional treatment modalities and heal in a predictable fashion, but chronic wounds are mainly accompanied with infection and prolonged inflammation, leading to healing impairments and continuous tissue degradation. Although a vast amount of products have been introduced in the market, claiming to provide a better optimization of local and systemic conditions of patients, they do not meet the expectations due to being expensive and not easily accessible, requiring wound care facilities, having patient-specific response, low efficiency, and severe side-effects. In this sense, developing new, safe, self-applicable, effective, and cheap wound care products with broad-range antimicrobial activity is still an attractive area of international research. In the present work, boron derivatives [boric acid and sodium pentaborate pentahydrate (NaB)] were evaluated for their antimicrobial activity, proliferation, migratory, angiogenesis, gene, and growth factor expression promoting effects on dermal cells in vitro. In addition, boron-containing hydrogel formulation was examined for its wound healing promoting potential using full-thickness wound model in streptozotocin-induced diabetic rats. The results revealed that while both boron compounds significantly increased proliferation, migration, vital growth factor, and gene expression levels of dermal cells along with displaying remarkable antimicrobial effects against bacteria, yeast, and fungi, NaB displayed greater antimicrobial properties as well as gene and growth factor expression inductive effects. Animal studies proved that NaB-containing gel formulation enhanced wound healing rate of diabetic animals and histopathological scores. Overall data suggest a potential promising therapeutic option for the management of chronic wounds but further studies are highly warranted to determine signaling pathways and target metabolisms in which boron is involved to elucidate the limitations

  16. Exosome-shuttling microRNA-21 promotes cell migration and invasion-targeting PDCD4 in esophageal cancer.

    PubMed

    Liao, Juan; Liu, Ran; Shi, Ya-Juan; Yin, Li-Hong; Pu, Yue-Pu

    2016-06-01

    Recent evidence indicates that exosomes can mediate certain microRNAs (miRNAs) involved in a series of biological functions in tumor occurrence and development. Our previous studies showed that microRNA-21 (miR-21) was abundant in both esophageal cancer cells and their corresponding exosomes. The present study explored the function of exosome-shuttling miR-21 involved in esophageal cancer progression. We found that exosomes could be internalized from the extracellular space to the cytoplasm. The exosome-derived Cy3-labeled miR-21 mimics could be transported into recipient cells in a neutral sphingomyelinase 2 (nSMase2)-dependent manner. miR-21 overexpression from donor cells significantly promoted the migration and invasion of recipient cells by targeting programmed cell death 4 (PDCD4) and activating its downstream c-Jun N-terminal kinase (JNK) signaling pathway after co-cultivation. Our population plasma sample analysis indicated that miR-21 was upregulated significantly in plasma from esophageal cancer patients and showed a significant risk association for esophageal cancer. Our data demonstrated that a close correlation existed between exosome-shuttling miR-21 and esophageal cancer recurrence and distant metastasis. Thus, exosome-shuttling miR-21 may become a potential biomarker for prognosis among esophageal cancer patients. PMID:27035745

  17. MicroRNA-616 promotes the migration, invasion and epithelial-mesenchymal transition of HCC by targeting PTEN.

    PubMed

    Zhang, Di; Zhou, Peihua; Wang, Wei; Wang, Xiaolong; Li, Junhui; Sun, Xuejun; Zhang, Li

    2016-01-01

    MicroRNAs, which can post-transcriptionally regulate gene expression by binding to the 3'-untranslated regions of the mRNAs, have been found to be the critical regulators of the development and progression of hepatocellular carcinoma (HCC). The present study demonstrated for the first time that microRNA-616 (miR-616) was markedly upregulated in HCC tissues, and was associated with the recurrence and metastasis of HCC. Elevated level of miR-616 was correlated with adverse clinicopathological features and poor prognosis of HCC patients. Gain- and loss-of-function studies revealed that miR-616 could potentiate the migration, invasion and the epithelial-mesenchymal transtion (EMT) phenotype of HCC cells. Phosphatase and tensin homolog (PTEN), the predicted target of miR-616 by bioinformatics analysis, was confirmed as a direct downstream target of miR-616 through western blotting, luciferase reporter and immunohistochemical assays. Furthermore, we demonstrated that miR-616 exerted the promoting effects on EMT and metastatic ability of HCC cells through suppressing PTEN expression. Based on these results, we conclude that miR-616 is a promising prognostic biomarker of HCC and targeting miR-616 may be a potential option to prevent the progression of HCC.

  18. Liver fatty acid-binding protein (L-FABP) promotes cellular angiogenesis and migration in hepatocellular carcinoma.

    PubMed

    Ku, Chung-Yu; Liu, Yu-Huei; Lin, Hsuan-Yuan; Lu, Shao-Chun; Lin, Jung-Yaw

    2016-04-01

    Liver fatty acid-binding protein (L-FABP) is abundant in hepatocytes and known to be involved in lipid metabolism. Overexpression of L-FABP has been reported in various cancers; however, its role in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigated L-FABP and its association with vascular endothelial growth factors (VEGFs) in 90 HCC patients. We found that L-FABP was highly expressed in their HCC tissues, and that this expression was positively correlated with that of VEGF-A. Additionally, L-FABP significantly promoted tumor growth and metastasis in a xenograft mouse model. We also assessed the mechanisms of L-FABP activity in tumorigenesis; L-FABP was found to associate with VEGFR2 on membrane rafts and subsequently activate the Akt/mTOR/P70S6K/4EBP1 and Src/FAK/cdc42 pathways, which resulted in up-regulation of VEGF-A accompanied by an increase in both angiogenic potential and migration activity. Our results thus suggest that L-FABP could be a potential target for HCC chemotherapy. PMID:26919097

  19. Migration-inducing gene 7 promotes tumorigenesis and angiogenesis and independently predicts poor prognosis of epithelial ovarian cancer

    PubMed Central

    Huang, Bihui; Yin, Mingzhu; Li, Xia; Cao, Guosheng; Qi, Jin; Lou, Ge; Sheng, Shijie; Kou, Junping; Chen, Kang; Yu, Boyang

    2016-01-01

    Epithelial ovarian carcinomas (EOC) cause more mortality than any other cancer of the female reproductive system. New therapeutic approaches to reduce EOC mortality have been largely unsuccessful due to the poor understanding of the mechanisms underlying EOC proliferation and metastasis. Progress in EOC treatment is further hampered by a lack of reliable prognostic biomarkers for early risk assessment. In this study, we identify that Migration-Inducting Gene 7 (MIG-7) is specifically induced in human EOC tissues but not normal ovaries or ovarian cyst. Ovarian MIG-7 expression strongly correlated with EOC progression. Elevated MIG-7 level at the time of primary cytoreductive surgery was a strong and independent predictor of poor survival of EOC patients. Cell and murine xenograft models showed that MIG-7 was required for EOC proliferation and invasion, and MIG-7 enhanced EOC-associated angiogenesis by promoting the expression of vascular endothelial growth factor. Inhibiting MIG-7 by RNA interference in grafted EOC cells retarded tumor growth, angiogenesis and improved host survival, and suppressing MIG-7 expression with a small molecule inhibitor D-39 identified from the medicinal plant Liriope muscari mitigated EOC growth and invasion and specifically abrogated the expression of vascular endothelial growth factor. Our data not only reveal a critical function of MIG-7 in EOC growth and metastasis and support MIG-7 as an independent prognostic biomarker for EOC, but also demonstrate that therapeutic targeting of MIG-7 is likely beneficial in the treatment of EOC. PMID:27050277

  20. Photobiomodulation with low-level diode laser promotes osteoblast migration in an in vitro micro wound model

    NASA Astrophysics Data System (ADS)

    Tschon, Matilde; Incerti-Parenti, Serena; Cepollaro, Simona; Checchi, Luigi; Fini, Milena

    2015-07-01

    Laser photobiomodulation can improve bone healing, but well-defined treatment parameters are lacking. Saos-2 human osteoblast-like cells were subjected to an in vitro scratch-wound healing assay and irradiated by a 915-nm gallium-aluminum-arsenide diode laser for 0, 48, 96, and 144 s using doses of, respectively, 0, 5, 10, and 15 J/cm2. Wound area was measured after 4, 24, 48, and 72 h. Cell viability, DNA content, gene expression, and release of bone-related proteins were evaluated after 24, 48, and 72 h. Laser significantly improved wound healing compared with nonirradiated controls. Cells treated with laser doses of 5 and 10 J/cm2 reached wound closure after 72 h, followed by 15 J/cm2 after 96 h. With the cell proliferation inhibitor Mitomycin C, the doses of 10 and 15 J/cm2 maintained an improved wound healing compared with controls. Laser increased collagen type 1 gene expression with higher doses inducing a longer-lasting effect, whereas transforming growth factor-beta 1 showed comparable or decreased levels in irradiated versus nonirradiated groups, with no effect on protein release. This study demonstrated that laser photobiomodulation at 915 nm promoted wound healing mainly through stimulation of cell migration and collagen deposition by osteoblasts.

  1. Liver fatty acid-binding protein (L-FABP) promotes cellular angiogenesis and migration in hepatocellular carcinoma

    PubMed Central

    Ku, Chung-Yu; Liu, Yu-Huei; Lin, Hsuan-Yuan; Lu, Shao-Chun; Lin, Jung-Yaw

    2016-01-01

    Liver fatty acid-binding protein (L-FABP) is abundant in hepatocytes and known to be involved in lipid metabolism. Overexpression of L-FABP has been reported in various cancers; however, its role in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigated L-FABP and its association with vascular endothelial growth factors (VEGFs) in 90 HCC patients. We found that L-FABP was highly expressed in their HCC tissues, and that this expression was positively correlated with that of VEGF-A. Additionally, L-FABP significantly promoted tumor growth and metastasis in a xenograft mouse model. We also assessed the mechanisms of L-FABP activity in tumorigenesis; L-FABP was found to associate with VEGFR2 on membrane rafts and subsequently activate the Akt/mTOR/P70S6K/4EBP1 and Src/FAK/cdc42 pathways, which resulted in up-regulation of VEGF-A accompanied by an increase in both angiogenic potential and migration activity. Our results thus suggest that L-FABP could be a potential target for HCC chemotherapy. PMID:26919097

  2. Liver fatty acid-binding protein (L-FABP) promotes cellular angiogenesis and migration in hepatocellular carcinoma.

    PubMed

    Ku, Chung-Yu; Liu, Yu-Huei; Lin, Hsuan-Yuan; Lu, Shao-Chun; Lin, Jung-Yaw

    2016-04-01

    Liver fatty acid-binding protein (L-FABP) is abundant in hepatocytes and known to be involved in lipid metabolism. Overexpression of L-FABP has been reported in various cancers; however, its role in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigated L-FABP and its association with vascular endothelial growth factors (VEGFs) in 90 HCC patients. We found that L-FABP was highly expressed in their HCC tissues, and that this expression was positively correlated with that of VEGF-A. Additionally, L-FABP significantly promoted tumor growth and metastasis in a xenograft mouse model. We also assessed the mechanisms of L-FABP activity in tumorigenesis; L-FABP was found to associate with VEGFR2 on membrane rafts and subsequently activate the Akt/mTOR/P70S6K/4EBP1 and Src/FAK/cdc42 pathways, which resulted in up-regulation of VEGF-A accompanied by an increase in both angiogenic potential and migration activity. Our results thus suggest that L-FABP could be a potential target for HCC chemotherapy.

  3. Slit2-Robo1 signaling promotes the adhesion, invasion and migration of tongue carcinoma cells via upregulating matrix metalloproteinases 2 and 9, and downregulating E-cadherin

    PubMed Central

    Zhao, Yuan; Zhou, Feng-Li; Li, Wei-Ping; Wang, Jing; Wang, Li-Jing

    2016-01-01

    Whether Slit homologue 2 (Slit2) inhibits or promotes tumor cell migration remains controversial, and the role of Slit2-Roundabout 1 (Robo1) signaling in oral cancer remains to be fully elucidated. The aim of the present study was to investigate the role of Slit2-Robo1 signaling in the adhesion, invasion and migration of tongue carcinoma cells, and the mechanism by which Slit2-Robo1 signaling inhibits or promotes tumor cell migration. Tca8113 tongue carcinoma cells were treated with the monoclonal anti-human Robo1 antibody, R5, to inhibit the Slit2-Robo1 signaling pathway, with immunoglobulin (Ig)G2b treatment as a negative control. The expression levels of Slit2 and Robo1 were determined using flow cytometry. The effects of R5 on the adhesion, invasion and migration of Tca8113 tongue carcinoma cells were investigated. Gelatin zymography was used to investigate the activity of matrix metalloproteinase 2 (MMP2) and MMP9. Western blot analysis was used to evaluate the expression levels of E-cadherin in Tca8113 cells treated with 10 µg/ml of either R5 or IgG2b. Slit2 and Robo1 proteins were found to be expressed in the Tca8113 cells. R5 significantly inhibited the adhesion, invasion and migration of Tca8113 cells in vitro. R5 also inhibited the activities of MMP2 and MMP9, and increased the expression of E-cadherin in the Tca8113 cells. These results suggested that Slit2-Robo1 signaling promoted the adhesion, invasion and migration of tongue carcinoma cells by upregulating the expression levels of MMP2 and MMP9 and, downregulating the expression of E-cadherin. PMID:27431199

  4. TGF-β1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis.

    PubMed

    Pang, M-F; Georgoudaki, A-M; Lambut, L; Johansson, J; Tabor, V; Hagikura, K; Jin, Y; Jansson, M; Alexander, J S; Nelson, C M; Jakobsson, L; Betsholtz, C; Sund, M; Karlsson, M C I; Fuxe, J

    2016-02-11

    Tumor cells frequently disseminate through the lymphatic system during metastatic spread of breast cancer and many other types of cancer. Yet it is not clear how tumor cells make their way into the lymphatic system and how they choose between lymphatic and blood vessels for migration. Here we report that mammary tumor cells undergoing epithelial-mesenchymal transition (EMT) in response to transforming growth factor-β (TGF-β1) become activated for targeted migration through the lymphatic system, similar to dendritic cells (DCs) during inflammation. EMT cells preferentially migrated toward lymphatic vessels compared with blood vessels, both in vivo and in 3D cultures. A mechanism of this targeted migration was traced to the capacity of TGF-β1 to promote CCR7/CCL21-mediated crosstalk between tumor cells and lymphatic endothelial cells. On one hand, TGF-β1 promoted CCR7 expression in EMT cells through p38 MAP kinase-mediated activation of the JunB transcription factor. Blockade of CCR7, or treatment with a p38 MAP kinase inhibitor, reduced lymphatic dissemination of EMT cells in syngeneic mice. On the other hand, TGF-β1 promoted CCL21 expression in lymphatic endothelial cells. CCL21 acted in a paracrine fashion to mediate chemotactic migration of EMT cells toward lymphatic endothelial cells. The results identify TGF-β1-induced EMT as a mechanism, which activates tumor cells for targeted, DC-like migration through the lymphatic system. Furthermore, it suggests that p38 MAP kinase inhibition may be a useful strategy to inhibit EMT and lymphogenic spread of tumor cells.

  5. CC-chemokine receptor 7 and its ligand CCL19 promote mitral valve interstitial cell migration and repair.

    PubMed

    Wang, Xiaozhi; Wang, Liang; Miao, Liping; Zhao, Rong; Wu, Yanhu; Kong, Xiangqing

    2015-11-01

    The effect of CC-chemokine receptor 7 (CCR7) and CC-chemokine ligand 19 (CCL19) on rheumatic mitral stenosis is unknown. This study aimed to explore the roles of CCR7 and CCL19 in rheumatic mitral stenosis by measuring the expression of CCR7 and CCL19 in human mitral valves from rheumatic mitral stenosis patients. Additionally, we examined their effects on human mitral valve interstitial cells (hMVICs) proliferation, apoptosis and wound repair. CCR7 and CCL19 expression was measured in the mitral valves from rheumatic mitral stenosis patients (n = 10) and compared to normal mitral valves (n = 5). CCR7 was measured in cultured hMVICs from rheumatic mitral stenosis patients and normal donors by RT-PCR and immunofluorescence. The cells were also treated with exogenous CCL19, and the effects on wound healing, proliferation and apoptosis were assayed. In the rheumatic mitral valves, valve interstitial cells expressed CCR7, while mononuclear cells and the endothelium expressed CCL19. Healthy mitral valves did not stain positive for CCR7 or CCL19. CCR7 was also detected in cultured rheumatic hMVICs or in normal hMVICs treated with CCL19. In a wound healing experiment, wound closure rates of both rheumatic and normal hMVICs were significantly accelerated by CCL19. These effects were abrogated by a CCR7 neutralizing antibody. The CCR7/CCL19 axis did not influence the proliferation or apoptosis of hMVICs, indicating that wound healing was due to increased migration rates rather than increased proliferation. In conclusion, CCR7 and CCL19 were expressed in rheumatic mitral valves. The CCR7/CCL19 axis may regulate remodeling of rheumatic valve injury through promoting migratory ability of hMVICs.

  6. IL-33 promotes the migration and proliferation of circulating fibrocytes from patients with allergen-exacerbated asthma

    SciTech Connect

    Bianchetti, Lorenza; Marini, Maurizio A.; Isgro, Mirko; Bellini, Alberto; Schmidt, Matthias; Mattoli, Sabrina

    2012-09-14

    Highlights: Black-Right-Pointing-Pointer IL-33 is considered a new therapeutic target for reducing inflammation in asthma. Black-Right-Pointing-Pointer This study shows that IL-33 is a potent chemoattractant for fibrocytes in asthma. Black-Right-Pointing-Pointer IL-33 also promotes fibrocyte proliferation without reducing collagen production. Black-Right-Pointing-Pointer The study uncovers a novel non-inflammatory, profibrotic function of IL-33. -- Abstract: The release of IL-33 increases in the bronchial mucosa of asthmatic patients in relation to disease severity and several studies have demonstrated that IL-33 may enhance airway inflammation in asthma. This study tested the hypothesis that IL-33 may also contribute to the development of irreversible structural changes in asthma by favoring the airway recruitment and profibrotic function of circulating fibrocytes during episodes of allergen-induced asthma exacerbation. The circulating fibrocytes from patients with allergen-exacerbated asthma (PwAA) showed increased expression of the specific IL-33 receptor component ST2L in comparison with the cells from non-asthmatic individuals (NAI). Recombinant IL-33 induced the migration of circulating fibrocytes from PwAA at clinically relevant concentrations and stimulated their proliferation in a concentration-dependent manner between 0.1 and 10 ng/ml, without affecting the constitutive release of type I collagen. The recombinant protein did not induce similar responses in circulating fibrocytes from NAI. This study uncovers an important mechanism through which fibrocytes may accumulate in the airways of allergic asthmatics when their disease is not adequately controlled by current treatment and provides novel information on the function of IL-33 in asthma.

  7. Down-regulation of Dicer1 promotes cellular senescence and decreases the differentiation and stem cell-supporting capacities of mesenchymal stromal cells in patients with myelodysplastic syndrome.

    PubMed

    Zhao, Youshan; Wu, Dong; Fei, Chengming; Guo, Juan; Gu, Shuncheng; Zhu, Yang; Xu, Feng; Zhang, Zheng; Wu, Lingyun; Li, Xiao; Chang, Chunkang

    2015-02-01

    Although it has been reported that mesenchymal stromal cells are unable to provide sufficient hematopoietic support in myelodysplastic syndrome, the underlying mechanisms remain elusive. In this study, we found that mesenchymal stromal cells from patients with myelodysplastic syndrome displayed a significant increase in senescence, as evidenced by their decreased proliferative capacity, flattened morphology and increased expression of SA-β-gal and p21. Senescent mesenchymal stromal cells from patients had decreased differentiation potential and decreased stem cell support capacity. Gene knockdown of Dicer1, which was down-regulated in mesenchymal stromal cells from patients, induced senescence. The differentiation and stem cell-supporting capacities were significantly inhibited by Dicer1 knockdown. Overexpression of Dicer1 in mesenchymal stromal cells from patients reversed cellular senescence and enhanced stem cell properties. Furthermore, we identified reduced expression in the microRNA-17 family (miR-17-5p, miR-20a/b, miR-106a/b and miR-93) as a potential factor responsible for increased p21 expression, a key senescence mediator, in Dicer1 knockdown cells. Moreover, we found that miR-93 and miR-20a expression levels were significantly reduced in mesenchymal stromal cells from patients and miR-93/miR-20a gain of function resulted in a decrease of cellular senescence. Collectively, the results of our study show that mesenchymal stromal cells from patients with myelodysplastic syndrome are prone to senescence and that Dicer1 down-regulation promotes cellular senescence and decreases the differentiation and stem cell-supporting capacities of mesenchymal stromal cells. Dicer1 down-regulation seems to contribute to the insufficient hematopoietic support capacities of mesenchymal stromal cells from patients with myelodysplastic syndrome.

  8. Hydrogen peroxide activates focal adhesion kinase and c-Src by a phosphatidylinositol 3 kinase-dependent mechanism and promotes cell migration in Caco-2 cell monolayers.

    PubMed

    Basuroy, Shyamali; Dunagan, Mitzi; Sheth, Parimal; Seth, Ankur; Rao, R K

    2010-07-01

    Recent studies showed that c-Src and phosphatidylinositol 3 (PI3) kinase mediate the oxidative stress-induced disruption of tight junctions in Caco-2 cell monolayers. The present study evaluated the roles of PI3 kinase and Src kinase in the oxidative stress-induced activation of focal adhesion kinase (FAK) and acceleration of cell migration. Oxidative stress, induced by xanthine and xanthine oxidase system, rapidly increased phosphorylation of FAK on Y397, Y925, and Y577 in the detergent-insoluble and soluble fractions and increased its tyrosine kinase activity. The PI3 kinase inhibitors, wortmannin and LY294002, and the Src kinase inhibitor, 4-amino-5[chlorophyll]-7-[t-butyl]pyrazolo[3-4-d]pyrimidine, attenuated tyrosine phosphorylation of FAK. Oxidative stress induced phosphorylation of c-Src on Y418 by a PI3 kinase-dependent mechanism, whereas oxidative stress-induced activation of PI3 kinase was independent of Src kinase activity. Hydrogen peroxide accelerated Caco-2 cell migration in a concentration-dependent manner. Promotion of cell migration by hydrogen peroxide was attenuated by LY294002 and PP2. Reduced expression of FAK by siRNA attenuated hydrogen peroxide-induced acceleration of cell migration. The expression of constitutively active c-Src(Y527F) enhanced cell migration, whereas the expression of dominant negative c-Src(K296R/Y528F) attenuated hydrogen peroxide-induced stimulation of cell migration. Oxidative stress-induced activation of c-Src and FAK was associated with a rapid increase in the tyrosine phosphorylation and the levels of paxillin and p130(CAS) in actin-rich, detergent-insoluble fractions. This study shows that oxidative stress activates FAK and accelerates cell migration in an intestinal epithelium by a PI3 kinase- and Src kinase-dependent mechanism. PMID:20378826

  9. Loss of CAR promotes migration and proliferation of HaCaT cells, and accelerates wound healing in rats via Src-p38 MAPK pathway

    PubMed Central

    Su, Linlin; Fu, Lanqing; Li, Xiaodong; Zhang, Yue; Li, Zhenzhen; Wu, Xue; Li, Yan; Bai, Xiaozhi; Hu, Dahai

    2016-01-01

    The coxsackie and adenovirus receptor (CAR) is a cell adhesion molecule mostly localized to cell-cell contacts in epithelial and endothelial cells. CAR is known to regulate tumor progression, however, its physiological role in keratinocyte migration and proliferation, two essential steps in re-epithelialization during wound healing, has less been investigated. Here we showed that CAR was predominantly expressed in the epidermis of human skin, CAR knockdown by RNAi significantly accelerated HaCaT cell migration and proliferation. In addition, knockdown of CAR in vitro increased p-Src, p-p38, and p-JNK protein levels; however, Src inhibitor PP2 prevented the increase of p-Src and p-p38 induced by CAR RNAi, but not p-JNK, and decelerated cell migration and proliferation. More intriguingly, in vivo CAR RNAi on the skin area surrounding the wounds on rat back visually accelerated wound healing and re-epithelialization process, while treatment with PP2 or p38 inhibitor SB203580 obviously inhibited these effects. By contrast, overexpressing CAR in HaCaT cells significantly decelerated cell migration and proliferation. Above results demonstrate that suppression of CAR could accelerate HaCaT cell migration and proliferation, and promote wound healing in rat skin, probably via Src-p38 MAPK pathway. CAR thus might serve as a novel therapeutic target for facilitating wound healing. PMID:26804208

  10. Migration-stimulating factor (MSF) is over-expressed in non-small cell lung cancer and promotes cell migration and invasion in A549 cells over-expressing MSF

    SciTech Connect

    Deng, Xuefeng; Ma, Qunfeng; Zhang, Bo; Jiang, Hong; Zhang, Zhipei; Wang, Yunjie

    2013-10-15

    Migration-stimulating factor (MSF), an oncofetal truncated isoform of fibronectin, is a potent stimulator of cell invasion. However, its distribution and motogenic role in non-small cell lung cancer (NSCLC) have never been identified. In this study, real-time PCR and immunohistochemical staining (IHC) were performed to detect MSF mRNA and protein levels in tumor tissues and matched adjacent tumor-free tissues. Furthermore, to examine the effect of MSF on invasiveness, MSF was upregulated in A549 cells. The invasiveness and viability of A549 cells were then determined using a transwell migration assay and the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assays, respectively. The expression level of MSF in NSCLC tissue was markedly higher than in matched adjacent tumor-free tissue. Additionally, the level of MSF protein expression in stage III and IV NSCLC samples was higher than in stage I and II NSCLC samples. More importantly, we also demonstrated that migration and invasion of A549 cells increased substantially after upregulating MSF, although proliferation remained unchanged. Meanwhile, we found no correlation between increasing motility and invasiveness of MSF-overexpressing cells and expression levels and activities of matrix metalloprotease MMP-2 and MMP-9. Our current study shows that MSF plays a role in migration and invasion of A549 cells and suggests that MSF may be a potential biomarker of NSCLC progression. - Highlights: • MSF expression was upregulated in NSCLC and correlated with TNM stages. • MSF may be a new biomarker for NSCLC progression. • MSF promoted migration and invasion in A549 cells, independent of MMP-2/MMP-9 expression.

  11. Mesenchymal stem cells derived from breast cancer tissue promote the proliferation and migration of the MCF-7 cell line in vitro

    PubMed Central

    ZHANG, CHUNFU; ZHAI, WEI; XIE, YAN; CHEN, QIAOLIN; ZHU, WEI; SUN, XIAOCHUN

    2013-01-01

    Mesenchymal stem cells (MSCs) are critical in promoting cancer progression, including tumor growth and metastasis. MSCs, as a subpopulation of cells found in the tumor microenvironment, have been isolated from several tumor tissues, but have not been isolated from breast cancer tissue to date. Therefore, the purpose of this study was to isolate MSCs from primary human breast cancer tissue, and to study the effect of breast cancer MSCs (BC-MSCs) on the proliferation and migration of the MCF-7 cell line in vitro. MSCs were isolated and identified from primary breast cancer tissue obtained from 9 patients. The MCF-7 cell line was treated with 10 and 20% breast cancer-associated MSC (BC-MSC)-conditioned medium (CM) for 10–48 h, and changes in proliferation and migration were observed. Furthermore, we investigated the migration of 10 and 20% CM concentrations on MCF-7 through a scratch wound assay and a transwell migration assay. We successfully isolated and identified MSCs from primary breast cancer tissues. BC-MSCs showed characteristics similar to those of bone marrow MSCs, and possessed the capability of multipotential differentiation into osteoblasts and adipocytes. The results of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that 10 and 20% CM concentrations increased the proliferation of MCF-7 cells to different levels. The results also revealed a greater increase in different levels compared with the control group. In conclusion, MSCs were confirmed to exist in human breast cancer tissues, and BC-MSCs may promote the proliferation and migration of breast cancer cells. PMID:24260049

  12. CIZ/NMP4 is expressed in B16 melanoma and forms a positive feedback loop with RANKL to promote migration of the melanoma cells.

    PubMed

    Sakuma, Tomomi; Nakamoto, Tetsuya; Hemmi, Hiroaki; Kitazawa, Sohei; Kitazawa, Riko; Notomi, Takuya; Hayata, Tadayoshi; Ezura, Yoichi; Amagasa, Teruo; Noda, Masaki

    2012-07-01

    Tumor metastasis to bone is a serious pathological situation that causes severe pain, and deterioration in locomoter function. However, the mechanisms underlying tumor metastasis is still incompletely understood. CIZ/NMP4 is a nucleocytoplasmic shuttling protein and its roles in tumor cells have not been known. We, therefore, hypothesized the role of CIZ/NMP4 in B16 melanoma cells that metastasize to bone. CIZ/NMP4 is expressed in B16 cells. The CIZ/NMP4 expression levels are correlated to the metastatic activity in divergent types of melanoma cells. Overexpression of CIZ/NMP4 increased B16 cell migration in Trans-well assay. Conversely, siRNA-based knockdown of CIZ/NMP4 suppressed migratory activity of these cells. As RANKL promotes metastasis of tumor cells in bone, we tested its effect on CIZ in melanoma cells. RANKL treatment enhanced CIZ/NMP4 expression. This increase of CIZ by RANKL promoted migration. Conversely, we identified CIZ/NMP4 binding site in the promoter of RANKL. Furthermore, luciferase assay indicated that CIZ/NMP4 overexpression enhanced RANKL promoter activities, revealing a positive feedback loop of CIZ/NMP4 and RANKL in melanoma. These observations indicate that CIZ/NMP4 is critical regulator of metastasis of melanoma cells. PMID:22307584

  13. [Knockdown of dachshund homolog 1 (DACH1) promotes cell apoptosis and inhibits the invasion and migration abilities of Capan-1 pancreatic cancer cells].

    PubMed

    Bu, Xiaona; Wang, Chuan; Jiang, Zheng

    2016-09-01

    Objective To investigate the impact of the decreased expression of dachshund homolog 1 (DACH1) on cell cycle, apoptosis, invasion and migration of Capan-1 pancreatic cancer cells. Methods After four pairs of DACH1 siRNA were designed and synthesized, double-stranded short hairpin RNA (shRNA) were annealed and inserted into pGenesil-1 vector. The product was then confirmed by enzyme digestion and sequencing analysis. The recombinant plasmids were transfected into Capan-1 cells via Lipofectamine(TM) 2000. Fluorescence microscopy, reverse transcription PCR (RT-PCR) and Western blotting were used to detect the transfection efficiency. Cell apoptosis and cell cycle were tested by flow cytometry. Transwell(TM) assay was used to monitor the invasion and migration abilities of Capan-1 cells. Results Recombinant plasmid pshRNA-DACH1 was successfully constructed and transfected into Capan-1 cells. After transfection, the expression of DACH1 was reduced to some extent. Flow cytometry revealed that cell apoptosis was promoted in the pshRNA-DACH1 transfected group compared with control groups, whereas cell cycle had no significant differences among the groups. Transwell(TM) assay validated that the abilities of migration and invasion were inhibited in the pshRNA-DACH1 transfected group. Conclusion Knockdown of DACH1 expression can remarkably enhance the cell apoptosis, restrain the proliferation, migration and invasion of Capan-1 cells. PMID:27609579

  14. Sulfated polysaccharide isolated from the sea cucumber Stichopus japonicus promotes neurosphere migration and differentiation via up-regulation of N-cadherin.

    PubMed

    Sheng, Xiehuang; Li, Min; Song, Shuliang; Zhang, Nannan; Wang, Yunshan; Liang, Hao; Wang, Weili; Ji, Aiguo

    2012-04-01

    In this report, the sulfated polysaccharide (SJP) from the body wall of the sea cucumber Stichopus japonicas was extracted and tested for its capacity to affect migration and differentiation of neural stem/progenitor cells. SJP is an intensely sulfated polysaccharide with a molecular weight of 1.79 × 10(5) Da that is capable of promoting neurosphere attachment and migration in a dose-dependent manner. Moreover, SJP effectively maintains cell viability even after being deprived of mitogens. Our current results demonstrate that neurosphere are differentiated into neuronal and glial cells when exposed to SJP. These effects were accompanied by an up-regulation of the adhesion molecule, N-cadherin. In addition, we observed that blocking of PI3K activity inhibited N-cadherin-mediated activity. This SJP-induced up-regulation of N-cadherin mediates neurosphere adhesion migration and differentiation via the PI3K/Akt signaling pathway. These results suggest that SJP could be used as a therapeutic agent to mobilize neuroblast migration under conditions of brain injury and disease.

  15. Understanding the “black box” of a health-promotion program: Keys to enable health among older persons aging in the context of migration

    PubMed Central

    Barenfeld, Emmelie; Gustafsson, Susanne; Wallin, Lars; Dahlin-Ivanoff, Synneve

    2015-01-01

    Although the need to make health services more accessible to persons who have migrated has been identified, knowledge about health-promotion programs (HPPs) from the perspective of older persons born abroad is lacking. This study explores the design experiences and content implemented in an adapted version of a group-based HPP developed in a researcher–community partnership. Fourteen persons aged 70–83 years or older who had migrated to Sweden from Finland or the Balkan Peninsula were included. A grounded theory approach guided the data collection and analysis. The findings showed how participants and personnel jointly helped raise awareness. The participants experienced three key processes that could open doors to awareness: enabling community, providing opportunities to understand and be understood, and confirming human values and abilities. Depending on how the HPP content and design are being shaped by the group, the key processes could both inhibit or encourage opening doors to awareness. Therefore, this study provides key insights into how to enable health by deepening the understanding of how the exchange of health-promoting messages is experienced to be facilitated or hindered. This study adds to the scientific knowledge base of how the design and content of HPP may support and recognize the capabilities of persons aging in the context of migration. PMID:26654636

  16. Understanding the "black box" of a health-promotion program: Keys to enable health among older persons aging in the context of migration.

    PubMed

    Barenfeld, Emmelie; Gustafsson, Susanne; Wallin, Lars; Dahlin-Ivanoff, Synneve

    2015-01-01

    Although the need to make health services more accessible to persons who have migrated has been identified, knowledge about health-promotion programs (HPPs) from the perspective of older persons born abroad is lacking. This study explores the design experiences and content implemented in an adapted version of a group-based HPP developed in a researcher-community partnership. Fourteen persons aged 70-83 years or older who had migrated to Sweden from Finland or the Balkan Peninsula were included. A grounded theory approach guided the data collection and analysis. The findings showed how participants and personnel jointly helped raise awareness. The participants experienced three key processes that could open doors to awareness: enabling community, providing opportunities to understand and be understood, and confirming human values and abilities. Depending on how the HPP content and design are being shaped by the group, the key processes could both inhibit or encourage opening doors to awareness. Therefore, this study provides key insights into how to enable health by deepening the understanding of how the exchange of health-promoting messages is experienced to be facilitated or hindered. This study adds to the scientific knowledge base of how the design and content of HPP may support and recognize the capabilities of persons aging in the context of migration. PMID:26654636

  17. Intraperitoneal Mesenchymal Cells Promote the Development of Peritoneal Metastasis Partly by Supporting Long Migration of Disseminated Tumor Cells.

    PubMed

    Kitayama, Joji; Yamaguchi, Hironori; Ishigami, Hironori; Matsuzaki, Keisuke; Sata, Naohiro

    2016-01-01

    The human peritoneal cavity contains a small number of free cells of mesenchymal cell lineage. Intraperitoneal mesenchymal cells (PMC) play supportive roles in metastasis formation on the peritoneum. In this study, we found that PMC, when co-cultuerd with human gastric cancer cells, MKN45, enhanced the proliferation of MKN45 when cultured at low, but not high, cellular density. Also, PMC suppressed apoptotic cell death of MKN45 only under low density culture conditions. Time-lapse videoanalysis clearly demonstrated that PMC randomly migrated more vigorously than did MKN45, and strongly enhanced the migration behavior of co-cultured MKN45. In fact, the majority of MKN45 migrated together in direct physical contact with PMC, and the sum of migration lengths from original position of co-cultured MKN45 for 48 hours was approximately 10 times longer than that of MKN45 cultured alone. Our data suggest that enhanced migration can increase the chance of direct contact or positional proximity among sparcely distributed MKN45, which may bring survival advantages to tumor cells. This may be one of the important mechanisms of peritoneal metastasis, since only a small number of tumor cells are considered to be disseminated in the early step of metastasis formation on the peritoneum. PMID:27136922

  18. Fibronectin Modulates Cell Adhesion and Signaling to Promote Single Cell Migration of Highly Invasive Oral Squamous Cell Carcinoma.

    PubMed

    Ramos, Grasieli de Oliveira; Bernardi, Lisiane; Lauxen, Isabel; Sant'Ana Filho, Manoel; Horwitz, Alan Rick; Lamers, Marcelo Lazzaron

    2016-01-01

    Cell migration is regulated by adhesion to the extracellular matrix (ECM) through integrins and activation of small RhoGTPases, such as RhoA and Rac1, resulting in changes to actomyosin organization. During invasion, epithelial-derived tumor cells switch from laminin-enriched basal membrane to collagen and fibronectin-enriched connective tissue. How this switch affects the tumor migration is still unclear. We tested the hypothesis that ECM dictates the invasiveness of Oral Squamous Cell Carcinoma (OSCC). We analyzed the migratory properties of two OSCC lines, a low invasive cell line with high e-cadherin levels (Linv/HE-cad) or a highly invasive cell line with low e-cadherin levels (Hinv/LE-cad), plated on different ECM components. Compared to laminin, fibronectin induced non-directional collective migration and decreased RhoA activity in Linv/HE-cad OSCC. For Hinv/LE-cad OSCC, fibronectin increased Rac1 activity and induced smaller adhesions, resulting in a fast single cell migration in both 2D and 3D environments. Consistent with these observations, human OSCC biopsies exhibited similar changes in cell-ECM adhesion distribution at the invasive front of the tumor, where cells encounter fibronectin. Our results indicate that ECM composition might induce a switch from collective to single cell migration according to tumor invasiveness due to changes in cell-ECM adhesion and the resulting signaling pathways that alter actomyosin organization. PMID:26978651

  19. Promotion of formyl peptide receptor 1-mediated neutrophil chemotactic migration by antimicrobial peptides isolated from the centipede Scolopendra subspinipes mutilans.

    PubMed

    Park, Yoo Jung; Lee, Sung Kyun; Jung, Young Su; Lee, Mingyu; Lee, Ha Young; Kim, Sang Doo; Park, Joon Seong; Koo, JaeHyung; Hwang, Jae Sam; Bae, Yoe-Sik

    2016-09-01

    We investigated the effects of two antimicrobial peptides (AMPs) isolated from Scolopendra subspinipes mutilans on neutrophil activity. Stimulation of mouse neutrophils with the two AMPs elicited chemotactic migration of the cells in a pertussis toxin-sensitive manner. The two AMPs also stimulated activation of ERK and Akt, which contribute to chemotactic migration of neutrophils. We found that AMP-stimulated neutrophil chemotaxis was blocked by a formyl peptide receptor (FPR) 1 antagonist (cyclosporin H); moreover the two AMPs stimulated the chemotactic migration of FPR1-expressing RBL-2H3 cells but not of vector-expressing RBL-2H3 cells. We also found that the two AMPs stimulate neutrophil migration in vivo, and that this effect is blocked in FPR1-deficient mice. Taken together, our results suggest that the two AMPs stimulate neutrophils, leading to chemotactic migration through FPR1, and the two AMPs will be useful for the study of FPR1 signaling and neutrophil activation. [BMB Reports 2016; 49(9): 520-525].

  20. Promotion of formyl peptide receptor 1-mediated neutrophil chemotactic migration by antimicrobial peptides isolated from the centipede Scolopendra subspinipes mutilans.

    PubMed

    Park, Yoo Jung; Lee, Sung Kyun; Jung, Young Su; Lee, Mingyu; Lee, Ha Young; Kim, Sang Doo; Park, Joon Seong; Koo, JaeHyung; Hwang, Jae Sam; Bae, Yoe-Sik

    2016-09-01

    We investigated the effects of two antimicrobial peptides (AMPs) isolated from Scolopendra subspinipes mutilans on neutrophil activity. Stimulation of mouse neutrophils with the two AMPs elicited chemotactic migration of the cells in a pertussis toxin-sensitive manner. The two AMPs also stimulated activation of ERK and Akt, which contribute to chemotactic migration of neutrophils. We found that AMP-stimulated neutrophil chemotaxis was blocked by a formyl peptide receptor (FPR) 1 antagonist (cyclosporin H); moreover the two AMPs stimulated the chemotactic migration of FPR1-expressing RBL-2H3 cells but not of vector-expressing RBL-2H3 cells. We also found that the two AMPs stimulate neutrophil migration in vivo, and that this effect is blocked in FPR1-deficient mice. Taken together, our results suggest that the two AMPs stimulate neutrophils, leading to chemotactic migration through FPR1, and the two AMPs will be useful for the study of FPR1 signaling and neutrophil activation. [BMB Reports 2016; 49(9): 520-525]. PMID:27502013

  1. Intraperitoneal Mesenchymal Cells Promote the Development of Peritoneal Metastasis Partly by Supporting Long Migration of Disseminated Tumor Cells

    PubMed Central

    Yamaguchi, Hironori; Ishigami, Hironori; Matsuzaki, Keisuke; Sata, Naohiro

    2016-01-01

    The human peritoneal cavity contains a small number of free cells of mesenchymal cell lineage. Intraperitoneal mesenchymal cells (PMC) play supportive roles in metastasis formation on the peritoneum. In this study, we found that PMC, when co-cultuerd with human gastric cancer cells, MKN45, enhanced the proliferation of MKN45 when cultured at low, but not high, cellular density. Also, PMC suppressed apoptotic cell death of MKN45 only under low density culture conditions. Time-lapse videoanalysis clearly demonstrated that PMC randomly migrated more vigorously than did MKN45, and strongly enhanced the migration behavior of co-cultured MKN45. In fact, the majority of MKN45 migrated together in direct physical contact with PMC, and the sum of migration lengths from original position of co-cultured MKN45 for 48 hours was approximately 10 times longer than that of MKN45 cultured alone. Our data suggest that enhanced migration can increase the chance of direct contact or positional proximity among sparcely distributed MKN45, which may bring survival advantages to tumor cells. This may be one of the important mechanisms of peritoneal metastasis, since only a small number of tumor cells are considered to be disseminated in the early step of metastasis formation on the peritoneum. PMID:27136922

  2. Fibronectin Modulates Cell Adhesion and Signaling to Promote Single Cell Migration of Highly Invasive Oral Squamous Cell Carcinoma

    PubMed Central

    Ramos, Grasieli de Oliveira; Bernardi, Lisiane; Lauxen, Isabel; Sant’Ana Filho, Manoel; Horwitz, Alan Rick; Lamers, Marcelo Lazzaron

    2016-01-01

    Cell migration is regulated by adhesion to the extracellular matrix (ECM) through integrins and activation of small RhoGTPases, such as RhoA and Rac1, resulting in changes to actomyosin organization. During invasion, epithelial-derived tumor cells switch from laminin-enriched basal membrane to collagen and fibronectin-enriched connective tissue. How this switch affects the tumor migration is still unclear. We tested the hypothesis that ECM dictates the invasiveness of Oral Squamous Cell Carcinoma (OSCC). We analyzed the migratory properties of two OSCC lines, a low invasive cell line with high e-cadherin levels (Linv/HE-cad) or a highly invasive cell line with low e-cadherin levels (Hinv/LE-cad), plated on different ECM components. Compared to laminin, fibronectin induced non-directional collective migration and decreased RhoA activity in Linv/HE-cad OSCC. For Hinv/LE-cad OSCC, fibronectin increased Rac1 activity and induced smaller adhesions, resulting in a fast single cell migration in both 2D and 3D environments. Consistent with these observations, human OSCC biopsies exhibited similar changes in cell-ECM adhesion distribution at the invasive front of the tumor, where cells encounter fibronectin. Our results indicate that ECM composition might induce a switch from collective to single cell migration according to tumor invasiveness due to changes in cell-ECM adhesion and the resulting signaling pathways that alter actomyosin organization. PMID:26978651

  3. C-Kit Promotes Growth and Migration of Human Cardiac Progenitor Cells via the PI3K-AKT and MEK-ERK Pathways

    PubMed Central

    Al-Maqtari, Tareq; Cao, Pengxiao; Keith, Matthew C. L.; Wysoczynski, Marcin; Zhao, John; Moore IV, Joseph B.; Bolli, Roberto

    2015-01-01

    A recent phase I clinical trial (SCIPIO) has shown that autologous c-kit+ cardiac progenitor cells (CPCs) improve cardiac function and quality of life when transplanted into patients with ischemic heart disease. Although c-kit is widely used as a marker of resident CPCs, its role in the regulation of the cellular characteristics of CPCs remains unknown. We hypothesized that c-kit plays a role in the survival, growth, and migration of CPCs. To test this hypothesis, human CPCs were grown under stress conditions in the presence or absence of SCF, and the effects of SCF-mediated activation of c-kit on CPC survival/growth and migration were measured. SCF treatment led to a significant increase in cell survival and a reduction in cell death under serum depletion conditions. In addition, SCF significantly promoted CPC migration in vitro. Furthermore, the pro-survival and pro-migratory effects of SCF were augmented by c-kit overexpression and abrogated by c-kit inhibition with imatinib. Mechanistically, c-kit activation in CPCs led to activation of the PI3K and the MAPK pathways. With the use of specific inhibitors, we confirmed that the SCF/c-kit-dependent survival and chemotaxis of CPCs are dependent on both pathways. Taken together, our findings suggest that c-kit promotes the survival/growth and migration of human CPCs cultured ex vivo via the activation of PI3K and MAPK pathways. These results imply that the efficiency of CPC homing to the injury site as well as their survival after transplantation may be improved by modulating the activity of c-kit. PMID:26474484

  4. LncRNAs BCYRN1 promoted the proliferation and migration of rat airway smooth muscle cells in asthma via upregulating the expression of transient receptor potential 1

    PubMed Central

    Zhang, Xiao-Yu; Zhang, Luo-Xian; Tian, Cui-Jie; Tang, Xue-Yi; Zhao, Li-Min; Guo, Ya-Li; Cheng, Dong-Jun; Chen, Xian-Liang; Ma, Li-Jun; Chen, Zhuo-Chang

    2016-01-01

    Background: Long noncoding RNAs (lncRNAs) played important roles in several biological processes through regulating the expression of protein. However, the function of lncRNA BCYRN1 in airway smooth muscle cells (ASMCs) has not been reported. Methods: Male Sprague-Dawley (SD) rats were divided into control and asthma groups and the ovalbumin (OVA) model was constructed. The expression of BCYRN1 and transient receptor potential 1 (TRPC1) were detected in the ASMCs separated from these rats. Then 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (WST-1) assay, Roche real-time cell analyzer (RTCA) DP assay and Transwell cell migration assay were performed to detect the effect of BCYRN1 on the viability/proliferation and migration of ASMCs. RNA pull-down assays and RNA immunoprecipitation assay were used to identify and verify the binding between BCYRN1 and TRPC1. Inspiratory resistance and expiratory resistance were measured in OVA challenged rats with BCYRN1 knockdown. Results: We foundthe high expression of BCYRN1 and TRPC1 in asthma groups and ASMCs treated with PDGF-BB. Overexpression of BCYRN1 greatly promoted the proliferation and migration of ASMCs. In addition,TRPC1 overexpression reversed the function of si-BCYRN1 indecreasing the viability/proliferation and migration of ASMCs treated with PDGF-BB. BCYRN1 could up-regulate the protein level of TRPC1 through increasing the stability of TRPC1. Finally, we found that BCYRN1 knockdown reduced the inspiratory resistance and expiratory resistance in OVA challenged rats. Conclusion: Our study indicated that BCYRN1 promotedthe proliferation and migration of rat ASMCs in asthma via upregulating the expression of TRPC1. PMID:27648131

  5. LncRNAs BCYRN1 promoted the proliferation and migration of rat airway smooth muscle cells in asthma via upregulating the expression of transient receptor potential 1

    PubMed Central

    Zhang, Xiao-Yu; Zhang, Luo-Xian; Tian, Cui-Jie; Tang, Xue-Yi; Zhao, Li-Min; Guo, Ya-Li; Cheng, Dong-Jun; Chen, Xian-Liang; Ma, Li-Jun; Chen, Zhuo-Chang

    2016-01-01

    Background: Long noncoding RNAs (lncRNAs) played important roles in several biological processes through regulating the expression of protein. However, the function of lncRNA BCYRN1 in airway smooth muscle cells (ASMCs) has not been reported. Methods: Male Sprague-Dawley (SD) rats were divided into control and asthma groups and the ovalbumin (OVA) model was constructed. The expression of BCYRN1 and transient receptor potential 1 (TRPC1) were detected in the ASMCs separated from these rats. Then 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (WST-1) assay, Roche real-time cell analyzer (RTCA) DP assay and Transwell cell migration assay were performed to detect the effect of BCYRN1 on the viability/proliferation and migration of ASMCs. RNA pull-down assays and RNA immunoprecipitation assay were used to identify and verify the binding between BCYRN1 and TRPC1. Inspiratory resistance and expiratory resistance were measured in OVA challenged rats with BCYRN1 knockdown. Results: We foundthe high expression of BCYRN1 and TRPC1 in asthma groups and ASMCs treated with PDGF-BB. Overexpression of BCYRN1 greatly promoted the proliferation and migration of ASMCs. In addition,TRPC1 overexpression reversed the function of si-BCYRN1 indecreasing the viability/proliferation and migration of ASMCs treated with PDGF-BB. BCYRN1 could up-regulate the protein level of TRPC1 through increasing the stability of TRPC1. Finally, we found that BCYRN1 knockdown reduced the inspiratory resistance and expiratory resistance in OVA challenged rats. Conclusion: Our study indicated that BCYRN1 promotedthe proliferation and migration of rat ASMCs in asthma via upregulating the expression of TRPC1.

  6. [MIP-1α promotes the migration ability of Jurkat cell through human brain microvascular endothelial cell monolayer].

    PubMed

    Ma, Yi-Ran; Zhang, Shuang; Sun, Ying; Liu, Yi-Yang; Song, Qian; Hao, Yi-Wen

    2014-02-01

    This study was purposed to explore the mechanism of central nervous system (CNS) leukemia resulting from brain metastasis of human acute T-cell leukemia (T-ALL) cells and the role of MIP-1α in migration of Jurkat cells through human brain microvascular endothelial cells (HBMEC). The real-time PCR, siRNA test, transendothelial migration test, endothelial permeability assay and cell adhesion assay were used to detect MIP-1α expression, penetration and migration ability as well as adhesion capability respectively. The results showed that the MIP-1α expression in Jurkat cells was higher than that in normal T cells and CCRF-HSB2, CCRF-CEM , SUP-T1 cells. The MIP-1α secreted from Jurkat cells enhanced the ability of Jurkat cells to penetrate through HBMEC, the ability of Jurkat cells treated by MIP-1α siRNA to adhere to HBMEC and to migrate trans endothelial cells decreased. It is concluded that the MIP-1α secreted from Jurkat cells participates in process of penetrating the Jurkat cells through HBMEC monolayer.

  7. Kaiso, a transcriptional repressor, promotes cell migration and invasion of prostate cancer cells through regulation of miR-31 expression.

    PubMed

    Wang, Honghe; Liu, Wei; Black, ShaNekkia; Turner, Omari; Daniel, Juliet M; Dean-Colomb, Windy; He, Qinghua P; Davis, Melissa; Yates, Clayton

    2016-02-01

    Kaiso, a member of the BTB/POZ zinc finger protein family, functions as a transcriptional repressor by binding to sequence-specific Kaiso binding sites or to methyl-CpG dinucleotides. Previously, we demonstrated that Kaiso overexpression and nuclear localization correlated with the progression of prostate cancer (PCa). Therefore, our objective was to explore the molecular mechanisms underlying Kaiso-mediated PCa progression. Comparative analysis of miRNA arrays revealed that 13 miRNAs were significantly altered (> 1.5 fold, p < 0.05) in sh-Kaiso PC-3 compared to sh-Scr control cells. Real-time PCR validated that three miRNAs (9, 31, 636) were increased in sh-Kaiso cells similar to cells treated with 5-aza-2'-deoxycytidine. miR-31 expression negatively correlated with Kaiso expression and with methylation of the miR-31 promoter in a panel of PCa cell lines. ChIP assays revealed that Kaiso binds directly to the miR-31 promoter in a methylation-dependent manner. Over-expression of miR-31 decreased cell proliferation, migration and invasiveness of PC-3 cells, whereas cells transfected with anti-miR-31 restored proliferation, migration and invasiveness of sh-Kaiso PC-3 cells. In PCa patients, Kaiso high/miR-31 low expression correlated with worse overall survival relative to each marker individually. In conclusion, these results demonstrate that Kaiso promotes cell migration and invasiveness through regulation of miR-31 expression.

  8. Kaiso, a transcriptional repressor, promotes cell migration and invasion of prostate cancer cells through regulation of miR-31 expression

    PubMed Central

    Wang, Honghe; Liu, Wei; Black, ShaNekkia; Turner, Omari; Daniel, Juliet M.; Dean-Colomb, Windy; He, Qinghua P.; Davis, Melissa; Yates, Clayton

    2016-01-01

    Kaiso, a member of the BTB/POZ zinc finger protein family, functions as a transcriptional repressor by binding to sequence-specific Kaiso binding sites or to methyl-CpG dinucleotides. Previously, we demonstrated that Kaiso overexpression and nuclear localization correlated with the progression of prostate cancer (PCa). Therefore, our objective was to explore the molecular mechanisms underlying Kaiso-mediated PCa progression. Comparative analysis of miRNA arrays revealed that 13 miRNAs were significantly altered (> 1.5 fold, p < 0.05) in sh-Kaiso PC-3 compared to sh-Scr control cells. Real-time PCR validated that three miRNAs (9, 31, 636) were increased in sh-Kaiso cells similar to cells treated with 5-aza-2′-deoxycytidine. miR-31 expression negatively correlated with Kaiso expression and with methylation of the miR-31 promoter in a panel of PCa cell lines. ChIP assays revealed that Kaiso binds directly to the miR-31 promoter in a methylation-dependent manner. Over-expression of miR-31 decreased cell proliferation, migration and invasiveness of PC-3 cells, whereas cells transfected with anti-miR-31 restored proliferation, migration and invasiveness of sh-Kaiso PC-3 cells. In PCa patients, Kaiso high/miR-31 low expression correlated with worse overall survival relative to each marker individually. In conclusion, these results demonstrate that Kaiso promotes cell migration and invasiveness through regulation of miR-31 expression. PMID:26734997

  9. The use of biomaterials for cell function enhancement: acceleration of fibroblast migration and promotion of stem cell proliferation

    NASA Astrophysics Data System (ADS)

    Qin, Sisi

    Wound healing and tissue regeneration proceed via fibroblast migration along three dimensional scaffolds composed of fibers with different diameters, spacing, and junction angles. In order to understand how each of these factors influences fibroblast migration, a technique for preparation of three dimensional fibrillar scaffolds was developed where the fiber diameters and the angles between adjacent fiber layers could be precisely controlled. In order to study the en-mass migration process, the agarose droplet method was chosen since it enabled accurate determinations of the dependence of the migration speed, focal adhesion distribution, and nuclear deformation on the fiber structures. Results showed that on oriented single fiber layers, if the fiber diameters exceeded 1microm, large focal adhesion complexes formed in a linear arrangement along the fiber axis and cell motion was highly correlated. For fibers 1microm or less, some cell alignment along the fiber direction was measured, but no correlation between the distribution of focal adhesion points and fiber orientation was found. On multi layered scaffolds the focal adhesion sites were found to concentrate at the junction points and the migration speed followed a parabolic function with a distinct minimum at 35°. When compared to fibroblasts plated on 90° fibers, fibroblasts plated on 30° fibers showed a decrease of 25% in the degree of nuclear deformation and an increase of 25% in the number of focal adhesion sites, indicating that cell migration speed was correlated to the angle and distance of approach to the junction point. The time dependence of the migration velocity on oriented fibers was measured for four days and compared to the value measured on flat surfaces. After the initial 24 hour incubation period, the cells on both the 8microm fibers and flat surfaces migrated with a similar speed. During the next three days the migration speed for the cells on the fibrillar surfaces doubled in magnitude

  10. MiR-138 promotes smooth muscle cells proliferation and migration in db/db mice through down-regulation of SIRT1

    SciTech Connect

    Xu, Juan; Li, Li; Yun, Hui-fang; Han, Ye-shan

    2015-08-07

    Background: Diabetic vascular smooth muscle cells (VSMCs) exhibit significantly increased rates of proliferation and migration, which was the most common pathological change in atherosclerosis. In addition, the study about the role for miRNAs in the regulation of VSMC proliferation is just beginning to emerge and additional miRNAs involved in VSMC proliferation modulation should be identified. Methods: The expression of miR-138 and SIRT1 were examined in SMCs separated from db/db mice and in SMC lines C-12511 exposed to high glucose with qRT-PCR and western blot. The regulation of miR-138 on the expression of SMCs was detected with luciferase report assay. VSMCs proliferation and migration assays were performed to examine the effect of miR-138 inhibitor on VSMCs proliferation and migration. Results: We discovered that higher mRNA level of miR-138 and reduced expression of SIRT1 were observed in SMCs separated from db/db mice and in SMC lines C-12511. Moreover, luciferase report assay showed that the activity of SIRT1 3′-UTR was highly increased by miR-138 inhibitor and reduced by miR-138 mimic. In addition, we examined that the up-regulation of NF-κB induced by high glucose in SMCs was reversed by resveratrol and miR-138 inhibitor. MTT and migration assays showed that miR-138 inhibitor attenuated the proliferation and migration of smooth muscle cells. Conclusion: In this study, we revealed that miR-138 might promote proliferation and migration of SMC in db/db mice through suppressing the expression of SIRT1. - Highlights: • Higher mRNA level of miR-138 was observed in SMCs from db/db mice. • The mRNA and protein level of SIRT1 in SMCs from db/db mice were greatly reduced. • miR-138 could regulate the expression of SIRT1 in SMCs. • SIRT1 overexpression reversed the up-regulation of acetylized p65 and NF-κB induced by high glucose. • MiR-138 inhibitor reversed VSMCs proliferation and migration induced by high glucose.

  11. Mst1 Kinase Regulates the Actin-Bundling Protein L-Plastin To Promote T Cell Migration.

    PubMed

    Xu, Xiaolu; Wang, Xinxin; Todd, Elizabeth M; Jaeger, Emily R; Vella, Jennifer L; Mooren, Olivia L; Feng, Yunfeng; Hu, Jiancheng; Cooper, John A; Morley, Sharon Celeste; Huang, Yina H

    2016-09-01

    Exploring the mechanisms controlling lymphocyte trafficking is essential for understanding the function of the immune system and the pathophysiology of immunodeficiencies. The mammalian Ste20-like kinase 1 (Mst1) has been identified as a critical signaling mediator of T cell migration, and loss of Mst1 results in immunodeficiency disease. Although Mst1 is known to support T cell migration through induction of cell polarization and lamellipodial formation, the downstream effectors of Mst1 are incompletely defined. Mice deficient for the actin-bundling protein L-plastin (LPL) have phenotypes similar to mice lacking Mst1, including decreased T cell polarization, lamellipodial formation, and cell migration. We therefore asked whether LPL functions downstream of Mst1. The regulatory N-terminal domain of LPL contains a consensus Mst1 phosphorylation site at Thr(89) We found that Mst1 can phosphorylate LPL in vitro and that Mst1 can interact with LPL in cells. Removal of the Mst1 phosphorylation site by mutating Thr(89) to Ala impaired localization of LPL to the actin-rich lamellipodia of T cells. Expression of the T89A LPL mutant failed to restore migration of LPL-deficient T cells in vitro. Furthermore, expression of T89A LPL in LPL-deficient hematopoietic cells, using bone marrow chimeras, failed to rescue the phenotype of decreased thymic egress. These results identify LPL as a key effector of Mst1 and establish a novel mechanism linking a signaling intermediate to an actin-binding protein critical to T cell migration. PMID:27465533

  12. Netrins and Frazzled/DCC promote the migration and mesenchymal to epithelial transition of Drosophila midgut cells

    PubMed Central

    Pert, Melissa; Gan, Miao; Saint, Robert; Murray, Michael J.

    2015-01-01

    ABSTRACT Mesenchymal-epithelial transitions (METs) are important in both development and the growth of secondary tumours. Although the molecular basis for epithelial polarity is well studied, less is known about the cues that induce MET. Here we show that Netrins, well known as chemotropic guidance factors, provide a basal polarising cue during the Drosophila midgut MET. Both netrinA and netrinB are expressed in the visceral mesoderm, the substrate upon which midgut cells migrate, while their receptor frazzled (fra) is expressed in midgut cells. Netrins are required to polarise Fra to the basal surface, and Netrins and Fra undergo mutually-dependent endocytosis, with Fra subsequently trafficking to late endosomes. Mutations to fra and netrins affect both migration and MET but to different degrees. Loss of fra strongly delays migration, midgut cells fail to extend protrusions, and apico-basal polarisation of proteins and epithelium formation is inhibited. In netrin mutants, the migration phenotype is weaker and cells still extend protrusions. However, apico-basal polarisation of proteins, including Fra, and FActin is greatly disrupted and a monolayer fails to form. Delocalised accumulations of FActin are prevalent in netrin mutants but not fra mutants suggesting delocalised Fra may disrupt the MET. βPS localisation is also affected in netrin mutants in that a basal gradient is reduced while localisation to the midgut/VM interface is increased. Since a similar effect is seen when endocytosis is inhibited, Netrin and Fra may regulate Integrin turnover. The results suggest Netrin-dependent basal polarisation of Fra is critical for the formation of an epithelium. PMID:25617422

  13. Netrins and Frazzled/DCC promote the migration and mesenchymal to epithelial transition of Drosophila midgut cells.

    PubMed

    Pert, Melissa; Gan, Miao; Saint, Robert; Murray, Michael J

    2015-01-23

    Mesenchymal-epithelial transitions (METs) are important in both development and the growth of secondary tumours. Although the molecular basis for epithelial polarity is well studied, less is known about the cues that induce MET. Here we show that Netrins, well known as chemotropic guidance factors, provide a basal polarising cue during the Drosophila midgut MET. Both netrinA and netrinB are expressed in the visceral mesoderm, the substrate upon which midgut cells migrate, while their receptor frazzled (fra) is expressed in midgut cells. Netrins are required to polarise Fra to the basal surface, and Netrins and Fra undergo mutually-dependent endocytosis, with Fra subsequently trafficking to late endosomes. Mutations to fra and netrins affect both migration and MET but to different degrees. Loss of fra strongly delays migration, midgut cells fail to extend protrusions, and apico-basal polarisation of proteins and epithelium formation is inhibited. In netrin mutants, the migration phenotype is weaker and cells still extend protrusions. However, apico-basal polarisation of proteins, including Fra, and FActin is greatly disrupted and a monolayer fails to form. Delocalised accumulations of FActin are prevalent in netrin mutants but not fra mutants suggesting delocalised Fra may disrupt the MET. βPS localisation is also affected in netrin mutants in that a basal gradient is reduced while localisation to the midgut/VM interface is increased. Since a similar effect is seen when endocytosis is inhibited, Netrin and Fra may regulate Integrin turnover. The results suggest Netrin-dependent basal polarisation of Fra is critical for the formation of an epithelium.

  14. Cross-talk between lysophosphatidic acid receptor 1 and tropomyosin receptor kinase A promotes lung epithelial cell migration.

    PubMed

    Nan, Ling; Wei, Jianxin; Jacko, Anastasia M; Culley, Miranda K; Zhao, Jing; Natarajan, Viswanathan; Ma, Haichun; Zhao, Yutong

    2016-02-01

    Lysophosphatidic acid (LPA) is a bioactive lysophospholipid, which plays a crucial role in the regulation of cell proliferation, migration, and differentiation. LPA exerts its biological effects mainly through binding to cell-surface LPA receptors (LPA1-6), which belong to the G protein-coupled receptor (GPCR) family. Recent studies suggest that cross-talk between receptor tyrosine kinases (RTKs) and GPCRs modulates GPCRs-mediated signaling. Tropomyosin receptor kinase A (TrkA) is a RTK, which mediates nerve growth factor (NGF)-induced biological functions including cell migration in neuronal and non-neuronal cells. Here, we show LPA1 transactivation of TrkA in murine lung epithelial cells (MLE12). LPA induced tyrosine phosphorylation of TrkA in both time- and dose-dependent manners. Down-regulation of LPA1 by siRNA transfection attenuated LPA-induced phosphorylation of TrkA, suggesting a cross-talk between LPA1 and TrkA. To investigate the molecular regulation of the cross-talk, we focused on the interaction between LPA1 and TrkA. We found that LPA induced interaction between LPA1 and TrkA. The LPA1/TrkA complex was localized on the plasma membrane and in the cytoplasm. The C-terminus of LPA1 was identified as the binding site for TrkA. Inhibition of TrkA attenuated LPA-induced phosphorylation of TrkA and LPA1 internalization, as well as lung epithelial cell migration. These studies provide a molecular mechanism for the transactivation of TrkA by LPA, and suggest that the cross-talk between LPA1 and TrkA regulates LPA-induced receptor internalization and lung epithelial cell migration. PMID:26597701

  15. MLK3 is critical for breast cancer cell migration and promotes a malignant phenotype in mammary epithelial cells.

    PubMed

    Chen, J; Miller, E M; Gallo, K A

    2010-08-01

    The malignant phenotype in breast cancer is driven by aberrant signal transduction pathways. Mixed-lineage kinase-3 (MLK3) is a mammalian mitogen-activated protein kinase kinase kinase (MAP3K) that activates multiple MAPK pathways. Depending on the cellular context, MLK3 has been implicated in apoptosis, proliferation, migration and differentiation. Here we investigated the effect of MLK3 and its signaling to MAPKs in the acquisition of malignancy in breast cancer. We show that MLK3 is highly expressed in breast cancer cells. We provide evidence that MLK3's catalytic activity and signaling to c-jun N-terminal kinase (JNK) is required for migration of highly invasive breast cancer cells and for MLK3-induced migration of mammary epithelial cells. Expression of active MLK3 is sufficient to induce the invasion of mammary epithelial cells, which requires AP-1 activity and is accompanied by the expression of several proteins corresponding to AP-1-regulated invasion genes. To assess MLK3's contribution to the breast cancer malignant phenotype in a more physiological setting, we implemented a strategy to inducibly express active MLK3 in the preformed acini of MCF10A cells grown in 3D Matrigel. Induction of MLK3 expression dramatically increases acinar size and modestly perturbs apicobasal polarity. Remarkably, MLK3 expression induces luminal repopulation and suppresses the expression of the pro-apoptotic protein BimEL, as has been observed in Her2/Neu-expressing acini. Taken together, our data show that MLK3-JNK-AP-1 signaling is critical for breast cancer cell migration and invasion. Our current study uncovers both a proliferative and novel antiapoptotic role for MLK3 in the acquisition of a malignant phenotype in mammary epithelial cells. Thus, MLK3 may be an important therapeutic target for the treatment of invasive breast cancer.

  16. Decorin-Mediated Inhibition of Human Trophoblast Cells Proliferation, Migration, and Invasion and Promotion of Apoptosis In Vitro.

    PubMed

    Zou, Yanfen; Yu, Xiang; Lu, Jing; Jiang, Ziyan; Zuo, Qing; Fan, Mingsong; Huang, Shiyun; Sun, Lizhou

    2015-01-01

    Preeclampsia (PE) is a unique complication of pregnancy, the pathogenesis of which has been generally accepted to be associated with the dysfunctions of extravillous trophoblast (EVT) including proliferation, apoptosis, and migration and invasion. Decorin (DCN) has been proved to be a decidua-derived TGF-binding proteoglycan, which negatively regulates proliferation, migration, and invasiveness of human extravillous trophoblast cells. In this study, we identified a higher expression level of decorin in severe PE placentas by both real-time reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). And an inhibitory effect of decorin on proliferation, migration, and invasion and an enhanced effect on apoptosis in trophoblast cells HTR-8/SVneo and JEG-3 were validated in vitro. Also the modulations of decorin on trophoblast cells' metastasis and invasion functions were detected through regulating the matrix metalloproteinases (MMP2 and MMP9). Thus, we suggested that the contribution of decorin to the modulation of trophoblast cells might have implications for the pathogenesis of preeclampsia. PMID:26357650

  17. TEM7 (PLXDC1), a key prognostic predictor for resectable gastric cancer, promotes cancer cell migration and invasion

    PubMed Central

    Zhang, Zi-Zhen; Hua, Rong; Zhang, Jun-Feng; Zhao, Wen-Yi; Zhao, En-Hao; Tu, Lin; Wang, Chao-Jie; Cao, Hui; Zhang, Zhi-Gang

    2015-01-01

    Tumor endothelial marker 7 (TEM7) is a new candidate of molecular target for antiangiogenic therapy. This study aims to evaluate its expression in gastric cancer (GC) and to explore the correlation between its expression and the clinical outcome of patients. Expression of TEM7 was analyzed in both tumor tissues and cell lines of GC by real-time quantitative RT-PCR (qRT-PCR) and Western blot. RNA interference (RNAi) approaches were used to investigate the biological functions of TEM7. The effects of TEM7 on cell migration and invasion were evaluated by Transwell assays. In vitro experiments revealed that TEM7 was significantly overexpressed in GC cell lines (N87, AGS and SGC-7901) by 2-fold to 4-fold, and knockdown of TEM7 could significantly inhibit cancer cell migration and invasion. For GC patients, TEM7 gene expression was elevated in tumors in most cases (25/31), and its expression was closely correlated with tumor differentiation, depth of cancer invasion, lymphatic metastasis and TNM stage. The overall survival of TEM7 (-) group was significantly higher than that of TEM7 (+) group (P = 0.048) and TEM7 (++) group (P = 0.003). TEM7 is highly expressed in GC and is likely correlated with tumor invasion and migration, and thus its expression is closely related to the clinical outcome of patients. PMID:25973314

  18. The Hemodynamically-Regulated Vascular Microenvironment Promotes Migration of the Steroidogenic Tissue during Its Interaction with Chromaffin Cells in the Zebrafish Embryo

    PubMed Central

    Chou, Chih-Wei; Zhuo, You-Lin; Jiang, Zhe-Yu; Liu, Yi-Wen

    2014-01-01

    -pFak dependent mechanisms. Conclusions and Significance These results demonstrate that hemodynamically regulated Fn-pFak signaling promotes the migration of steroidogenic cells, ensuring their interaction with chromaffin cells along both sides of the midline during interrenal gland development. PMID:25248158

  19. GPR30 decreases with vascular aging and promotes vascular smooth muscle cells maintaining differentiated phenotype and suppressing migration via activation of ERK1/2

    PubMed Central

    Huang, Fang; Yin, Jianguo; Li, Keyu; Li, Ying; Qi, Heng; Fang, Li; Yuan, Cong; Liu, Weiwei; Wang, Min; Li, Xiangping

    2016-01-01

    Estrogen receptors, including classic nuclear receptors ERα, ERβ, and membrane receptor GPR30, are expressed in vascular tissues and exert protective actions in vascular diseases. But the expression pattern and functional roles of GPR30 in vascular smooth muscle cells (VSMCs) remain unclear. In this study, we found that ERα, ERβ, and GPR30 were decreased with VSMCs passaging in vitro or growing in vivo and activation of GPR30 promoted ERα expression. Then, we validated that activation of GPR30 significantly decreased migratory capability of VSMCs and suppressed ERα, whereas PDGF-BB (20 ng/mL) treatment caused increase of migration. And activation of GPR30 led to reduction of osteopontin and cellular retinol binding protein 1, enhancement of calponin and 3F8, and upregulation of total and phosphorylated ERK1/2 expression in VSMCs knocked down by GPR30, ERα, and ERβ or treated with PDGF-BB. These data suggest that GPR30 promotes VSMCs reducing migration and maintaining differentiated phenotype via activation of ERK1/2 pathway. Our findings provide novel mechanisms of GPR30 protection of VSMCs as well as a new target for prevention of vascular aging. PMID:27354813

  20. Methylcobalamin promotes proliferation and migration and inhibits apoptosis of C2C12 cells via the Erk1/2 signaling pathway

    SciTech Connect

    Okamoto, Michio; Tanaka, Hiroyuki; Okada, Kiyoshi; Kuroda, Yusuke; Nishimoto, Shunsuke; Murase, Tsuyoshi; Yoshikawa, Hideki

    2014-01-17

    Highlights: •Methylcobalamin activated the Erk1/2 signaling pathway in C2C12 cells. •Methylcobalamin promoted the proliferation and migration in C2C12 cells. •C2C12 cell apoptosis during differentiation was inhibited by methylcobalamin. -- Abstract: Methylcobalamin (MeCbl) is a vitamin B12 analog that has some positive effects on peripheral nervous disorders. Although some previous studies revealed the effects of MeCbl on neurons, its effect on the muscle, which is the final target of motoneuron axons, remains to be elucidated. This study aimed to determine the effect of MeCbl on the muscle. We found that MeCbl promoted the proliferation and migration of C2C12 myoblasts in vitro and that these effects are mediated by the Erk1/2 signaling pathway without affecting the activity of the Akt signaling pathway. We also demonstrated that MeCbl inhibits C2C12 cell apoptosis during differentiation. Our results suggest that MeCbl has beneficial effects on the muscle in vitro. MeCbl administration may provide a novel therapeutic approach for muscle injury or degenerating muscle after denervation.

  1. Protein kinase Ciota promotes nicotine-induced migration and invasion of cancer cells via phosphorylation of micro- and m-calpains.

    PubMed

    Xu, Lijun; Deng, Xingming

    2006-02-17

    Nicotine is a major component in cigarette smoke that activates the growth-promoting pathways to facilitate the development of lung cancer. However, it is not clear whether nicotine affects cell motility to facilitate tumor metastasis. Here we discovered that nicotine potently induces phosphorylation of both mu- and m-calpains via activation of protein kinase Ciota (PKCiota), which is associated with accelerated migration and invasion of human lung cancer cells. Purified PKCiota directly phosphorylates mu- and m-calpains in vitro. Overexpression of PKCiota results in increased phosphorylation of both mu- and m-calpains in vivo. Nicotine also induces activation of c-Src, which is a known PKCiota upstream kinase. Treatment of cells with the alpha(7) nicotinic acetylcholine receptor inhibitor alpha-bungarotoxin can block nicotine-induced calpain phosphorylation with suppression of calpain activity, wound healing, cell migration, and invasion, indicating that nicotine-induced calpain phosphorylation occurs, at least in part, through a signaling pathway involving the upstream alpha(7) nicotinic acetylcholine receptor. Intriguingly, depletion of PKCiota by RNA interference suppresses nicotine-induced calpain phosphorylation, calpain activity, cell migration, and invasion, indicating that PKCiota is a necessary component in nicotine-mediated cell motility signaling. Importantly, nicotine potently induces secretion of mu- and m-calpains from lung cancer cells into culture medium, which may have potential to cleave substrates in the extracellular matrix. These findings reveal a novel role for PKCiota as a nicotine-activated, physiological calpain kinase that directly phosphorylates and activates calpains, leading to enhanced migration and invasion of human lung cancer cells.

  2. 2,2',4,4'-Tetrabromodiphenyl ether promotes human neuroblastoma SH-SY5Y cells migration via the GPER/PI3K/Akt signal pathway.

    PubMed

    Tian, P-C; Wang, H-L; Chen, G-H; Luo, Q; Chen, Z; Wang, Y; Liu, Y-F

    2016-02-01

    Neuroblastoma is the predominant tumor of early childhood. 2,2',4,4'-Tetrabromodiphenyl ether (BDE-47) has the highest concentration among all polybrominated diphenyl ether (PBDE) congeners in human body, particularly for children. Considering that accumulating evidences showed developmental neurotoxicity of PBDE, there is an urgent need to investigate the effects of BDE-47 on the development of neuroblastoma. This study revealed that BDE-47 had limited effects on the cytotoxicity while significantly increased the in vitro migration and invasion of human neuroblastoma SH-SY5Y cells. This was further confirmed by the results that BDE-47 treatment significantly downregulated the expression of E-cadherin and zona occludin-1 and upregulated the expression of matrix metalloproteinase-9 (MMP-9). Silencing of MMP-9 by specific small interfering RNA significantly abolished the BDE-47-induced migration and invasion of SH-SY5Y cells. Further, the signals G protein-coupled estrogen receptor 1 (GPER)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt) mediated the BDE-47-induced upregulation of MMP-9 and in vitro migration of SH-SY5Y cells since G15 (GPER inhibitor) and LY 294002 (PI3K/Akt inhibitor) significantly abolished the effects of BDE-47. Our results revealed that BDE-47 significantly triggered the metastasis of human neuroblastoma SH-SY5Y cells via upregulation of MMP-9 by the GPER/PI3K/Akt signal pathway. This study revealed for the first time that BDE-47 can promote the migration of SH-SY5Y cells. It also provided a better understanding about the metastasis of human neuroblastoma induced by environmental endocrine disruptors.

  3. SCF promotes dental pulp progenitor migration, neovascularization, and collagen remodeling – potential applications as a homing factor in dental pulp regeneration

    PubMed Central

    Pan, Shuang; Dangaria, Smit; Gopinathan, Gokul; Yan, Xiulin; Lu, Xuanyu; Kolokythas, Antonia; Niu, Yumei; Luan, Xianghong

    2014-01-01

    Stem cell factor (SCF) is a powerful chemokine that binds to the c-Kit receptor CD117 and has shown promise as a homing agent capable of progenitor cell recruitment. In the present study we have documented high levels of both SCF and its receptor c-Kit in differentiating dental pulp (DP) cells and in the sub-odontoblastic layer of Höhl. In vitro studies using human DP progenitors revealed a significant increase in cell proliferation after100nM SCF application, explained by a 2-fold upregulation in cyclin D3 and FGF2 cell cycle regulators, and a 7-fold increase in CDK4 expression. DP cell migration in the presence of SCF was up-regulated 2.7-fold after a 24 hour culture period, and this effect was accompanied by cytoskeletal rearrangement, a 1.5-fold increase in polymeric F-actin over G-actin, and a 1.8-fold increase in RhoA expression. Explaining the signaling effect of SCF on DP migration, PI3K/Akt and MEK/ERK pathway inhibitors were demonstrated to significantly reduce DP cell migration, while SCF alone doubled the number of migrated cells. ERK and AKT phosphorylation were dramatically upregulated already 3-5 minutes after SCF addition to the culture medium and declined thereafter, classifying SCF as a fast acting chemokine. When applied as an agent to promote tissue regeneration in subcutaneously implanted collagen sponges, SCF resulted in a 7-fold increase in the cell number in the implanted tissue construct, a more than 9-fold increase in capillaries, as well as collagen sponge remodeling and collagen fiber neogenesis. Together, these studies demonstrate the suitability of SCF as a potent aid in the regeneration of dental pulp and other mesenchymal tissues, capable of inducing cell homing, angiogenesis, and tissue remodeling. PMID:23703692

  4. Overexpression of activin-A and -B in malignant mesothelioma – Attenuated Smad3 signaling responses and ERK activation promote cell migration and invasive growth

    SciTech Connect

    Tamminen, Jenni A.; Yin, Miao; Rönty, Mikko; Sutinen, Eva; Pasternack, Arja; Ritvos, Olli; Myllärniemi, Marjukka; Koli, Katri

    2015-03-01

    Activin-A and activin-B, members of the TGF-β superfamily, are regulators of reproductive functions, inflammation and wound healing. These dimeric molecules regulate various cellular activities such as proliferation, migration and suvival. Malignant mesothelioma is an asbestos exposure related tumor affecting mainly pleura and it usually has a dismal prognosis. Here, we demonstrate that both activin-A and -B are abundantly expressed in mesothelioma tumor tissue as well as in cultured primary and established mesothelioma cells. Migratory and invasive mesothelioma cells were also found to have attenuated activation of the Smad2/3 pathway in response to activins. Migration and invasive growth of the cells in three-dimentional matrix was prevented by inhibition of activin activity using a soluble activin receptor 2B (sActR2B-Fc). This was associated with decreased ERK activity. Furthermore, migration and invasive growth was significantly inhibited by blocking ERK phosphorylation. Mesothelioma tumors are locally invasive and our results clearly suggest that acivins have a tumor-promoting function in mesothelioma through increasing expression and switching from canonical Smad3 pathway to non-canonical ERK pathway signaling. Blocking activin activity offers a new therapeutic approach for inhibition of mesothelioma invasive growth. - Highlights: • Activin-A and activin-B are highly expressed in mesothelioma. • Mesothelioma cell migration and invasive growth can be blocked with sActR2B. • Activin induced Smad3 activity is attenuated in invasive mesothelioma cells. • Activins induce ERK activity in mesothelioma cells.

  5. N-Cadherin Promotes Recruitment and Migration of Neural Progenitor Cells from the SVZ Neural Stem Cell Niche into Demyelinated Lesions

    PubMed Central

    Klingener, Michael; Chavali, Manideep; Singh, Jagdeep; McMillan, Nadia; Coomes, Alexandra; Dempsey, Peter J.; Chen, Emily I.

    2014-01-01

    Discrete cellular microenvironments regulate stem cell pools and their development, as well as function in maintaining tissue homeostasis. Although the signaling elements modulating neural progenitor cells (NPCs) of the adult subventricular zone (SVZ) niche are fairly well understood, the pathways activated following injury and the resulting outcomes, are less clear. In the present study, we used mouse models of demyelination and proteomics analysis to identify molecular cues present in the adult SVZ niche during injury, and analyzed their role on NPCs in the context of promoting myelin repair. Proteomic analysis of SVZ tissue from mice with experimental demyelination identified several proteins that are known to play roles in NPC proliferation, adhesion, and migration. Among the proteins found to be upregulated were members of the N-cadherin signaling pathway. During the onset of demyelination in the subcortical white matter (SCWM), activation of epidermal growth factor receptor (EGFR) signaling in SVZ NPCs stimulates the interaction between N-cadherin and ADAM10. Upon cleavage and activation of N-cadherin signaling by ADAM10, NPCs undergo cytoskeletal rearrangement and polarization, leading to enhanced migration out of the SVZ into demyelinated lesions of the SCWM. Genetically disrupting either EGFR signaling or ADAM10 inhibits this pathway, preventing N-cadherin regulated NPC polarization and migration. Additionally, in vivo experiments using N-cadherin gain- and loss-of-function approaches demonstrated that N-cadherin enhances the recruitment of SVZ NPCs into demyelinated lesions. Our data revealed that EGFR-dependent N-cadherin signaling physically initiated by ADAM10 cleavage is the response of the SVZ niche to promote repair of the injured brain. PMID:25031401

  6. IL-17A Promotes the Migration and Invasiveness of Cervical Cancer Cells by Coordinately Activating MMPs Expression via the p38/NF-κB Signal Pathway

    PubMed Central

    Chen, Kunlun; Bian, Zhuoqiong; Jinfang Wu; Gao, Qing

    2014-01-01

    Objective IL-17A plays an important role in many inflammatory diseases and cancers. We aimed to examine the effect of IL-17A on the invasion of cervical cancer cells and study its related mechanisms. Methods Wound healing and matrigel transwell assays were used to examine the effect of IL-17A on cervical cancer cell migration and invasion by a panel of cervical cancer cell lines. The levels of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) were investigated using western blotting. The activity of p38 and nuclear factor-kappa B (NF-κB) signal pathway was detected too. Results Here, we showed that IL-17A could promote the migration and invasion of cervical cancer cells. Further molecular analysis showed that IL-17A could up-regulate the expressions and activities of MMP2 and MMP9, and down-regulate the expressions of TIMP-1 and TIMP-2. Furthermore, IL-17A also activates p38 signal pathway and increased p50 and p65 nuclear expression. In addition, treatment of cervical cancer cells with the pharmacological p38/NF-κB signal pathway inhibitors, SB203580 and PDTC, potently restored the roles of invasion and upregulation of MMPs induced by IL-17A. Conclusion IL-17A could promote the migration and invasion of cervical cancer cell via up-regulating MMP2 and MMP9 expression, and down-regulating TIMP-1 and TIMP-2 expression via p38/NF-κB signal pathway. IL-17A may be a potential target to improve the prognosis for patients with cervical cancer. PMID:25250801

  7. USE OF CATIONIC SURFACTANTS TO MODIFY SOIL SURFACES TO PROMOTE SORPTION AND RETARD MIGRATION OF HYDROPHOBIC ORGANIC COMPOUNDS

    EPA Science Inventory

    Cationic surfactants can be used to modify surfaces of soils and subsurface materials to promote adsorption of hydrophobic organic compounds (HOC). Batch and column experiments were performed to investigate this phenomenon with the cationic surfactant dodecylpyridinium (DP), a se...

  8. MicroRNA-373 promotes migration and invasion in human esophageal squamous cell carcinoma by inhibiting TIMP3 expression.

    PubMed

    Liu, Wenzhi; Li, Mengkao; Chen, Xiangming; Zhang, Dakai; Wei, Lin; Zhang, Zicheng; Wang, Shuang; Meng, Li; Zhu, Shan; Li, Baosheng

    2016-01-01

    Esophageal squamous cell carcinoma (ESCC) is the predominant pathological type of esophageal carcinoma in Asia. MicroRNAs (miRNAs) are a class of 19-22-nucleotide non-coding RNAs acting on target mRNAs that function as either oncogenes or anti-oncogenes. It has been confirmed that miR-373 expression varies among different tumor types. However, its mechanism is still unclear in ESCC. In our current study, we found that miR-373 expression was upregulated in ESCC tissues compared with matched adjacent normal tissues, as well as in the plasma of ESCC patients compared with that of healthy volunteers. Overexpression of miR-373 in ECA109 cells enhanced proliferation, G1-phase cell proportion, migration, and invasion. On the other hand, suppression of miR-373 in KYSE410 cells decreased proliferation, G1-phase cell proportion, migration, and invasion and also improved cell apoptosis. Moreover, we found that TIMP3, which was reported to suppress invasion and metastasis of ESCC, was a direct target of miR-373. Overexpression of miR-373 in ECA109 caused a reduction of TIMP3 mRNA and protein, whereas suppression of miR-373 in KYSE410 led to an increase of TIMP3 mRNA and protein. Introducing TIMP3 in miR-373 over-expressed cells or knocking down TIMP3 in miR-373 suppressed cells could partially abrogate the effect of miR-373 on migration and invasion. Therefore, these results prove that as an oncogene, miRNA-373 would be an important and reliable biomarker for ESCC diagnosis and treatment by targeting TIMP3.

  9. MicroRNA-373 promotes migration and invasion in human esophageal squamous cell carcinoma by inhibiting TIMP3 expression

    PubMed Central

    Liu, Wenzhi; Li, Mengkao; Chen, Xiangming; Zhang, Dakai; Wei, Lin; Zhang, Zicheng; Wang, Shuang; Meng, Li; Zhu, Shan; Li, Baosheng

    2016-01-01

    Esophageal squamous cell carcinoma (ESCC) is the predominant pathological type of esophageal carcinoma in Asia. MicroRNAs (miRNAs) are a class of 19-22-nucleotide non-coding RNAs acting on target mRNAs that function as either oncogenes or anti-oncogenes. It has been confirmed that miR-373 expression varies among different tumor types. However, its mechanism is still unclear in ESCC. In our current study, we found that miR-373 expression was upregulated in ESCC tissues compared with matched adjacent normal tissues, as well as in the plasma of ESCC patients compared with that of healthy volunteers. Overexpression of miR-373 in ECA109 cells enhanced proliferation, G1-phase cell proportion, migration, and invasion. On the other hand, suppression of miR-373 in KYSE410 cells decreased proliferation, G1-phase cell proportion, migration, and invasion and also improved cell apoptosis. Moreover, we found that TIMP3, which was reported to suppress invasion and metastasis of ESCC, was a direct target of miR-373. Overexpression of miR-373 in ECA109 caused a reduction of TIMP3 mRNA and protein, whereas suppression of miR-373 in KYSE410 led to an increase of TIMP3 mRNA and protein. Introducing TIMP3 in miR-373 over-expressed cells or knocking down TIMP3 in miR-373 suppressed cells could partially abrogate the effect of miR-373 on migration and invasion. Therefore, these results prove that as an oncogene, miRNA-373 would be an important and reliable biomarker for ESCC diagnosis and treatment by targeting TIMP3. PMID:27429858

  10. MicroRNA-373 promotes migration and invasion in human esophageal squamous cell carcinoma by inhibiting TIMP3 expression

    PubMed Central

    Liu, Wenzhi; Li, Mengkao; Chen, Xiangming; Zhang, Dakai; Wei, Lin; Zhang, Zicheng; Wang, Shuang; Meng, Li; Zhu, Shan; Li, Baosheng

    2016-01-01

    Esophageal squamous cell carcinoma (ESCC) is the predominant pathological type of esophageal carcinoma in Asia. MicroRNAs (miRNAs) are a class of 19-22-nucleotide non-coding RNAs acting on target mRNAs that function as either oncogenes or anti-oncogenes. It has been confirmed that miR-373 expression varies among different tumor types. However, its mechanism is still unclear in ESCC. In our current study, we found that miR-373 expression was upregulated in ESCC tissues compared with matched adjacent normal tissues, as well as in the plasma of ESCC patients compared with that of healthy volunteers. Overexpression of miR-373 in ECA109 cells enhanced proliferation, G1-phase cell proportion, migration, and invasion. On the other hand, suppression of miR-373 in KYSE410 cells decreased proliferation, G1-phase cell proportion, migration, and invasion and also improved cell apoptosis. Moreover, we found that TIMP3, which was reported to suppress invasion and metastasis of ESCC, was a direct target of miR-373. Overexpression of miR-373 in ECA109 caused a reduction of TIMP3 mRNA and protein, whereas suppression of miR-373 in KYSE410 led to an increase of TIMP3 mRNA and protein. Introducing TIMP3 in miR-373 over-expressed cells or knocking down TIMP3 in miR-373 suppressed cells could partially abrogate the effect of miR-373 on migration and invasion. Therefore, these results prove that as an oncogene, miRNA-373 would be an important and reliable biomarker for ESCC diagnosis and treatment by targeting TIMP3. PMID:27073718

  11. Fibrin sealant promotes migration and proliferation of human articular chondrocytes: possible involvement of thrombin and protease-activated receptors.

    PubMed

    Kirilak, Yaowanuj; Pavlos, Nathan J; Willers, Craig R; Han, Renzhi; Feng, Haotian; Xu, Jiake; Asokananthan, Nithiananthan; Stewart, Geoffrey A; Henry, Peter; Wood, David; Zheng, Ming H

    2006-04-01

    Fibrin sealant (FS), a biological adhesive material, has been recently recommended as an adjunct in autologous chondrocyte implantation (ACI). While FS has been shown to possess osteoinductive potential, little is known about its effects on chondrogenic cells. In this study, we assessed the bioactivity of FS (Tisseel) on the migration and proliferation of human articular chondrocytes in vitro. Using a co-culture assay to mimic matrix-induced ACI (MACI), chondrocytes were found to migrate from collagen membranes towards FS within 12 h of culture, with significant migratory activity evident by 24 h. In addition, 5-bromo-2'-deoxyuridine (BrdU) incorporation experiments revealed that thrombin, the active component of the tissue glue, stimulated chondrocyte proliferation, with maximal efficacy observed at 48 h post-stimulation (1-10 U/ml). In an effort to elucidate the molecular mechanisms underlying these thrombin-induced effects, we examined the expression and activation of protease-activated receptors (PARs), established thrombin receptors. Using a combination of RT-PCR and immunohistochemistry, all four PARs were detected in human chondrocytes, with PAR-1 being the major isoform expressed. Moreover, thrombin and a PAR-1, but not other PAR-isotype-specific peptide agonists, were found to induce rapid intracellular Ca2+ responses in human chondrocytes in calcium mobilization assays. Together, these data demonstrate that FS supports both the migration and proliferation of human chondrocytes. We propose that these effects are mediated, at least in part, via thrombin-induced PAR-1 signalling in human chondrocytes. PMID:16525709

  12. Alpha-enolase as a potential cancer prognostic marker promotes cell growth, migration, and invasion in glioma

    PubMed Central

    2014-01-01

    Background The success of using glycolytic inhibitors for cancer treatment relies on better understanding the roles of each frequently deregulated glycolytic genes in cancer. This report analyzed the involvement of a key glycolytic enzyme, alpha-enolase (ENO1), in tumor progression and prognosis of human glioma. Methods ENO1 expression levels were examined in glioma tissues and normal brain (NB) tissues. The molecular mechanisms of ENO1 expression and its effects on cell growth, migration and invasion were also explored by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, Transwell chamber assay, Boyden chamber assay, Western blot and in vivo tumorigenesis in nude mice. Results ENO1 mRNA and protein levels were upregulated in glioma tissues compared to NB. In addition, increased ENO1 was associated disease progression in glioma samples. Knocking down ENO1 expression not only significantly decreased cell proliferation, but also markedly inhibited cell migration and invasion as well as in vivo tumorigenesis. Mechanistic analyses revealed that Cyclin D1, Cyclin E1, pRb, and NF-κB were downregulated after stable ENO1 knockdown in glioma U251 and U87 cells. Conversely, knockdown of ENO1 resulted in restoration of E-cadherin expression and suppression of mesenchymal cell markers, such as Vimentin, Snail, N-Cadherin, β-Catenin and Slug. Furthermore, ENO1 suppression inactivated PI3K/Akt pathway regulating the cell growth and epithelial-mesenchymal transition (EMT) progression. Conclusion Overexpression of ENO1 is associated with glioma progression. Knockdown of ENO1 expression led to suppressed cell growth, migration and invasion progression by inactivating the PI3K/Akt pathway in glioma cells. PMID:24650096

  13. miR-29b induces SOCS-1 expression by promoter demethylation and negatively regulates migration of multiple myeloma and endothelial cells.

    PubMed

    Amodio, Nicola; Bellizzi, Dina; Leotta, Marzia; Raimondi, Lavinia; Biamonte, Lavinia; D'Aquila, Patrizia; Di Martino, Maria Teresa; Calimeri, Teresa; Rossi, Marco; Lionetti, Marta; Leone, Emanuela; Passarino, Giuseppe; Neri, Antonino; Giordano, Antonio; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

    2013-12-01

    Epigenetic silencing of tumor suppressor genes frequently occurs and may account for their inactivation in cancer cells. We previously demonstrated that miR-29b is a tumor suppressor microRNA (miRNA) that targets de novo DNA methyltransferases and reduces the global DNA methylation of multiple myeloma (MM) cells. Here, we provide evidence that epigenetic activity of miR-29b leads to promoter demethylation of suppressor of cytokine signaling-1 (SOCS-1), a hypermethylated tumor suppressor gene. Enforced expression of synthetic miR-29b mimics in MM cell lines resulted in SOCS-1 gene promoter demethylation, as assessed by Sequenom MassARRAY EpiTYPER analysis, and SOCS-1 protein upregulation. miR-29b-induced SOCS-1 demethylation was associated with reduced STAT3 phosphorylation and impaired NFκB activity. Downregulation of VEGF-A and IL-8 mRNAs could be detected in MM cells transfected with miR-29b mimics as well as in endothelial (HUVEC) or stromal (HS-5) cells treated with conditioned medium from miR-29b-transfected MM cells. Notably, enforced expression of miR-29b mimics increased adhesion of MM cells to HS-5 and reduced migration of both MM and HUVEC cells. These findings suggest that miR-29b is a negative regulator of either MM or endothelial cell migration. Finally, the proteasome inhibitor bortezomib, which induces the expression of miR-29b, decreased global DNA methylation by a miR-29b-dependent mechanism and induced SOCS-1 promoter demethylation and protein upregulation. In conclusion, our data indicate that miR-29b is endowed with epigenetic activity and mediates previously unknown functions of bortezomib in MM cells. PMID:24091729

  14. miR-29b induces SOCS-1 expression by promoter demethylation and negatively regulates migration of multiple myeloma and endothelial cells

    PubMed Central

    Amodio, Nicola; Bellizzi, Dina; Leotta, Marzia; Raimondi, Lavinia; Biamonte, Lavinia; D’Aquila, Patrizia; Di Martino, Maria Teresa; Calimeri, Teresa; Rossi, Marco; Lionetti, Marta; Leone, Emanuela; Passarino, Giuseppe; Neri, Antonino; Giordano, Antonio; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

    2013-01-01

    Epigenetic silencing of tumor suppressor genes frequently occurs and may account for their inactivation in cancer cells. We previously demonstrated that miR-29b is a tumor suppressor microRNA (miRNA) that targets de novo DNA methyltransferases and reduces the global DNA methylation of multiple myeloma (MM) cells. Here, we provide evidence that epigenetic activity of miR-29b leads to promoter demethylation of suppressor of cytokine signaling-1 (SOCS-1), a hypermethylated tumor suppressor gene. Enforced expression of synthetic miR-29b mimics in MM cell lines resulted in SOCS-1 gene promoter demethylation, as assessed by Sequenom MassARRAY EpiTYPER analysis, and SOCS-1 protein upregulation. miR-29b-induced SOCS-1 demethylation was associated with reduced STAT3 phosphorylation and impaired NFκB activity. Downregulation of VEGF-A and IL-8 mRNAs could be detected in MM cells transfected with miR-29b mimics as well as in endothelial (HUVEC) or stromal (HS-5) cells treated with conditioned medium from miR-29b-transfected MM cells. Notably, enforced expression of miR-29b mimics increased adhesion of MM cells to HS-5 and reduced migration of both MM and HUVEC cells. These findings suggest that miR-29b is a negative regulator of either MM or endothelial cell migration. Finally, the proteasome inhibitor bortezomib, which induces the expression of miR-29b, decreased global DNA methylation by a miR-29b-dependent mechanism and induced SOCS-1 promoter demethylation and protein upregulation. In conclusion, our data indicate that miR-29b is endowed with epigenetic activity and mediates previously unknown functions of bortezomib in MM cells. PMID:24091729

  15. DENND2B activates Rab13 at the leading edge of migrating cells and promotes metastatic behavior

    PubMed Central

    Ioannou, Maria S.; Bell, Emily S.; Girard, Martine; Chaineau, Mathilde; Hamlin, Jason N.R.; Daubaras, Mark; Monast, Anie; Park, Morag; Hodgson, Louis

    2015-01-01

    The small guanosine triphosphatase Rab13 functions in exocytic vesicle trafficking in epithelial cells. Alterations in Rab13 activity have been observed in human cancers, yet the mechanism of Rab13 activation and its role in cancer progression remain unclear. In this paper, we identify the DENN domain protein DENND2B as the guanine nucleotide exchange factor for Rab13 and develop a novel Förster resonance energy transfer–based Rab biosensor to reveal activation of Rab13 by DENND2B at the leading edge of migrating cells. DENND2B interacts with the Rab13 effector MICAL-L2 at the cell periphery, and this interaction is required for the dynamic remodeling of the cell’s leading edge. Disruption of Rab13-mediated trafficking dramatically limits the invasive behavior of epithelial cells in vitro and the growth and migration of highly invasive cancer cells in vivo. Thus, blocking Rab13 activation by DENND2B may provide a novel target to limit the spread of epithelial cancers. PMID:25713415

  16. Migration Theories

    NASA Astrophysics Data System (ADS)

    Crida, Aurélien

    2015-08-01

    The great variety of the architectures of the extra-solar planetary systems has revealed the fundamental role played by planetary migration: the interactions between the planets and the gaseous disk in which they form leads to a modification of their orbits. Here, I will review the basic processes and the most recent results in this area.Planets up to ~50 Earth masses are prone to so-called type I migration.I will describe the processes at play, namely the Lindblad and corotation torques, and explain how the total torque depends on the planet mass and the local disk structure. Application to realistic disks shows one or two sweet spot(s) for outward migration of planets roughly between 5 and 30 Earth masses around the snowline ; this is confirmed by dedicated 3D numerical simulations. This has strong consequences on the formation of hot Super-Earths or mini-Neptunes.For smaller mass planets, it has been recently proposed that the heating of the neighboring gas by the luminous planet can lead to a positive torque, hence promoting outward migration. On the other hand, if the planet is not a heat source, a cold finger appears, whose resulting torque is negative. Applications of these two recent results should be discussed.Giant planets open gaps in the proto-planetary disk, and then are supposedly subject to type II migration, following the viscous accretion of the disk. This standard picture has been questioned recently, as gas appears to drift through the gap. Although the gap opening process is well understood in 2D for a planet on a fixed orbit, recent results on 3D simulations or migrating planets make the picture more accurate.Our ever better understanding of planet-disk interactions is of crucial importance as the statistics on extra solar systems keep growing and the results of these interactions are now imaged.

  17. Heparan Sulfate Proteoglycans May Promote or Inhibit Cancer Progression by Interacting with Integrins and Affecting Cell Migration

    PubMed Central

    Soares, Mariana A.; Teixeira, Felipe C. O. B.; Fontes, Miguel; Arêas, Ana Lúcia; Leal, Marcelo G.; Pavão, Mauro S. G.; Stelling, Mariana P.

    2015-01-01

    The metastatic disease is one of the main consequences of tumor progression, being responsible for most cancer-related deaths worldwide. This review intends to present and discuss data on the relationship between integrins and heparan sulfate proteoglycans in health and cancer progression. Integrins are a family of cell surface transmembrane receptors, responsible for cell-matrix and cell-cell adhesion. Integrins' main functions include cell adhesion, migration, and survival. Heparan sulfate proteoglycans (HSPGs) are cell surface molecules that play important roles as cell receptors, cofactors, and overall direct or indirect contributors to cell organization. Both molecules can act in conjunction to modulate cell behavior and affect malignancy. In this review, we will discuss the different contexts in which various integrins, such as α5, αV, β1, and β3, interact with HSPGs species, such as syndecans and perlecans, affecting tissue homeostasis. PMID:26558271

  18. CSF-1R as an inhibitor of apoptosis and promoter of proliferation, migration and invasion of canine mammary cancer cells

    PubMed Central

    2013-01-01

    Background Tumor-associated macrophages (TAMs) have high impact on the cancer development because they can facilitate matrix invasion, angiogenesis, and tumor cell motility. It gives cancer cells the capacity to invade normal tissues and metastasize. The signaling of colony-stimulating factor-1 receptor (CSF-1R) which is an important regulator of proliferation and differentiation of monocytes and macrophages regulates most of the tissue macrophages. However, CSF-1R is expressed also in breast epithelial tissue during some physiological stages i.g.: pregnancy and lactation. Its expression has been also detected in various cancers. Our previous study has showed the expression of CSF-1R in all examined canine mammary tumors. Moreover, it strongly correlated with grade of malignancy and ability to metastasis. This study was therefore designed to characterize the role of CSF-1R in canine mammary cancer cells proliferation, apoptosis, migration, and invasion. As far as we know, the study presented hereby is a pioneering experiment in this field of veterinary medicine. Results We showed that csf-1r silencing significantly increased apoptosis (Annexin V test), decreased proliferation (measured as Ki67 expression) and decreased migration (“wound healing” assay) of canine mammary cancer cells. Treatment of these cells with CSF-1 caused opposite effect. Moreover, csf-1r knock-down changed growth characteristics of highly invasive cell lines on Matrigel matrix, and significantly decreased the ability of these cells to invade matrix. CSF-1 treatment increased invasion of cancer cells. Conclusion The evidence of the expression and functional role of the CSF-1R in canine mammary cancer cells indicate that CSF-1R targeting may be a good therapeutic approach. PMID:23561040

  19. Progesterone promotes focal adhesion formation and migration in breast cancer cells through induction of protease-activated receptor-1.

    PubMed

    Diaz, Jorge; Aranda, Evelyn; Henriquez, Soledad; Quezada, Marisol; Espinoza, Estefanía; Bravo, Maria Loreto; Oliva, Bárbara; Lange, Soledad; Villalon, Manuel; Jones, Marius; Brosens, Jan J; Kato, Sumie; Cuello, Mauricio A; Knutson, Todd P; Lange, Carol A; Leyton, Lisette; Owen, Gareth I

    2012-08-01

    Progesterone and progestins have been demonstrated to enhance breast cancer cell migration, although the mechanisms are still not fully understood. The protease-activated receptors (PARs) are a family of membrane receptors that are activated by serine proteases in the blood coagulation cascade. PAR1 (F2R) has been reported to be involved in cancer cell migration and overexpressed in breast cancer. We herein demonstrate that PAR1 mRNA and protein are upregulated by progesterone treatment of the breast cancer cell lines ZR-75 and T47D. This regulation is dependent on the progesterone receptor (PR) but does not require PR phosphorylation at serine 294 or the PR proline-rich region mPRO. The increase in PAR1 mRNA was transient, being present at 3  h and returning to basal levels at 18  h. The addition of a PAR1-activating peptide (aPAR1) to cells treated with progesterone resulted in an increase in focal adhesion (FA) formation as measured by the cellular levels of phosphorylated FA kinase. The combined but not individual treatment of progesterone and aPAR1 also markedly increased stress fiber formation and the migratory capacity of breast cancer cells. In agreement with in vitro findings, data mining from the Oncomine platform revealed that PAR1 expression was significantly upregulated in PR-positive breast tumors. Our observation that PAR1 expression and signal transduction are modulated by progesterone provides new insight into how the progestin component in hormone therapies increases the risk of breast cancer in postmenopausal women.

  20. Cyclin D1b splice variant promotes αvβ3-mediated adhesion and invasive migration of breast cancer cells.

    PubMed

    Wu, Feng-Hua; Luo, Li-Qiong; Liu, Yi; Zhan, Qiu-Xiao; Luo, Chao; Luo, Jing; Zhang, Gui-Mei; Feng, Zuo-Hua

    2014-12-01

    Cyclin D1b, a splice variant of the cell cycle regulator cyclin D1, holds oncogenic functions in human cancer. However, the mechanisms underlying cyclin D1b function remain poorly understood. Here we introduced wild-type cyclin D1a or cyclin D1b variant into non-metastatic MCF-7 cells. Our results show that ectopic expression of cyclin D1b promotes invasiveness of the cancer cells in a cyclin D1a independent manner. Specifically, cyclin D1b is found to modulate the expression of αvβ3, which characterizes the metastatic phenotype, and enhance tumor cell invasive potential in cooperating with HoxD3. Notably, cyclin D1b promotes αvβ3-mediated adhesion and invasive migration, which are associated with invasive potential of breast cancer cells. Further exploration indicates that cyclin D1b makes breast cancer cells more sensitive to toll-like receptor 4 ligand released from damaged tumor cells. These findings reveal a role of cyclin D1b as a possible mediator of αvβ3 transcription to promote tumor metastasis.

  1. Cyclin D1b splice variant promotes αvβ3-mediated adhesion and invasive migration of breast cancer cells.

    PubMed

    Wu, Feng-Hua; Luo, Li-Qiong; Liu, Yi; Zhan, Qiu-Xiao; Luo, Chao; Luo, Jing; Zhang, Gui-Mei; Feng, Zuo-Hua

    2014-12-01

    Cyclin D1b, a splice variant of the cell cycle regulator cyclin D1, holds oncogenic functions in human cancer. However, the mechanisms underlying cyclin D1b function remain poorly understood. Here we introduced wild-type cyclin D1a or cyclin D1b variant into non-metastatic MCF-7 cells. Our results show that ectopic expression of cyclin D1b promotes invasiveness of the cancer cells in a cyclin D1a independent manner. Specifically, cyclin D1b is found to modulate the expression of αvβ3, which characterizes the metastatic phenotype, and enhance tumor cell invasive potential in cooperating with HoxD3. Notably, cyclin D1b promotes αvβ3-mediated adhesion and invasive migration, which are associated with invasive potential of breast cancer cells. Further exploration indicates that cyclin D1b makes breast cancer cells more sensitive to toll-like receptor 4 ligand released from damaged tumor cells. These findings reveal a role of cyclin D1b as a possible mediator of αvβ3 transcription to promote tumor metastasis. PMID:25193465

  2. Transforming growth factor-beta1 promotes the migration and invasion of sphere-forming stem-like cell subpopulations in esophageal cancer

    SciTech Connect

    Yue, Dongli; Zhang, Zhen; Li, Jieyao; Chen, Xinfeng; Ping, Yu; Liu, Shasha; Shi, Xiaojuan; Li, Lifeng; Wang, Liping; Huang, Lan; Zhang, Bin; and others

    2015-08-01

    Esophageal cancer is one of the most lethal solid malignancies. Mounting evidence demonstrates that cancer stem cells (CSCs) are able to cause tumor initiation, metastasis and responsible for chemotherapy and radiotherapy failures. As CSCs are thought to be the main reason of therapeutic failure, these cells must be effectively targeted to elicit long-lasting therapeutic responses. We aimed to enrich and identify the esophageal cancer cell subpopulation with stem-like properties and help to develop new target therapy strategies for CSCs. Here, we found esophageal cancer cells KYSE70 and TE1 could form spheres in ultra low attachment surface culture and be serially passaged. Sphere-forming cells could redifferentiate and acquire morphology comparable to parental cells, when return to adherent culture. The sphere-forming cells possessed the key criteria that define CSCs: persistent self-renewal, overexpression of stemness genes (SOX2, ALDH1A1 and KLF4), reduced expression of differentiation marker CK4, chemoresistance, strong invasion and enhanced tumorigenic potential. SB525334, transforming growth factor-beta 1(TGF-β1) inhibitor, significantly inhibited migration and invasion of sphere-forming stem-like cells and had no effect on sphere-forming ability. In conclusion, esophageal cancer sphere-forming cells from KYSE70 and TE1 cultured in ultra low attachment surface possess cancer stem cell properties, providing a model for CSCs targeted therapy. TGF-β1 promotes the migration and invasion of sphere-forming stem-like cells, which may guide future studies on therapeutic strategies targeting these cells. - Highlights: • Esophageal cancer sphere-forming cells possess cancer stem cell properties. • Sphere-forming cells enhance TGF-β1 pathway activity. • TGF-β 1 inhibitor suppresses the migration and invasion of sphere-forming cells.

  3. Mitochondrial dysfunction promotes breast cancer cell migration and invasion through HIF1α accumulation via increased production of reactive oxygen species.

    PubMed

    Ma, Jia; Zhang, Qing; Chen, Sulian; Fang, Binbin; Yang, Qingling; Chen, Changjie; Miele, Lucio; Sarkar, Fazlul H; Xia, Jun; Wang, Zhiwei

    2013-01-01

    Although mitochondrial dysfunction has been observed in various types of human cancer cells, the molecular mechanism underlying mitochondrial dysfunction mediated tumorigenesis remains largely elusive. To further explore the function of mitochondria and their involvement in the pathogenic mechanisms of cancer development, mitochondrial dysfunction clones of breast cancer cells were generated by rotenone treatment, a specific inhibitor of mitochondrial electron transport complex I. These clones were verified by mitochondrial respiratory defect measurement. Moreover, those clones exhibited increased reactive oxygen species (ROS), and showed higher migration and invasive behaviors compared with their parental cells. Furthermore, antioxidant N-acetyl cysteine, PEG-catalase, and mito-TEMPO effectively inhibited cell migration and invasion in these clones. Notably, ROS regulated malignant cellular behavior was in part mediated through upregulation of hypoxia-inducible factor-1 α and vascular endothelial growth factor. Our results suggest that mitochondrial dysfunction promotes cancer cell motility partly through HIF1α accumulation mediated via increased production of reactive oxygen species. PMID:23922721

  4. Exosomes derived from SW480 colorectal cancer cells promote cell migration in HepG2 hepatocellular cancer cells via the mitogen-activated protein kinase pathway.

    PubMed

    Chiba, Mitsuru; Watanabe, Narumi; Watanabe, Miki; Sakamoto, Maki; Sato, Akika; Fujisaki, Mizuki; Kubota, Shiori; Monzen, Satoru; Maruyama, Atsushi; Nanashima, Naoki; Kashiwakura, Ikuo; Nakamura, Toshiya

    2016-01-01

    Exosomes are membrane-derived extracellular vesicles that have recently been recognized as important mediators of intercellular communication. In the present study, we investigated the effects of exosomes derived from SW480 colorectal cancer cells in recipient HepG2 hepatocellular cancer cells. We demonstrated that SW480-derived exosomes were taken up by the recipient HepG2 cells via dynamin-dependent endocytosis and were localized to the HepG2 lysosomes. In addition, SW480-derived exosomes induced the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 following their uptake into HepG2 cells. Of note, these changes occurred during the early phase after exosome treatment. Furthermore, SW480-derived exosomes promoted the migration of recipient HepG2 cells in a wound-healing assay, which was suppressed by pretreatment with U0126, an upstream inhibitor of ERK1/2. These results indicated that SW480-derived exosomes activated a classical mitogen-activated protein kinase pathway in recipient HepG2 cells via dynamin-dependent endocytosis and subsequently enhanced cell migration by ERK1/2 activation. Our results provide new insights into the regulation of cellular functions by exosomes.

  5. 15-Hydroxyprostaglandin dehydrogenase associates with poor prognosis in breast cancer, induces epithelial-mesenchymal transition, and promotes cell migration in cultured breast cancer cells.

    PubMed

    Lehtinen, Laura; Vainio, Paula; Wikman, Harriet; Reemts, Johannes; Hilvo, Mika; Issa, Rana; Pollari, Sirkku; Brandt, Burkhard; Oresic, Matej; Pantel, Klaus; Kallioniemi, Olli; Iljin, Kristiina

    2012-03-01

    Breast cancer is the most frequent cancer and the leading cause of cancer-related deaths in women worldwide. The prognosis of breast cancer is tightly correlated with the degree of spread beyond the primary tumour. Arachidonic acid (AA) and prostaglandin E(2) (PGE(2)) are known to regulate tumour metastasis enabling epithelial-mesenchymal transition (EMT). However, the detailed role of 15-hydroxyprostaglandin dehydrogenase (HPGD), the key enzyme degrading prostaglandin E(2) , remains unclear in breast cancer. Here, we show that HPGD mRNA is overexpressed in a subset of clinical breast cancers compared to normal breast tissue samples and that high HPGD mRNA expression associates with poor prognosis. Immunohistochemical staining of primary breast cancer and lymph node metastasis tissue samples confirmed high HPGD protein expression in 20% of the samples, as well as associated HPGD expression with aggressive characteristics, such as increased risk of disease relapse and shorter disease-free survival. Results from cultured cells indicated abundant HPGD expression in highly metastatic breast cancer cells, and impairment of HPGD expression using RNA interference led to a significant decrease in transforming growth factor-β signalling, in cellular arachidonic acid levels as well as in cell migration. Furthermore, gene expression microarray analysis followed by quantitative RT-PCR validation showed that HPGD silencing decreased aryl hydrocarbon receptor signalling and induced mesenchymal-epithelial transition. In conclusion, our results indicate that HPGD is highly expressed in metastatic and aggressive breast cancer and promotes EMT and migration in breast cancer cells. PMID:22072156

  6. Leukemia Stem Cell-Released Microvesicles Promote the Survival and Migration of Myeloid Leukemia Cells and These Effects Can Be Inhibited by MicroRNA34a Overexpression

    PubMed Central

    Wang, Yue; Cheng, Qian; Liu, Jing; Dong, Min

    2016-01-01

    Leukemia stem cells (LSCs) play the major role in relapse of acute myeloid leukemia (AML). Recent evidence indicates that microvesicles (MVs) released from cancer stem cells can promote tumor growth and invasion. In this study, we investigated whether LSCs-released MVs (LMVs) can regulate the malignance of AML cells and whether overexpression of tumor suppressive microRNA (miR), miR34a, is able to interrupt this process. LSCs were transfected with miRNA control (miRCtrl) or miR34a mimic for producing LMVs, respectively, defined as LMVsmiRCtrl and LMVsmiR34a. The effect of miR34a transfection on LSC proliferation and the effects of LMVsmiRCtrl or LMVsmiR34a on the proliferation, migration, and apoptosis of AML cells (after LSC depletion) were determined. The levels of miR34a targets, caspase-3 and T cell immunoglobulin mucin-3 (Tim-3), were analyzed. Results showed that (1) LMVsmiRCtrl promoted proliferation and migration and inhibited apoptosis of AML cells, which were associated with miR34a deficit; (2) transfection of miR34a mimic inhibited LSC proliferation and increased miR34a level in LMVsmiR34a; (3) LMVsmiR34a produced opposite effects as compared with LMVsmiRCtrl, which were associated with the changes of caspase-3 and Tim-3 levels. In summary, LMVs support AML cell malignance and modulating miR34a could offer a new approach for the management of AML. PMID:27127521

  7. Leukemia Stem Cell-Released Microvesicles Promote the Survival and Migration of Myeloid Leukemia Cells and These Effects Can Be Inhibited by MicroRNA34a Overexpression.

    PubMed

    Wang, Yue; Cheng, Qian; Liu, Jing; Dong, Min

    2016-01-01

    Leukemia stem cells (LSCs) play the major role in relapse of acute myeloid leukemia (AML). Recent evidence indicates that microvesicles (MVs) released from cancer stem cells can promote tumor growth and invasion. In this study, we investigated whether LSCs-released MVs (LMVs) can regulate the malignance of AML cells and whether overexpression of tumor suppressive microRNA (miR), miR34a, is able to interrupt this process. LSCs were transfected with miRNA control (miRCtrl) or miR34a mimic for producing LMVs, respectively, defined as LMVs(miRCtrl) and LMVs(miR34a). The effect of miR34a transfection on LSC proliferation and the effects of LMVs(miRCtrl) or LMVs(miR34a) on the proliferation, migration, and apoptosis of AML cells (after LSC depletion) were determined. The levels of miR34a targets, caspase-3 and T cell immunoglobulin mucin-3 (Tim-3), were analyzed. Results showed that (1) LMVs(miRCtrl) promoted proliferation and migration and inhibited apoptosis of AML cells, which were associated with miR34a deficit; (2) transfection of miR34a mimic inhibited LSC proliferation and increased miR34a level in LMVs(miR34a); (3) LMVs(miR34a) produced opposite effects as compared with LMVs(miRCtrl), which were associated with the changes of caspase-3 and Tim-3 levels. In summary, LMVs support AML cell malignance and modulating miR34a could offer a new approach for the management of AML. PMID:27127521

  8. Lysyl oxidase-like 2 promotes migration in noninvasive breast cancer cells but not in normal breast epithelial cells.

    PubMed

    Hollosi, Peter; Yakushiji, Jana K; Fong, Keith S K; Csiszar, Katalin; Fong, Sheri F T

    2009-07-15

    A growing number of studies indicate the importance of the lysyl oxidase family in the promotion of epithelial neoplasms towards their more aggressive forms. However, the role of individual family members in carcinoma progression has yet to be ascertained. In this study, we analyzed LOXL2 expression in malignantly transformed MCF-7 and normal MCF-10A mammary epithelial cell line clones stably transduced with LOXL2 in vitro, and in normal and cancerous breast tissue samples in vivo. We found LOXL2 to be catalytically active in both MCF-7 and MCF-10 clones. LOXL2 overexpression promoted a more mesenchymal morphology in both cell types, but LOXL2-induced increase in migratory ability could only be established in MCF-7 clones. We demonstrated altered localization of the LOXL2 protein in breast cancer tissue compared to normal mammary tissue, and altered localization and processing of LOXL2 protein in breast cancer cell lines compared to normal cell lines, which may allow LOXL2 to interact with different intra and extracellular components during tumor progression. Results support the role of LOXL2 in selectively promoting a metastatic phenotype in breast tumor cells. Additional data suggest epigenetic molecular mechanisms in tumor specific regulation of LOXL2 expression that could be explored as a molecular target in the prevention of breast cancer progression.

  9. Ionizing Radiation Promotes Migration and Invasion of Cancer Cells Through Transforming Growth Factor-Beta-Mediated Epithelial-Mesenchymal Transition

    SciTech Connect

    Zhou Yongchun; Liu Junye; Li Jing; Zhang Jie; Xu Yuqiao; Zhang Huawei; Qiu Lianbo; Ding Guirong; Su Xiaoming; Mei Shi; Guo Guozhen

    2011-12-01

    Purpose: To examine whether ionizing radiation enhances the migratory and invasive abilities of cancer cells through transforming growth factor (TGF-{beta})-mediated epithelial-mesenchymal transition (EMT). Methods and Materials: Six cancer cell lines originating from different human organs were irradiated by {sup 60}Co {gamma}-ray at a total dose of 2 Gy, and the changes associated with EMT, including morphology, EMT markers, migration and invasion, were observed by microscope, Western blot, immunofluorescence, scratch assay, and transwell chamber assay, respectively. Then the protein levels of TGF-{beta} in these cancer cells were detected by enzyme-linked immunosorbent assay, and the role of TGF-{beta} signaling pathway in the effect of ionizing radiation on EMT was investigate by using the specific inhibitor SB431542. Results: After irradiation with {gamma}-ray at a total dose of 2 Gy, cancer cells presented the mesenchymal phenotype, and compared with the sham-irradiation group the expression of epithelial markers was decreased and of mesenchymal markers was increased, the migratory and invasive capabilities were strengthened, and the protein levels of TGF-{beta} were enhanced. Furthermore, events associated with EMT induced by IR in A549 could be reversed through inhibition of TGF-{beta} signaling. Conclusions: These results suggest that EMT mediated by TGF-{beta} plays a critical role in IR-induced enhancing of migratory and invasive capabilities in cancer cells.

  10. Bone morphogenetic protein-4 is overexpressed in colonic adenocarcinomas and promotes migration and invasion of HCT116 cells

    SciTech Connect

    Deng Haiyun; Makizumi, Ryouji; Ravikumar, T.S.; Dong Huali; Yang Wancai; Yang, W.-L. . E-mail: wlyang@nshs.edu

    2007-03-10

    Bone morphogenetic protein (BMP), a member of the TGF-{beta} superfamily, is involved in development, morphogenesis, cell proliferation and apoptosis. Dysregulation of BMP signaling has been suggested in tumorigenesis. In an analysis of human colon normal mucosa and tumors at different stages by immunohistochemistry, we observed that the intensity of BMP-4 staining in late-adenocarcinomas was stronger than that in normal mucosa and adenomas, while there was no difference in the staining of its receptors (BMPR-IA and BMPR-II) at all stages. The up-regulation of BMP-4 was further validated in another panel of tumor tissues by real-time RT-PCR, showing that BMP-4 mRNA levels in primary colonic carcinomas with liver metastasis were significantly higher than that in the matched normal mucosa. In order to understand the functional relevance of BMP-4 expression in colon cancer progression, BMP-4-overexpressing cell clones were generated from HCT116 cells. Overexpression of BMP-4 did not affect the HCT116 cell growth. The cells overexpressing BMP-4 became resistant to serum-starvation-induced apoptosis and exhibited enhanced migration and invasion characteristics. Overexpression of BMP-4 changed cell morphology to invasive spindle phenotype and induced the expression and activity of urokinase plasminogen activator (uPA). These results indicate that BMP-4 confers invasive phenotype during progression of colon cancer.

  11. p75 neurotrophin receptor and pro-BDNF promote cell survival and migration in clear cell renal cell carcinoma

    PubMed Central

    Sánchez-Prieto, Ricardo; Saada, Sofiane; Naves, Thomas; Guillaudeau, Angélique; Perraud, Aurélie; Sindou, Philippe; Lacroix, Aurélie; Descazeaud, Aurélien; Lalloué, Fabrice; Jauberteau, Marie-Odile

    2016-01-01

    p75NTR, a member of TNF receptor family, is the low affinity receptor common to several mature neurotrophins and the high affinity receptor for pro-neurotrophins. Brain-Derived Neurotrophic Factor (BDNF), a member of neurotrophin family has been described to play an important role in development and progression of several cancers, through its binding to a high affinity tyrosine kinase receptor B (TrkB) and/or p75NTR. However, the functions of these two receptors in renal cell carcinoma (RCC) have never been investigated. An overexpression of p75NTR, pro-BDNF, and to a lesser extent for TrkB and sortilin, was detected by immunohistochemistry in a cohort of 83 clear cell RCC tumors. p75NTR, mainly expressed in tumor tissues, was significantly associated with higher Fuhrman grade in multivariate analysis. In two derived-RCC lines, 786-O and ACHN cells, we demonstrated that pro-BDNF induced cell survival and migration, through p75NTR as provided by p75NTR RNA silencing or blocking anti-p75NTR antibody. This mechanism is independent of TrkB activation as demonstrated by k252a, a tyrosine kinase inhibitor for Trk neurotrophin receptors. Taken together, these data highlight for the first time an important role for p75NTR in renal cancer and indicate a putative novel target therapy in RCC. PMID:27120782

  12. Paracrine release from nonviral engineered adipose-derived stem cells promotes endothelial cell survival and migration in vitro.

    PubMed

    Deveza, Lorenzo; Choi, Jeffrey; Imanbayev, Galym; Yang, Fan

    2013-02-01

    Stem cells hold great potential for therapeutic angiogenesis due to their ability to directly contribute to new vessel formation or secrete paracrine signals. Adipose-derived stem cells (ADSCs) are a particularly attractive autologous cell source for therapeutic angiogenesis due to their ease of isolation and relative abundance. Gene therapy may be used to further enhance the therapeutic efficacy of ADSCs by overexpressing desired therapeutic factors. Here, we developed vascular endothelial growth factor (VEGF)-overexpressing ADSCs utilizing poly(β-amino esters) (PBAEs), a hydrolytically biodegradable polymer, and examined the effects of paracrine release from nonviral modified ADSCs on the angiogenic potential of human umbilical vein endothelial cells (HUVECs) in vitro. PBAE polymeric vectors delivered DNA into ADSCs with high efficiency and low cytotoxicity, leading to an over 3-fold increase in VEGF production by ADSCs compared with Lipofectamine 2000. Paracrine release from PBAE/VEGF-transfected ADSCs enhanced HUVEC viability and decreased HUVEC apoptosis under hypoxia. Further, paracrine release from PBAE/VEGF-transfected ADSCs significantly enhanced HUVEC migration and tube formation, two critical cellular processes for effective angiogenesis. Our results demonstrate that genetically engineered ADSCs using biodegradable polymeric nanoparticles may provide a promising autologous cell source for therapeutic angiogenesis in treating cardiovascular diseases.

  13. Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion.

    PubMed

    Gu, Y; Lin, S; Li, J-L; Nakagawa, H; Chen, Z; Jin, B; Tian, L; Ucar, D A; Shen, H; Lu, J; Hochwald, S N; Kaye, F J; Wu, L

    2012-01-26

    LKB1 is a tumor susceptibility gene for the Peutz-Jeghers cancer syndrome and is a target for mutational inactivation in sporadic human malignancies. LKB1 encodes a serine/threonine kinase that has critical roles in cell growth, polarity and metabolism. A novel and important function of LKB1 is its ability to regulate the phosphorylation of CREB-regulated transcription co-activators (CRTCs) whose aberrant activation is linked with oncogenic activities. However, the roles and mechanisms of LKB1 and CRTC in the pathogenesis of esophageal cancer have not been previously investigated. In this study, we observed altered LKB1-CRTC signaling in a subset of human esophageal cancer cell lines and patient samples. LKB1 negatively regulates esophageal cancer cell migration and invasion in vitro. Mechanistically, we determined that CRTC signaling becomes activated because of LKB1 loss, which results in the transcriptional activation of specific downstream targets including LYPD3, a critical mediator for LKB1 loss-of-function. Our data indicate that de-regulated LKB1-CRTC signaling might represent a crucial mechanism for esophageal cancer progression.

  14. Activation of EGFR promotes squamous carcinoma SCC10A cell migration and invasion via inducing EMT-like phenotype change and MMP-9-mediated degradation of E-cadherin.

    PubMed

    Zuo, Jian-Hong; Zhu, Wei; Li, Mao-Yu; Li, Xin-Hui; Yi, Hong; Zeng, Gu-Qing; Wan, Xun-Xun; He, Qiu-Yan; Li, Jian-Huang; Qu, Jia-Quan; Chen, Yu; Xiao, Zhi-Qiang

    2011-09-01

    EGFR is a potent stimulator of invasion and metastasis in head and neck squamous cell carcinomas (HNSCC). However, the mechanism by which EGFR may stimulate tumor cell invasion and metastasis still need to be elucidated. In this study, we showed that activation of EGFR by EGF in HNSCC cell line SCC10A enhanced cell migration and invasion, and induced loss of epitheloid phenotype in parallel with downregulation of E-cadherin and upregulation of N-cadherin and vimentin, indicating that EGFR promoted SCC10A cell migration and invasion possibly by an epithelial to mesenchymal transition (EMT)-like phenotype change. Interestingly, activation of EGFR by EGF induced production of matrix metalloproteinase-9 (MMP-9) and soluble E-cadherin (sE-cad), and knockdown of MMP-9 by siRNA inhibited sE-cad production induced by EGF in SCC10A. Moreover, both MMP-9 knockdown and E-cadherin overexpression inhibited cell migration and invasion induced by EGF in SCC10A. The results indicate that EGFR activation promoted cell migration and invasion through inducing MMP-9-mediated degradation of E-cadherin into sE-cad. Pharmacologic inhibition of EGFR, MEK, and PI3K kinase activity in SCC10A reduced phosphorylated levels of ERK-1/2 and AKT, production of MMP-9 and sE-cad, cell migration and invasion, and expressional changes of EMT markers (E-cadherin and N-cadherin) induced by EGF, indicating that EGFR activation promotes cell migration and invasion via ERK-1/2 and PI3K-regulated MMP-9/E-cadherin signaling pathways. Taken together, the data suggest that EGFR activation promotes HNSCC SCC10A cell migration and invasion by inducing EMT-like phenotype change and MMP-9-mediated degradation of E-cadherin into sE-cad related to activation of ERK-1/2 and PI3K signaling pathways.

  15. Human Adipose Tissue-Derived Stromal/Stem Cells Promote Migration and Early Metastasis of Triple Negative Breast Cancer Xenografts

    PubMed Central

    Rowan, Brian G.; Gimble, Jeffrey M.; Sheng, Mei; Anbalagan, Muralidharan; Jones, Ryan K.; Frazier, Trivia P.; Asher, Majdouline; Lacayo, Eduardo A.; Friedlander, Paul L.; Kutner, Robert; Chiu, Ernest S.

    2014-01-01

    Background Fat grafting is used to restore breast defects after surgical resection of breast tumors. Supplementing fat grafts with adipose tissue-derived stromal/stem cells (ASCs) is proposed to improve the regenerative/restorative ability of the graft and retention. However, long term safety for ASC grafting in proximity of residual breast cancer cells is unknown. The objective of this study was to determine the impact of human ASCs derived from abdominal lipoaspirates of three donors, on a human breast cancer model that exhibits early metastasis. Methodology/Principal Findings Human MDA-MB-231 breast cancer cells represents “triple negative” breast cancer that exhibits early micrometastasis to multiple mouse organs [1]. Human ASCs were derived from abdominal adipose tissue from three healthy female donors. Indirect co-culture of MDA-MB-231 cells with ASCs, as well as direct co-culture demonstrated that ASCs had no effect on MDA-MB-231 growth. Indirect co-culture, and ASC conditioned medium (CM) stimulated migration of MDA-MB-231 cells. ASC/RFP cells from two donors co-injected with MDA-MB-231/GFP cells exhibited a donor effect for stimulation of primary tumor xenografts. Both ASC donors stimulated metastasis. ASC/RFP cells were viable, and integrated with MDA-MB-231/GFP cells in the tumor. Tumors from the co-injection group of one ASC donor exhibited elevated vimentin, matrix metalloproteinase-9 (MMP-9), IL-8, VEGF and microvessel density. The co-injection group exhibited visible metastases to the lung/liver and enlarged spleen not evident in mice injected with MDA-MB-231/GFP alone. Quantitation of the total area of GFP fluorescence and human chromosome 17 DNA in mouse organs, H&E stained paraffin sections and fluorescent microscopy confirmed multi-focal metastases to lung/liver/spleen in the co-injection group without evidence of ASC/RFP cells. Conclusions Human ASCs derived from abdominal lipoaspirates of two donors stimulated metastasis of MDA-MB-231

  16. Growth and migration of LNCaP prostate cancer cells are promoted by triclosan and benzophenone-1 via an androgen receptor signaling pathway.

    PubMed

    Kim, Seung-Hee; Hwang, Kyung-A; Shim, Soon-Mi; Choi, Kyung-Chul

    2015-03-01

    Prostate cancer (PCa) is a global health concern in human males. Recently, it has been known that endocrine-disrupting chemicals (EDCs) may act as an exogenous factor to enhance cancer progression. Triclosan (TCS) and 2,4-dihydroxybenzophenone (BP-1) were reported to bioaccumulate in human bodies through the skin absorption. However, there has been insufficient evidence on the findings that the intervention of EDCs may promote the cancer progression in PCa. In the present study, to verify the risk of TCS and BP-1 to a PCa progression, cancer cell proliferation and migration were investigated in LNCaP PCa cells. TCS and BP-1 increased LNCaP cell proliferative activity and migration as did dihydrotestosterone (DHT). This phenomenon was reversed by the treatment with bicalutamide, a well known AR antagonist, suggesting that TCS and BP-1 acted as a xenoandrogen in LNCaP cells via AR signaling pathway by mimicking the action of DHT. A Western blot assay was performed to identify the alterations in the translational levels of cell growth- and metastasis-related markers, i.e., c-fos, cyclin E, p21, and cathepsin D genes. The expressions of genes related with G1/S transition of cell cycle and metastasis were increased by DHT, TCS, and BP-1, while the expression of p21 protein responsible for cell cycle arrest was reduced by DHT, TCS, and BP-1. Taken together, these results indicated that TCS and BP-1 may enhance the progression of PCa by regulating cell cycle and metastasis-related genes via AR signaling pathway.

  17. Autophagy facilitates TLR4- and TLR3-triggered migration and invasion of lung cancer cells through the promotion of TRAF6 ubiquitination.

    PubMed

    Zhan, Zhenzhen; Xie, Xuefeng; Cao, Hao; Zhou, Xiaohui; Zhang, Xu Dong; Fan, Huimin; Liu, Zhongmin

    2014-02-01

    Autophagy contributes to the pathogenesis of cancer, whereas toll-like receptors (TLRs) also play an important role in cancer development and immune escape. However, little is known about the potential interaction between TLR signaling and autophagy in cancer cells. Here we show that autophagy induced by TLR4 or TLR3 activation enhances various cytokine productions through promoting TRAF6 (TNF receptor-associated factor 6, E3 ubiquitin protein ligase) ubiquitination and thus facilitates migration and invasion of lung cancer cells. Stimulation of TLR4 and TLR3 with lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid [poly(I:C)] respectively triggered autophagy in lung cancer cells. This was mediated by the adaptor protein, toll-like receptor adaptor molecule 1 (TICAM1/TRIF), and was required for TLR4- and TLR3-induced increases in the production of IL6, CCL2/MCP-1 [chemokine (C-C motif) ligand 2], CCL20/MIP-3α [chemokine (C-C motif) ligand 20], VEGFA (vascular endothelial growth factor A), and MMP2 [matrix metallopeptidase 2 (gelatinase A, 72 kDa gelatinase, 72 kDa type IV collagenase)]. These cytokines appeared to be necessary for enhanced migration and invasion of lung cancer cells upon TLR activation. Remarkably, inhibition of autophagy by chemical or genetic approaches blocked TLR4- or TLR3-induced Lys63 (K63)-linked ubiquitination of TRAF6 that was essential for activation of MAPK and NFKB (nuclear factor of kappa light polypeptide gene enhancer in B-cells) pathways, both of which were involved in the increased production of the cytokines. Collectively, these results identify induction of autophagy by TLR4 and TLR3 as an important mechanism that drives lung cancer progression, and indicate that inhibition of autophagy may be a useful strategy in the treatment of lung cancer.

  18. Myocardin-related transcription factor A is up-regulated by 17β-estradiol and promotes migration of MCF-7 breast cancer cells via transactivation of MYL9 and CYR61.

    PubMed

    Zhang, Chunling; Luo, Xuegang; Liu, Lei; Guo, Shu; Zhao, Wenwen; Mu, Ai; Liu, Zhipeng; Wang, Nan; Zhou, Hao; Zhang, Tongcun

    2013-11-01

    Many lines of evidence have suggested that estrogen plays important roles not only in the initiation and proliferation of breast cancer, but also in cancer metastasis. However, the mechanistic basis of the latter events is poorly understood. In addition, recent studies have suggested that myocardin-related transcription factor A (MRTF-A) might be related to cancer metastasis. However, as reports are contradictory, certain of its roles still remain confusing. In the present study, we showed that excessive 17β-estradiol could promote the migration of MCF-7 breast cancer cells and up-regulate the expression of MRTF-A, myosin regulatory light chain 9 (MYL9), and cysteine-rich angiogenic inducer 61 (CYR61). Overexpression of MRTF-A significantly promoted the migration of MCF-7 cells through its transactivation effects on MYL9 and CYR61 genes, while RNA interference-mediated knockdown of MRTF-A strongly inhibited transcription and expression of the target genes and reduced the migration ability of MCF-7 cells. These results provided novel evidence supporting the metastasis-promoting functions of MRTF-A, and implied that MRTF-A might be a switch for the estrogen pathway to change its proliferation-promoting roles into migration-stimulating roles in breast cancer. PMID:24084383

  19. TNF-α and IFN-γ promote lymphocyte adhesion to endothelial junctional regions facilitating transendothelial migration.

    PubMed

    Jaczewska, Justyna; Abdulreda, Midhat H; Yau, Chi Y; Schmitt, Martin M; Schubert, Irene; Berggren, Per-Olof; Weber, Christian; Koenen, Rory R; Moy, Vincent T; Wojcikiewicz, Ewa P

    2014-02-01

    Inflammatory conditions induce redistribution of junctional adhesion receptors toward the apical regions of endothelial cells promoting lymphocyte TEM. Much of the molecular structures of TEM have been revealed; however, the biophysical mechanisms underlying this process remain to be fully elucidated. Here, we used immunofluorescence microscopy and AFM to study endothelial distribution of adhesion molecules upon lymphocyte activation and transmigration. Our immunofluorescence results revealed redistribution of JAM-A and PECAM-1 but not ICAM-1 or VCAM-1 toward the apical junctional regions of HUVECs following a 6-h stimulation with TNF-α and IFN-γ. Consistently, our SCFS studies revealed that Jurkat cell adhesion to stimulated HUVEC monolayers was significantly greater in junctional regions. Enhanced adhesion was mediated mostly by JAM-A receptors. Further AFM adhesion mapping of the homophilic JAM-A/JAM-A interaction on the surfaces of HUVECs revealed a greater number of JAM-A receptors available for binding along junctional regions after TNF-α and IFN-γ stimulation. Our data reveal for the first time that adhesion "hot spots" of JAM-A receptors are involved in initiating lymphocyte TEM under inflammatory conditions. PMID:24072879

  20. TNF-α and IFN-γ promote lymphocyte adhesion to endothelial junctional regions facilitating transendothelial migration

    PubMed Central

    Jaczewska, Justyna; Abdulreda, Midhat H.; Yau, Chi Y.; Schmitt, Martin M.; Schubert, Irene; Berggren, Per-Olof; Weber, Christian; Koenen, Rory R.; Moy, Vincent T.; Wojcikiewicz, Ewa P.

    2014-01-01

    Inflammatory conditions induce redistribution of junctional adhesion receptors toward the apical regions of endothelial cells promoting lymphocyte TEM. Much of the molecular structures of TEM have been revealed; however, the biophysical mechanisms underlying this process remain to be fully elucidated. Here, we used immunofluorescence microscopy and AFM to study endothelial distribution of adhesion molecules upon lymphocyte activation and transmigration. Our immunofluorescence results revealed redistribution of JAM-A and PECAM-1 but not ICAM-1 or VCAM-1 toward the apical junctional regions of HUVECs following a 6-h stimulation with TNF-α and IFN-γ. Consistently, our SCFS studies revealed that Jurkat cell adhesion to stimulated HUVEC monolayers was significantly greater in junctional regions. Enhanced adhesion was mediated mostly by JAM-A receptors. Further AFM adhesion mapping of the homophilic JAM-A/JAM-A interaction on the surfaces of HUVECs revealed a greater number of JAM-A receptors available for binding along junctional regions after TNF-α and IFN-γ stimulation. Our data reveal for the first time that adhesion “hot spots” of JAM-A receptors are involved in initiating lymphocyte TEM under inflammatory conditions. PMID:24072879

  1. Up-Regulation of miRNA-21 Expression Promotes Migration and Proliferation of Sca-1+ Cardiac Stem Cells in Mice.

    PubMed

    Zhou, Qingling; Sun, Qiang; Zhang, Yongshan; Teng, Fei; Sun, Jinhui

    2016-01-01

    BACKGROUND This study, by regulating the expression level of microRNA-21 (miRNA-21) in antigen-1+ (Sca-1+) cardiac stem cells (CSCs), examined the role of miRNA-21 in migration, proliferation, and differentiation of Sca-1+ CSCs, and explored the use of miRNA-21 in treatment of heart-related diseases in mice. MATERIAL AND METHODS The CSCs of 20 healthy 2-month-old C57BL/6 mice were collected in our study. Immunomagnetic beads were used to separate and prepare pure Sca-1+ CSCs, which were further examined by flow cytometry. The samples were assigned to 4 groups: the blank group, the miRNA-21 mimic group, the miRNA-21 inhibitor group, and the negative control (NC) group. Quantitative real-time polymerase chain reaction (qRT-PCR), Transwell chamber assay, and the methyl thiazolylte-trazolium (MTT) assay were performed. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to measure the expression levels of GATA-4, MEF2c, TNI, and β-MHC differentiation-related genes. RESULTS Immunomagnetic separation results indicated that Sca-1+ CSCs accounted for more than 87.4% of CSCs. RT-PCR results also showed that the expression level of miRNA-21 of the miRNA-21 mimic group was higher than those of the other groups (all P<0.05). Compared to the NC and the blank group, the migration of Sca-1+ CSCs was more active in the miRNA-21 mimic group and less active in the miRNA-21 inhibitor group (all P<0.05). Moreover, compared to the blank group, the proliferation of Sca-1+ CSCs was enhanced in the miRNA-21 mimic group and inhibited in the miRNA-21 inhibitor group (all P<0.05). The results of RT-PCR indicated that neither miRNA-21 mimics nor miR-21 inhibitors influenced the gene expression levels of GATA-4, MEF2c, TNI, or β-MHC. CONCLUSIONS Our study provides evidence that up-regulation of miRNA-21 can promote migration and proliferation of Sca-1+ CSCs to enhance the capacity of Sca-1+ CSCs to repair damaged myocardium, which may pave the way for therapeutic strategies

  2. A synthetic mechano-growth factor E peptide promotes rat tenocyte migration by lessening cell stiffness and increasing F-actin formation via the FAK-ERK1/2 signaling pathway

    SciTech Connect

    Zhang, Bingyu; Luo, Qing; Mao, Xinjian; Xu, Baiyao; Yang, Li; Ju, Yang; Song, Guanbin

    2014-03-10

    Tendon injuries are common in sports and are frequent reasons for orthopedic consultations. The management of damaged tendons is one of the most challenging problems in orthopedics. Mechano-growth factor (MGF), a recently discovered growth repair factor, plays positive roles in tissue repair through the improvement of cell proliferation and migration and the protection of cells against injury-induced apoptosis. However, it remains unclear whether MGF has the potential to accelerate tendon repair. We used a scratch wound assay in this study to demonstrate that MGF-C25E (a synthetic mechano-growth factor E peptide) promotes the migration of rat tenocytes and that this promotion is accompanied by an elevation in the expression of the following signaling molecules: focal adhesion kinase (FAK) and extracellular signal regulated kinase1/2 (ERK1/2). Inhibitors of the FAK and ERK1/2 pathways inhibited the MGF-C25E-induced tenocyte migration, indicating that MGF-C25E promotes tenocyte migration through the FAK-ERK1/2 signaling pathway. The analysis of the mechanical properties showed that the Young's modulus of tenocytes was decreased through treatment of MGF-C25E, and an obvious formation of pseudopodia and F-actin was observed in MGF-C25E-treated tenocytes. The inhibition of the FAK or ERK1/2 signals restored the decrease in Young's modulus and inhibited the formation of pseudopodia and F-actin. Overall, our study demonstrated that MGF-C25E promotes rat tenocyte migration by lessening cell stiffness and increasing pseudopodia formation via the FAK-ERK1/2 signaling pathway. - Highlights: • Mechano-growth factor E peptide (MGF-C25E) promotes migration of rat tenocytes. • MGF-C25E activates the FAK-ERK1/2 pathway in rat tenocytes. • MGF-C25E induces the actin remodeling and the formation of pseudopodia, and decreases the stiffness in rat tenocytes. • MGF-C25E promotes tenocyte migration via altering stiffness and forming pseudopodia by the activation of the FAK-ERK1

  3. Over-expression of TRIM37 promotes cell migration and metastasis in hepatocellular carcinoma by activating Wnt/β-catenin signaling

    SciTech Connect

    Jiang, Jianxin; Yu, Chao; Chen, Meiyuan; Tian, She; Sun, Chengyi

    2015-09-04

    Hepatocellular carcinoma (HCC) is the most common cancer in the world especially in East Asia and Africa. Advanced stage, metastasis and frequent relapse are responsible for the poor prognosis of HCC. However, the precise mechanisms underlying HCC remained unclear. So it is urgent to identify the pathological processes and relevant molecules of HCC. TRIM37 is an E3 ligase and has been observed deregulated expression in various tumors. Recent studies of TRIM37 have implicated that TRIM37 played critical roles in cell proliferation and other processes. In the present study, we demonstrated that TRIM37 expression was notably up-regulated in HCC samples and was associated with advanced stage and tumor volume, which all indicating the poor outcomes. We also found that TRIM37 could serve as an independent prognostic factor of HCC. During the course of in vitro and in vivo work, we showed that TRIM37 promoted HCC cells migration and metastasis by inducing EMT. Furthermore, we revealed that the effect of TRIM37 mediated EMT in HCC cells was achieved by the activation of Wnt/β-catenin signaling. These finding may provide insight into the understanding of TRIM37 as a novel critical factor of HCC and a candidate target for HCC treatment. - Highlights: • Highly expression of TRIM37 is found in HCC samples compared with nontumorous samples. • TRIM37 expression is correlated with advanced HCC stages and could be an independent prognostic factor. • TRIM37 promotes cell proliferation and metastasis. • We report an E3 ligase TRIM37 affects Wnt/β-catenin signaling.

  4. Loss of OLFM4 promotes tumor migration through inducing interleukin-8 expression and predicts lymph node metastasis in early gastric cancer

    PubMed Central

    Zhao, J; Shu, P; Duan, F; Wang, X; Min, L; Shen, Z; Ruan, Y; Qin, J; Sun, Y; Qin, X

    2016-01-01

    Endoscopic surgery is increasingly used for early gastric cancer (EGC) treatment worldwide, and lymph node metastasis remains the most important risk factor for endoscopic surgery in EGC patients. Olfactomedin 4 (OLFM4) is mainly expressed in the digestive system and upregulated in several types of tumors. However, the role of OLFM4 in EGC has not been explored. We evaluated OLFM4 expression by immunohistochemical staining in 105 patients with EGC who underwent gastrectomy. The clinicopathological factors and OLFM4 expression were co-analyzed to predict lymph node metastasis in EGC. The metastatic mechanism of OLFM4 in gastric cancer was also investigated. We found that OLFM4 was upregulated in EGC tumor sections, and relatively low expression of OLFM4 was observed in patients with lymph node metastasis. OLFM4 expression as well as tumor size and differentiation were identified as independent factors, which could be co-analyzed to generate a better model for predicting lymph node metastasis in EGC patients. In vitro studies revealed that knockdown of OLFM4 promoted the migration of gastric cancer cells through activating the NF-κB/interleukin-8 axis. Negative correlation between OLFM4 and interleukin-8 expression was also observed in EGC tumor samples. Our study implies that OLFM4 expression is a potential predictor of lymph node metastasis in EGC, and combing OLFM4 with tumor size and differentiation could better stratify EGC patients with different risks of lymph node metastasis. PMID:27294866

  5. Loss of OLFM4 promotes tumor migration through inducing interleukin-8 expression and predicts lymph node metastasis in early gastric cancer.

    PubMed

    Zhao, J; Shu, P; Duan, F; Wang, X; Min, L; Shen, Z; Ruan, Y; Qin, J; Sun, Y; Qin, X

    2016-01-01

    Endoscopic surgery is increasingly used for early gastric cancer (EGC) treatment worldwide, and lymph node metastasis remains the most important risk factor for endoscopic surgery in EGC patients. Olfactomedin 4 (OLFM4) is mainly expressed in the digestive system and upregulated in several types of tumors. However, the role of OLFM4 in EGC has not been explored. We evaluated OLFM4 expression by immunohistochemical staining in 105 patients with EGC who underwent gastrectomy. The clinicopathological factors and OLFM4 expression were co-analyzed to predict lymph node metastasis in EGC. The metastatic mechanism of OLFM4 in gastric cancer was also investigated. We found that OLFM4 was upregulated in EGC tumor sections, and relatively low expression of OLFM4 was observed in patients with lymph node metastasis. OLFM4 expression as well as tumor size and differentiation were identified as independent factors, which could be co-analyzed to generate a better model for predicting lymph node metastasis in EGC patients. In vitro studies revealed that knockdown of OLFM4 promoted the migration of gastric cancer cells through activating the NF-κB/interleukin-8 axis. Negative correlation between OLFM4 and interleukin-8 expression was also observed in EGC tumor samples. Our study implies that OLFM4 expression is a potential predictor of lymph node metastasis in EGC, and combing OLFM4 with tumor size and differentiation could better stratify EGC patients with different risks of lymph node metastasis. PMID:27294866

  6. Surface reconstruction of titania with g-C3N4 and Ag for promoting efficient electrons migration and enhanced visible light photocatalysis

    NASA Astrophysics Data System (ADS)

    Leong, Kah Hon; Liu, Sze Ling; Sim, Lan Ching; Saravanan, Pichiah; Jang, Min; Ibrahim, Shaliza

    2015-12-01

    The developments of heterogeneous photocatalysts are one among the competent reconstruction approach to enrich the visible light responsiveness of conventional TiO2. In the present work the TiO2 was reconstructed with graphitic carbon nitride (g-C3N4) and silver (Ag) to form a ternary (g-C3N4)-Ag/TiO2. The graphitic carbon nitride an intriguing material was prepared through a facile pyrolysis by using urea as a precursor. The silver (Ag) that plays a role as electron-conduction mobiliser in the ternary was synthesised through solar mediated photodeposition method. The synthesised ternary composite characteristics were thoroughly investigated through various physical and chemical analyses. The presence of g-C3N4 in the ternary photocatalysts promoted the formation of interface between the Ag/TiO2 and g-C3N4 and stimulated the electron transfer between them. These electrons migration acknowledged by the synergic effect prolonged the lifetime of charge carriers. The g-C3N4 also significantly tuned the energy band of conventional TiO2. The prepared ternary exhibited significantly high visible light photocatalytic performance by degrading Amoxicillin (AMX) a poor photosensitising pollutant at highest rate.

  7. EphA2 silencing promotes growth, migration, and metastasis in salivary adenoid cystic carcinoma: in vitro and in vivo study

    PubMed Central

    Wang, Meng; Zhao, Xiao-Ping; Xu, Zhi; Yan, Ting-Lin; Song, Yong; Song, Kai; Huang, Chun-Ming; Wang, Lin; Zhou, Xiao-Cheng; Jiang, Er-Hui; Shao, Zhe; Shang, Zheng-Jun

    2016-01-01

    EphA2 is associated with tumor growth and distant metastasis in numerous human tumors. Considering the controversial effects of EphA2 in different tumors and the lack of reports in salivary adenoid cystic carcinoma (SACC), we evaluated the effects of EphA2 inhibition by short hairpin RNA on SACC through in vivo and in vitro researches for the first time. Real-time reverse transcriptase-PCR and western blot analysis were conducted to verify the interference effect on SACC cells. Using Cell Counting Kit-8, wound healing, Transwell and Matrigel adhesion assays, we confirm that inhibition of EphA2 promotes the migration, invasion and adhesion ability of SACC cells. In vivo research, we prove that silencing of EphA2 significantly accelerates tumor growth and lung metastasis ability by establishing xenograft models in mice, including subcutaneous inoculation and tail vein injection. In addition, immunostaining of EphA2, E-cadherin and Slug from 40 specimens and in vitro simulation of perineural invasion (PNI) assay imply that suppression of EphA2 partially contribute to epithelial-mesenchymal transition and enhancement of PNI in SACC. In conclusion, all the data suggest that EphA2 may act as a tumor suppressor in SACC progression. PMID:27186278

  8. MicroRNA-194 promotes the growth, migration, and invasion of ovarian carcinoma cells by targeting protein tyrosine phosphatase nonreceptor type 12

    PubMed Central

    Liang, Tian; Li, Liru; Cheng, Yan; Ren, Chengcheng; Zhang, Guangmei

    2016-01-01

    Ovarian carcinoma is the most lethal gynecologic malignancy among women. Ovarian cancer metastasis is the main reason for poor prognosis. MicroRNAs (miRNAs) have been shown to play an important role in tumorigenesis and metastasis in various cancers by affecting the expression of their targets. In this study, we explored the role of miR-194 in ovarian cancer. Real-time polymerase chain reaction assays showed that miR-194 was significantly upregulated in ovarian cancer tissues. Overexpression of miR-194 in ovarian cancer cells promotes cell proliferation, migration, and invasion; in contrast, inhibition of the expression of miR-194 has the opposite effects. Meanwhile, bioinformatics tools were used to identify protein tyrosine phosphatase nonreceptor type 12 (PTPN12) as a potential target of miR-194. The luciferase assay showed that miR-194 directly binds to the 3′-untranslated region of PTPN12. Western blot analysis and quantitative real-time polymerase chain reaction assay revealed that PTPN12 expression was negatively associated with miR-194 expression in both ovarian cancer tissues and cells. Thus, we conclude that miR-194 targets PTPN12 and functions as an oncogene in ovarian cancer cells. This novel pathway may provide a new insight to explain ovarian cancer development and metastasis. PMID:27486333

  9. EZH2 promotes cell migration and invasion but not alters cell proliferation by suppressing E-cadherin, partly through association with MALAT-1 in pancreatic cancer

    PubMed Central

    Han, Ting; Jiao, Feng; Hu, Hai; Yuan, Cuncun; Wang, Lei; Jin, Zi-Liang; Song, Wei-feng; Wang, Li-Wei

    2016-01-01

    Enhancer of zeste homolog 2 (EZH2) is an essential component of the polycomb repressive complex 2 (PRC2), which is required for epigenetic silencing of target genes, including those affecting cancer progression. Its role in pancreatic cancer remains to be clarified; therefore, we investigated the effects of aberrantly expressed EZH2 on pancreatic cancer. We found that EZH2 expression is up-regulated in pancreatic cancer tissues and positively correlated with lymph node metastasis and advanced clinical stage in pancreatic cancer patients. EZH2 knockdown in pancreatic cancer cell lines inhibited cell migration and invasion, but did not alter cell proliferation. Silencing of EZH2 also increased E-cadherin expression in vitro, and E-cadherin expression was inversely correlated with EZH2 expression in pancreatic cancer tissue samples. Patients with high EZH2 and low E-cadherin expression had the worst prognosis. RIP and ChIP assays suggest that EZH2 is recruited to the E-cadherin promoter by the long non-coding RNA, MALAT-1 (metastasis associated in lung adenocarcinoma transcript 1), where it represses E-cadherin expression. Our results show that EZH2-based therapies may be an option for the treatment of pancreatic cancer. PMID:26848980

  10. EZH2 promotes cell migration and invasion but not alters cell proliferation by suppressing E-cadherin, partly through association with MALAT-1 in pancreatic cancer.

    PubMed

    Han, Ting; Jiao, Feng; Hu, Hai; Yuan, Cuncun; Wang, Lei; Jin, Zi-Liang; Song, Wei-Feng; Wang, Li-Wei

    2016-03-01

    Enhancer of zeste homolog 2 (EZH2) is an essential component of the polycomb repressive complex 2 (PRC2), which is required for epigenetic silencing of target genes, including those affecting cancer progression. Its role in pancreatic cancer remains to be clarified; therefore, we investigated the effects of aberrantly expressed EZH2 on pancreatic cancer. We found that EZH2 expression is up-regulated in pancreatic cancer tissues and positively correlated with lymph node metastasis and advanced clinical stage in pancreatic cancer patients. EZH2 knockdown in pancreatic cancer cell lines inhibited cell migration and invasion, but did not alter cell proliferation. Silencing of EZH2 also increased E-cadherin expression in vitro, and E-cadherin expression was inversely correlated with EZH2 expression in pancreatic cancer tissue samples. Patients with high EZH2 and low E-cadherin expression had the worst prognosis. RIP and ChIP assays suggest that EZH2 is recruited to the E-cadherin promoter by the long non-coding RNA, MALAT-1 (metastasis associated in lung adenocarcinoma transcript 1), where it represses E-cadherin expression. Our results show that EZH2-based therapies may be an option for the treatment of pancreatic cancer.

  11. C-terminal fragment of amebin promotes actin filament bundling, inhibits acto-myosin ATPase activity and is essential for amoeba migration.

    PubMed

    Jóźwiak, Jolanta; Rzhepetskyy, Yuriy; Sobczak, Magdalena; Kocik, Elżbieta; Skórzewski, Radosław; Kłopocka, Wanda; Rędowicz, Maria Jolanta

    2011-02-01

    Amebin [formerly termed as ApABP-FI; Sobczak et al. (2007) Biochem. Cell Biol. 85] is encoded in Amoeba proteus by two transcripts, 2672-nt and 1125-nt. A product of the shorter transcript (termed as C-amebin), comprising C-terminal 375 amino-acid-residue fragment of amebin, has been expressed and purified as the recombinant GST-fusion protein. GST-C-amebin bound both to monomeric and filamentous actin. The binding was Ca(2+)-independent and promoted filament bundling, as revealed with the transmission electron microscopy. GST-C-amebin significantly decreased MgATPase activity of rabbit skeletal muscle acto-S1. Removal with endoproteinase ArgC of a positively charged C-terminal region of GST-amebin containing KLASMWEQ sequence abolished actin-binding and bundling as well as the ATPase-inhibitory effect of C-amebin, indicating that this protein region was involved in the interaction with actin. Microinjection of amoebae with antibody against C-terminus of amebin significantly affected amoebae morphology, disturbed cell polarization and transport of cytoplasmic granules as well as blocked migration. These data indicate that amebin may be one of key regulators of the actin-cytoskeleton dynamics and actin-dependent motility in A. proteus.

  12. Th2 lymphocytes migrating to the bone marrow under high-altitude hypoxia promote erythropoiesis via activin A and interleukin-9.

    PubMed

    Li, Peng; Zheng, Shan-jun; Jiang, Chun-hua; Zhou, Si-min; Tian, Huai-jun; Zhang, Gang; Gao, Yu-qi

    2014-09-01

    The mechanism of accelerated erythropoiesis under the hypoxic conditions of high altitude (HA) remains largely obscure. Here, we investigated the potential role of bone marrow (BM) T cells in the increased production of erythrocytes at HA. We found that mice exposed to a simulated altitude of 6,000 m for 1-3 weeks exhibited a significant expansion of BM CD4+ cells, mainly caused by increasing T helper 2 (Th2) cells. Using a coculture model of BM T cells and hematopoietic stem/progenitor cells, we observed that BM CD4+ cells from hypoxic mice induced erythroid output more easily, in agreement with the erythroid-enhancing effect observed for Th2-condition-cultured BM CD4+ cells. It was further demonstrated that elevated secretion of activin A and interleukin-9 by BM Th2 cells of hypoxic mice promoted erythroid differentiation of hematopoietic stem/progenitor cells and the growth of erythroblasts, respectively. Our study also provided evidence that the CXCL12-CXCR4 interaction played an important role in Th2 cell trafficking to the BM under HA conditions. These results collectively suggest that Th2 cells migrating to the BM during HA exposure have a regulatory role in erythropoiesis, which provides new insight into the mechanism of high altitude polycythemia.

  13. PTH/SDF-1α cotherapy induces CD90+CD34− stromal cells migration and promotes tissue regeneration in a rat periodontal defect model

    PubMed Central

    Wang, Fang; Du, Lingqian; Ge, Shaohua

    2016-01-01

    Stromal cell-derived factor-1α (SDF-1α) is a key stem cell homing factor that is crucial for recruitment of stem cells to many diseased organs. However, the therapeutic activity of SDF-1α is potentially limited by N-terminal cleavage at position-2 proline by a cell surface protein CD26/dipeptidyl peptidase-IV (DPP-IV). Parathyroid hormone (PTH) is a DPP-IV inhibitor and has been suggested as a promising agent for periodontal tissue repair. The purpose of this study was to explore the effects of a cell-free system comprising SDF-1α and scaffold plus PTH systemic application on periodontal tissue regeneration in vivo. The results showed that PTH/SDF-1α cotherapy improved the quantity of regenerated bone and resulted in better organization of ligament interface. We further investigated the possible mechanisms, and found that PTH/SDF-1α cotherapy enhanced CD90+CD34− stromal cells migration in vivo, increased the number of CXCR4 + cells in periodontal defects, induced early bone osteoclastogenesis and enhanced the expression of runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP) and collagen I (Col I) in newly formed bone tissue. In conclusion, this cell-free tissue engineering system with local administration of SDF-1α and systemic application of PTH could be employed to induce CD90+CD34− stromal cells recruitment and promote periodontal tissue regeneration. PMID:27480134

  14. A Heterodimeric Cytokine, Consisting of IL-17A and IL-17F, Promotes Migration and Capillary-Like Tube Formation of Human Vascular Endothelial Cells.

    PubMed

    Numasaki, Muneo; Tsukamoto, Hiroki; Tomioka, Yoshihisa; Nishioka, Yasuhiko; Ohrui, Takashi

    2016-01-01

    The interleukin (IL)-17 family, consisting of six homodimeric cytokines IL-17A, IL-17B, IL-17C, IL-17D, IL-17E/IL-25, and IL-17F, mediates a variety of biological activities including regulation of chemokine secretion and angiogenesis. Among the IL-17 family members, IL-17A and IL-17E/IL-25 are angiogenesis stimulators, while IL-17B and IL-17F are angiogenesis inhibitors. Recently, IL-17A/F heterodimer, comprised of the IL-17A and IL-17F subunits, was found as another member of the IL-17 cytokine family. However, to date, it has been unknown whether IL-17A/F has biological actions to affect the angiogenesis-related vascular endothelial functions. Therefore, in this study, we investigated the biological effects of IL-17A/F on the growth, migration and capillary-like tube formation of vascular endothelial cells. Recombinant IL-17A/F protein had no direct effects on the growth of human dermal microvascular endothelial cells (HMVECs), whereas, after 4-hour incubation in a modified Boyden Chemotaxicell chamber, IL-17A/F significantly induced migration of HMVECs over a wide range of doses via the phosphatidylinositol-3 kinase (PI3K) signaling pathway. We further investigated the biological effect of IL-17A/F on capillary-like tube formation using a co-culture system of human umbilical vein endothelial cells (HUVECs) and human dermal fibroblasts (HDFs), which mimicked the in vivo microenvironment. In this co-culture system, IL-17A/F significantly promoted capillary-like endothelial tube formation in a dose-dependent fashion via the PI3K and extracellular signal-regulated kinase (ERK) signaling pathways. Additionally, IL-17A/F up-regulated secretion of angiogenic growth factors such as IL-8 and growth-related oncogene (GRO)-α by HDFs. These findings identify a novel biological function for IL-17A/F as an indirect angiogenic agent. PMID:27594509

  15. The sGC activator inhibits the proliferation and migration, promotes the apoptosis of human pulmonary arterial smooth muscle cells via the up regulation of plasminogen activator inhibitor-2

    SciTech Connect

    Zhang, Shuai; Zou, Lihui; Yang, Ting; Yang, Yuanhua; Zhai, Zhenguo; Xiao, Fei; Wang, Chen

    2015-03-15

    Background: Different types of pulmonary hypertension (PH) share the same process of pulmonary vascular remodeling, the molecular mechanism of which is not entirely clarified by far. The abnormal biological behaviors of pulmonary arterial smooth muscle cells (PASMCs) play an important role in this process. Objectives: We investigated the regulation of plasminogen activator inhibitor-2 (PAI-2) by the sGC activator, and explored the effect of PAI-2 on PASMCs proliferation, apoptosis and migration. Methods: After the transfection with PAI-2 overexpression vector and specific siRNAs or treatment with BAY 41-2272 (an activator of sGC), the mRNA and protein levels of PAI-2 in cultured human PASMCs were detected, and the proliferation, apoptosis and migration of PASMCs were investigated. Results: BAY 41-2272 up regulated the endogenous PAI-2 in PASMCs, on the mRNA and protein level. In PAI-2 overexpression group, the proliferation and migration of PASMCs were inhibited significantly, and the apoptosis of PASMCs was increased. In contrast, PAI-2 knockdown with siRNA increased PASMCs proliferation and migration, inhibited the apoptosis. Conclusions: PAI-2 overexpression inhibits the proliferation and migration and promotes the apoptosis of human PASMCs. Therefore, sGC activator might alleviate or reverse vascular remodeling in PH through the up-regulation of PAI-2. - Highlights: • sGC activator BAY41-2272 up regulated PAI-2 in PASMCs, on the mRNA and protein level. • PAI-2 overexpression inhibits the proliferation and migration of human PASMCs. • PAI-2 overexpression promotes the apoptosis of human PASMCs. • sGC activator might alleviate the vascular remodeling in pulmonary hypertension.

  16. Return migration.

    PubMed

    Gmelch, G

    1980-01-01

    The author reviews the findings of the growing literature on return migration. Topics covered include typologies of return migrants, reasons for return, adaptation and readjustment of returnees, and the impact of return migration on the migrants' home societies. The focus of the study is on international return migration, migration to Northern Europe and northeastern North America, and return migration to the southern and eastern fringes of Europe and the Caribbean

  17. Analysis of Phosphorylation-dependent Protein Interactions of Adhesion and Degranulation Promoting Adaptor Protein (ADAP) Reveals Novel Interaction Partners Required for Chemokine-directed T cell Migration.

    PubMed

    Kuropka, Benno; Witte, Amelie; Sticht, Jana; Waldt, Natalie; Majkut, Paul; Hackenberger, Christian P R; Schraven, Burkhart; Krause, Eberhard; Kliche, Stefanie; Freund, Christian

    2015-11-01

    Stimulation of T cells leads to distinct changes of their adhesive and migratory properties. Signal propagation from activated receptors to integrins depends on scaffolding proteins such as the adhesion and degranulation promoting adaptor protein (ADAP)(1). Here we have comprehensively investigated the phosphotyrosine interactome of ADAP in T cells and define known and novel interaction partners of functional relevance. While most phosphosites reside in unstructured regions of the protein, thereby defining classical SH2 domain interaction sites for master regulators of T cell signaling such as SLP76, Fyn-kinase, and NCK, other binding events depend on structural context. Interaction proteomics using different ADAP constructs comprising most of the known phosphotyrosine motifs as well as the structured domains confirm that a distinct set of proteins is attracted by pY571 of ADAP, including the ζ-chain-associated protein kinase of 70 kDa (ZAP70). The interaction of ADAP and ZAP70 is inducible upon stimulation either of the T cell receptor (TCR) or by chemokine. NMR spectroscopy reveals that the N-terminal SH2 domains within a ZAP70-tandem-SH2 construct is the major site of interaction with phosphorylated ADAP-hSH3(N) and microscale thermophoresis (MST) indicates an intermediate binding affinity (Kd = 2.3 μm). Interestingly, although T cell receptor dependent events such as T cell/antigen presenting cell (APC) conjugate formation and adhesion are not affected by mutation of Y571, migration of T cells along a chemokine gradient is compromised. Thus, although most phospho-sites in ADAP are linked to T cell receptor related functions we have identified a unique phosphotyrosine that is solely required for chemokine induced T cell behavior.

  18. miR-3646 promotes cell proliferation, migration, and invasion via regulating G2/M transition in human breast cancer cells

    PubMed Central

    Tao, Shuang; Liu, Yao-Bang; Zhou, Zhi-Wei; Lian, Bin; Li, Hong; Li, Jin-Ping; Zhou, Shu-Feng

    2016-01-01

    MicroRNAs (miRNAs) are small non-coding RNAs that are often located in genomic breakpoint regions and play a critical role in regulating a variety of the cellular processes in human cancer. miR-3646 has been reported to take part in tumorigenic progression in breast and bladder cancer, but its potential functions and exact mechanistic roles in breast cancer are still unclear. The objective of this study was to investigate the role of miR-3646 in breast cancer growth and metastasis using both bioinformatic and experimental approaches. Before starting the bench work, we conducted a bioinformatic study to predict the target genes regulated by miR-3646 using a panel of different algorithms. The results showed that miR-3646 might regulate a large number of genes that are related to cell growth, proliferation, metabolis, transport, and apoptosis and some were cancer-related genes. We found that the expression level of miR-3646 was significantly upregulated in breast cancer cells and tissues compared with normal breast cells and no tumor tissues. Subsequently, the MTT and colony formation assay results showed that up-regulation of miR-3646 promoted the cell viability and proliferation. Our results also showed that down-regulation of miR-3646 arrested the cells in G2/M phase in MCF7 and MDA-MB-231 cells which was accompanied by the down-regulation of CDK1/CDC2 and cyclin B1 and upregulation of p21Waf1/Cip1, p27 Kip1, and p53, suggesting that down-regulation of miR-3646 induces G2/M arrest through activation of the p53/p21/CDC2/cyclin B1 pathway. In addition, overexpression of miR-3646 promoted migration and invasion of MCF7 and MDA-MB-231 cells. Taken together, miR-3646 is a potential oncogene in breast cancer and it may represent a new niomarker in the diagnosis and prediction of prognosis and therapeutic response. PMID:27186291

  19. S100B-p53 disengagement by pentamidine promotes apoptosis and inhibits cellular migration via aquaporin-4 and metalloproteinase-2 inhibition in C6 glioma cells

    PubMed Central

    CAPOCCIA, ELENA; CIRILLO, CARLA; MARCHETTO, ANNALISA; TIBERI, SAMANTA; SAWIKR, YOUSSEF; PESCE, MARCELLA; D'ALESSANDRO, ALESSANDRA; SCUDERI, CATERINA; SARNELLI, GIOVANNI; CUOMO, ROSARIO; STEARDO, LUCA; ESPOSITO, GIUSEPPE

    2015-01-01

    S100 calcium-binding protein B (S100B) is highly expressed in glioma cells and promotes cancer cell survival via inhibition of the p53 protein. In melanoma cells, this S100B-p53 interaction is known to be inhibited by pentamidine isethionate, an antiprotozoal agent. Thus, the aim of the present study was to evaluate the effect of pentamidine on rat C6 glioma cell proliferation, migration and apoptosis in vitro. The change in C6 cell proliferation following treatment with pentamidine was determined by performing a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide-formazan assay. Significant dose-dependent decreases in proliferation were observed at pentamidine concentrations of 0.05 µM (58.5±5%; P<0.05), 0.5 µM (40.6±7%; P<0.01) and 5 µM (13±4%; P<0.001) compared with the control (100% viability). Furthermore, treatment with 0.05, 0.5 and 5 µM pentamidine was associated with a significant increase in apoptosis versus the untreated cells, as determined by DNA fragmentation assays, immunofluorescence analysis of C6 chromatin using Hoechst staining, and immunoblot analysis of B-cell lymphoma-2 (Bcl-2)-associated X protein (100%, P<0.05; 453%, P<0.01; and 1000%, P<0.001, respectively) and Bcl-2 (-60%, P<0.001; −80.13%, P<0.001; −95%, P<0.001, respectively). In addition, the administration of 0.05, 0.5 and 5 µM pentamidine significantly upregulated the protein expression levels of p53 (681±87.5%, P<0.05; 1244±94.3%, P<0.01; and 2244±111%, P<0.001, respectively), and significantly downregulated the expression levels of matrix metalloproteinase-2 (42±2.3%, P<0.05; 71±2.5%, P<0.01; and 95.8±3.3%, P<0.001, respectively) and aquaporin 4 (38±2.5%, P<0.05; 69±2.6%, P<0.01; and 88±3.0%, P<0.001, respectively), compared with the untreated cells. The wound healing assay demonstrated that cell migration was significantly impaired by treatment with 0.05, 0.5 and 5 µM pentamidine compared with untreated cells (88±4.2%, P<0.05; 64±2%, P<0.01; and 42

  20. A KSHV microRNA Directly Targets G Protein-Coupled Receptor Kinase 2 to Promote the Migration and Invasion of Endothelial Cells by Inducing CXCR2 and Activating AKT Signaling

    PubMed Central

    Bai, Zhiqiang; Qin, Di; Yan, Qin; Zhu, Jianzhong; Krueger, Brian J.; Renne, Rolf; Gao, Shou-Jiang; Lu, Chun

    2015-01-01

    Kaposi's sarcoma (KS) is a highly disseminated angiogenic tumor of endothelial cells linked to infection by Kaposi's sarcoma-associated herpesvirus (KSHV). KSHV encodes more than two dozens of miRNAs but their roles in KSHV-induced tumor dissemination and metastasis remain unknown. Here, we found that ectopic expression of miR-K12-3 (miR-K3) promoted endothelial cell migration and invasion. Bioinformatics and luciferase reporter analyses showed that miR-K3 directly targeted G protein-coupled receptor (GPCR) kinase 2 (GRK2, official gene symbol ADRBK1). Importantly, overexpression of GRK2 reversed miR-K3 induction of cell migration and invasion. Furthermore, the chemokine receptor CXCR2, which was negatively regulated by GRK2, was upregulated in miR-K3-transduced endothelial cells. Knock down of CXCR2 abolished miR-K3-induced cell migration and invasion. Moreover, miR-K3 downregulation of GRK2 relieved its direct inhibitory effect on AKT. Both CXCR2 induction and the release of AKT from GRK2 were required for miR-K3 maximum activation of AKT and induction of cell migration and invasion. Finally, deletion of miR-K3 from the KSHV genome abrogated its effect on the GRK2/CXCR2/AKT pathway and KSHV-induced migration and invasion. Our data provide the first-line evidence that, by repressing GRK2, miR-K3 facilitates cell migration and invasion via activation of CXCR2/AKT signaling, which likely contribute to the dissemination of KSHV-induced tumors. PMID:26402907

  1. Macrophage migration inhibitory factor (MIF) promoter polymorphisms (-794 CATT5-8 and -173 G>C): association with MIF and TNFα in psoriatic arthritis

    PubMed Central

    Morales-Zambrano, Ramsés; Bautista-Herrera, Luis A; la Cruz-Mosso, Ulises De; Villanueva-Quintero, Guadalupe D; Padilla-Gutiérrez, Jorge R; Valle, Yeminia; Parra-Rojas, Isela; Rangel-Villalobos, Héctor; Gutiérrez-Ureña, Sergio R; Muñoz-Valle, José F

    2014-01-01

    Psoriatic arthritis (PsA) is an autoimmune disease with a complex interaction of gene and with a dysregulation of pro-inflammatory cytokine such as Macrophage migration Inhibitory Factor (MIF) and Tumor Necrosis Factor-alpha (TNFα). Two polymorphisms identified in the promoter region of the MIF gene have been described: the STR-794 CATT5-8 (rs5844572) and the SNP-173 G>C (rs755622), which are associated with increased MIF levels in circulation and with autoimmune diseases in several populations. In this case-control study we investigated whether commonly occurring functional MIF polymorphisms are associated with PsA susceptibility and clinical variables as well as with MIF and TNFα serum levels in a Mexican-Mestizo population. Genotyping of the -794 CATT5-8 and -173 G>C MIF polymorphisms was performed by PCR and PCR-RFLP respectively in 50 PsA patients and 100 healthy subjects (HS). MIF and TNFα serum levels were determined by ELISA. A significant increase of MIF (PsA: 7.8 vs. HS: 5.25 ng/mL; p < 0.001) and TNFα (PsA: 24.6 vs. HS: 9.9 pg/mL; p < 0.001) levels was found in PsA patients, a significant correlation was observed between MIF and TNFα (r = 0.41; p < 0.01). The 5,6 repeats genotype of the -794 CATT5-8 MIF was associated with protection to PsA (OR = 0.29; CI 0.77-0.98; p = 0.03), and the G/C genotype (OR = 7.5; CI 2.92-21.64; p < 0.001) and the -173*C allele (OR = 2.45; CI 1.43-4.20; p < 0.001) of the -173 G>C MIF were associated with susceptibility to PsA. In conclusion the -173*C allele is associated with susceptibility to PsA in Mexican-Mestizo population, whereas the correlation between MIF and TNFα soluble levels provided evidence that both cytokines are closely related in the pathophysiology of the PsA. PMID:25356116

  2. Macrophage migration inhibitory factor (MIF) promoter polymorphisms (-794 CATT5-8 and -173 G>C): association with MIF and TNFα in psoriatic arthritis.

    PubMed

    Morales-Zambrano, Ramsés; Bautista-Herrera, Luis A; De la Cruz-Mosso, Ulises; Villanueva-Quintero, Guadalupe D; Padilla-Gutiérrez, Jorge R; Valle, Yeminia; Parra-Rojas, Isela; Rangel-Villalobos, Héctor; Gutiérrez-Ureña, Sergio R; Muñoz-Valle, José F

    2014-01-01

    Psoriatic arthritis (PsA) is an autoimmune disease with a complex interaction of gene and with a dysregulation of pro-inflammatory cytokine such as Macrophage migration Inhibitory Factor (MIF) and Tumor Necrosis Factor-alpha (TNFα). Two polymorphisms identified in the promoter region of the MIF gene have been described: the STR-794 CATT5-8 (rs5844572) and the SNP-173 G>C (rs755622), which are associated with increased MIF levels in circulation and with autoimmune diseases in several populations. In this case-control study we investigated whether commonly occurring functional MIF polymorphisms are associated with PsA susceptibility and clinical variables as well as with MIF and TNFα serum levels in a Mexican-Mestizo population. Genotyping of the -794 CATT5-8 and -173 G>C MIF polymorphisms was performed by PCR and PCR-RFLP respectively in 50 PsA patients and 100 healthy subjects (HS). MIF and TNFα serum levels were determined by ELISA. A significant increase of MIF (PsA: 7.8 vs. HS: 5.25 ng/mL; p < 0.001) and TNFα (PsA: 24.6 vs. HS: 9.9 pg/mL; p < 0.001) levels was found in PsA patients, a significant correlation was observed between MIF and TNFα (r = 0.41; p < 0.01). The 5,6 repeats genotype of the -794 CATT5-8 MIF was associated with protection to PsA (OR = 0.29; CI 0.77-0.98; p = 0.03), and the G/C genotype (OR = 7.5; CI 2.92-21.64; p < 0.001) and the -173*C allele (OR = 2.45; CI 1.43-4.20; p < 0.001) of the -173 G>C MIF were associated with susceptibility to PsA. In conclusion the -173*C allele is associated with susceptibility to PsA in Mexican-Mestizo population, whereas the correlation between MIF and TNFα soluble levels provided evidence that both cytokines are closely related in the pathophysiology of the PsA.

  3. Basic fibroblast growth factor promotes melanocyte migration via activating PI3K/Akt-Rac1-FAK-JNK and ERK signaling pathways.

    PubMed

    Shi, Hongxue; Lin, Beibei; Huang, Yan; Wu, Jiang; Zhang, Hongyu; Lin, Cai; Wang, Zhouguang; Zhu, Jingjing; Zhao, Yingzhen; Fu, Xiaobing; Lou, Zhencai; Li, Xiaokun; Xiao, Jian

    2016-09-01

    Vitiligo is a depigmentation disorder characterized by loss of functional melanocytes of the skin epidermis. The pathogenesis of vitiligo remains elusive. The purpose of this study is to investigate the effects of basic fibroblast growth factor (bFGF) on melanocyte migration, including its biochemical mechanism using transwell assay in vitro. We found that melanocyte treated with bFGF showed a significant increase in migration and cytoskeletal rearrangement. These changes were associated with increased activation of PI3K/Akt, Rac1, FAK, JNK, and ERK. Likewise, reduction of PI3K/Akt, Rac1, FAK, JNK, and ERK activity using selective inhibitors or siRNA was associated with impediment of bFGF-induced melanocyte migration. In addition, activity of Rac1, FAK, and JNK was reduced in cells in which PI3K/Akt was inhibited, activity of FAK and JNK was reduced in cells in which the Rac1 was inhibited, and activity of JNK was reduced in cells in which the FAK was inhibited. Collectively, these data demonstrate that bFGF facilitated melanocyte migration via PI3K/Akt-Rac1-FAK-JNK and ERK signaling pathways. © 2016 IUBMB Life, 68(9):735-747, 2016. PMID:27350596

  4. The Drosophila FHOD1-like formin Knittrig acts through Rok to promote stress fiber formation and directed macrophage migration during the cellular immune response.

    PubMed

    Lammel, Uwe; Bechtold, Meike; Risse, Benjamin; Berh, Dimitri; Fleige, Astrid; Bunse, Ingrid; Jiang, Xiaoyi; Klämbt, Christian; Bogdan, Sven

    2014-03-01

    A tight spatiotemporal control of actin polymerization is important for many cellular processes that shape cells into a multicellular organism. The formation of unbranched F-actin is induced by several members of the formin family. Drosophila encodes six formin genes, representing six of the seven known mammalian subclasses. Knittrig, the Drosophila homolog of mammalian FHOD1, is specifically expressed in the developing central nervous system midline glia, the trachea, the wing and in macrophages. knittrig mutants exhibit mild tracheal defects but survive until late pupal stages and mainly die as pharate adult flies. knittrig mutant macrophages are smaller and show reduced cell spreading and cell migration in in vivo wounding experiments. Rescue experiments further demonstrate a cell-autonomous function of Knittrig in regulating actin dynamics and cell migration. Knittrig localizes at the rear of migrating macrophages in vivo, suggesting a cellular requirement of Knittrig in the retraction of the trailing edge. Supporting this notion, we found that Knittrig is a target of the Rho-dependent kinase Rok. Co-expression with Rok or expression of an activated form of Knittrig induces actin stress fibers in macrophages and in epithelial tissues. Thus, we propose a model in which Rok-induced phosphorylation of residues within the basic region mediates the activation of Knittrig in controlling macrophage migration. PMID:24553290

  5. Krüppel-like factor 8 activates the transcription of C-X-C cytokine receptor type 4 to promote breast cancer cell invasion, transendothelial migration and metastasis

    PubMed Central

    Yu, Lin; He, Chunjiang; Lahiri, Satadru K.; Li, Tianshu; Zhao, Jihe

    2016-01-01

    Krüppel-like factor 8 (KLF8) has been strongly implicated in breast cancer metastasis. However, the underlying mechanisms remain largely unknown. Here we report a novel signaling from KLF8 to C-X-C cytokine receptor type 4 (CXCR4) in breast cancer. Overexpression of KLF8 in MCF-10A cells induced CXCR4 expression at both mRNA and protein levels, as determined by quantitative real-time PCR and immunoblotting. This induction was well correlated with increased Boyden chamber migration, matrigel invasion and transendothelial migration (TEM) of the cells towards the ligand CXCL12. On the other hand, knockdown of KLF8 in MDA-MB-231 cells reduced CXCR4 expression associated with decreased cell migration, invasion and TEM towards CXCL12. Histological and database mining analyses of independent cohorts of patient tissue microarrays revealed a correlation of aberrant co-elevation of KLF8 and CXCR4 with metastatic potential. Promoter analysis indicated that KLF8 directly binds and activates the human CXCR4 gene promoter. Interestingly, a CXCR4-dependent activation of focal adhesion kinase (FAK), a known upregulator of KLF8, was highly induced by CXCL12 treatment in KLF8-overexpressing, but not KLF8 deficient cells. This activation of FAK in turn induced a further increase in KLF8 expression. Xenograft studies showed that overexpression of CXCR4, but not a dominant-negative mutant of it, in the MDA-MB-231 cells prevented the invasive growth of primary tumor and lung metastasis from inhibition by knockdown of KLF8. These results collectively suggest a critical role for a previously unidentified feed-forward signaling wheel made of KLF8, CXCR4 and FAK in promoting breast cancer metastasis and shed new light on potentially more effective anti-cancer strategies. PMID:26993780

  6. Cell Migration

    PubMed Central

    Trepat, Xavier; Chen, Zaozao; Jacobson, Ken

    2015-01-01

    Cell migration is fundamental to establishing and maintaining the proper organization of multicellular organisms. Morphogenesis can be viewed as a consequence, in part, of cell locomotion, from large-scale migrations of epithelial sheets during gastrulation, to the movement of individual cells during development of the nervous system. In an adult organism, cell migration is essential for proper immune response, wound repair, and tissue homeostasis, while aberrant cell migration is found in various pathologies. Indeed, as our knowledge of migration increases, we can look forward to, for example, abating the spread of highly malignant cancer cells, retarding the invasion of white cells in the inflammatory process, or enhancing the healing of wounds. This article is organized in two main sections. The first section is devoted to the single-cell migrating in isolation such as occurs when leukocytes migrate during the immune response or when fibroblasts squeeze through connective tissue. The second section is devoted to cells collectively migrating as part of multicellular clusters or sheets. This second type of migration is prevalent in development, wound healing, and in some forms of cancer metastasis. PMID:23720251

  7. Tumor-associated Endo180 requires stromal-derived LOX to promote metastatic prostate cancer cell migration on human ECM surfaces.

    PubMed

    Caley, Matthew P; King, Helen; Shah, Neel; Wang, Kai; Rodriguez-Teja, Mercedes; Gronau, Julian H; Waxman, Jonathan; Sturge, Justin

    2016-02-01

    The diverse composition and structure of extracellular matrix (ECM) interfaces encountered by tumor cells at secondary tissue sites can influence metastatic progression. Extensive in vitro and in vivo data has confirmed that metastasizing tumor cells can adopt different migratory modes in response to their microenvironment. Here we present a model that uses human stromal cell-derived matrices to demonstrate that plasticity in tumor cell movement is controlled by the tumor-associated collagen receptor Endo180 (CD280, CLEC13E, KIAA0709, MRC2, TEM9, uPARAP) and the crosslinking of collagen fibers by stromal-derived lysyl oxidase (LOX). Human osteoblast-derived and fibroblast-derived ECM supported a rounded 'amoeboid-like' mode of cell migration and enhanced Endo180 expression in three prostate cancer cell lines (PC3, VCaP, DU145). Genetic silencing of Endo180 reverted PC3 cells from their rounded mode of migration towards a bipolar 'mesenchymal-like' mode of migration and blocked their translocation on human fibroblast-derived and osteoblast-derived matrices. The concomitant decrease in PC3 cell migration and increase in Endo180 expression induced by stromal LOX inhibition indicates that the Endo180-dependent rounded mode of prostate cancer cell migration requires ECM crosslinking. In conclusion, this study introduces a realistic in vitro model for the study of metastatic prostate cancer cell plasticity and pinpoints the cooperation between tumor-associated Endo180 and the stiff microenvironment imposed by stromal-derived LOX as a potential target for limiting metastatic progression in prostate cancer. PMID:26567111

  8. Cathepsin E generates a sumoylated intracellular fragment of the cell adhesion molecule L1 to promote neuronal and Schwann cell migration as well as myelination.

    PubMed

    Lutz, David; Wolters-Eisfeld, Gerrit; Schachner, Melitta; Kleene, Ralf

    2014-03-01

    The cell adhesion molecule L1 regulates cellular responses in the developing and adult nervous system. Here, we show that stimulation of cultured mouse cerebellar neurons by a function-triggering L1 antibody leads to cathepsin E-mediated generation of a sumoylated 30 kDa L1 fragment (L1-30) and to import of L1-30 into the nucleus. Mutation of the sumoylation site at K1172 or the cathepsin E cleavage site at E1167 abolishes generation of L1-30, while mutation of the nuclear localization signal at K1147 prevents nuclear import of L1-30. Moreover, the aspartyl protease inhibitor pepstatin impairs the generation of L1-30 and inhibits L1-induced migration of cerebellar neurons and Schwann cells as well as L1-dependent in vitro myelination on axons of dorsal root ganglion neurons by Schwann cells. L1-stimulated migration of HEK293 cells expressing L1 with mutated cathepsin E cleavage site is diminished in comparison to migration of cells expressing non-mutated L1. In addition, L1-stimulated migration of HEK293 cells expressing non-mutated L1 is also abolished upon knock-down of cathepsin E expression and enhanced by over-expression of cathepsin E. The findings of the present study indicate that generation and nuclear import of L1-30 regulate neuronal and Schwann cell migration as well as myelination. Cell adhesion molecule L1 regulates cellular responses in the developing and adult nervous system. L1 stimulation triggers sumoylation and cleavage of L1, thus generating the L1-70 fragment (1) which is cleaved by cathepsin E (2) yielding the L1-30 fragment that is imported to the nucleus (3), may bind to DNA and/or nuclear proteins (4), to regulate diverse cellular functions. PMID:24118054

  9. CD133+ cancer stem-like cells promote migration and invasion of salivary adenoid cystic carcinoma by inducing vasculogenic mimicry formation

    PubMed Central

    Wang, Sha-sha; Gao, Xiao-lei; Liu, Xin; Gao, Shi-yu; Fan, Yun-long; Jiang, Ya-ping; Ma, Xiang-rui; Jiang, Jian; Feng, Hao; Chen, Qian-ming; Tang, Ya-jie; Tang, Ya-ling; Liang, Xin-hua

    2016-01-01

    Cancer stem cells (CSCs) have gained much attention due to their roles in the invasion and metastasis of numerous kinds of human cancers. Here, we showed that the positive expression of CD133, the stemness marker, was positively associated with vasculogenic mimicry (VM) formation, local regional recurrence, distant metastasis and poorer prognosis in salivary adenoid cystic carcinoma (ACC) specimens. Compared with CD133− ACC cells, CD133+ cancer stem-like cells had more migration and invasion capabilities, as well as more VM formation. The levels of endothelial cell marker VE-cadherin, MMP-2 and MMP-9 expression in CD133+ cancer stem-like cells and xenograft tumors of nude mice injected with CD133+ cells were significantly higher than those with CD133− cells. The data indicated that CD133+ cancer stem-like cells might contribute to the migration and invasion of ACC through inducing VM formation. PMID:27074560

  10. Sema4D, the ligand for Plexin B1, suppresses c-Met activation and migration and promotes melanocyte survival and growth.

    PubMed

    Soong, Joanne; Chen, Yulin; Shustef, Elina M; Scott, Glynis A

    2012-04-01

    Semaphorins are secreted and membrane-bound proteins involved in neural pathfinding, organogenesis, and tumor progression, through Plexin and neuropilin receptors. We recently reported that Plexin B1, the Semaphorin 4D (Sema4D) receptor, is a tumor-suppressor protein for melanoma, which functions, in part, through inhibition of the oncogenic c-Met tyrosine kinase receptor. In this report, we show that Sema4D is a protective paracrine factor for normal human melanocyte survival in response to UV irradiation, and that it stimulates proliferation and regulates the activity of the c-Met receptor. c-Met receptor signaling stimulates melanocyte migration, partly through downregulation of the cell adhesion molecule E-cadherin. Sema4D suppressed activation of c-Met in response to its ligand, hepatocyte growth factor (HGF), and partially blocked the suppressive effects of HGF on E-cadherin expression in melanocytes and HGF-dependent migration. These data demonstrate a role for Plexin B1 in maintenance of melanocyte survival and proliferation in the skin, and suggest that Sema4D and Plexin B1 act cooperatively with HGF and c-Met to regulate c-Met-dependent effects in human melanocytes. Because our data show that Plexin B1 is profoundly downregulated by UVB in melanocytes, loss of Plexin B1 may accentuate HGF-dependent effects on melanocytes, including melanocyte migration.

  11. Intradermal immunization in the ear with cholera toxin and its non-toxic β subunit promotes efficient Th1 and Th17 differentiation dependent on migrating DCs.

    PubMed

    Meza-Sánchez, David; Pérez-Montesinos, Gibrán; Sánchez-García, Javier; Moreno, José; Bonifaz, Laura C

    2011-10-01

    The nature of CD4(+) T-cell responses after skin immunization and the role of migrating DCs in the presence of adjuvants in the elicited response are interesting issues to be investigated. Here, we evaluated the priming of CD4(+) T cells following ear immunization with low doses of model antigens in combination with either cholera toxin (CT) or the non-toxic β CT subunit (CTB) as an adjuvant. Following immunization with CT, we found efficient antigen presentation that is reflected in the production of IFN-γ and IL-17 by CD4(+) T cells over IL-4 or IL-5 production. The CTB-induced activation of DCs in the ear occurred without visible inflammation, which reflects a similar type of CD4(+) T-cell differentiation. In both cases, the elicited response was dependent on the presence of migrating skin cells. Remarkably, immunization with CT or with CTB led to the induction of a delayed-type hypersensitivity (DTH) response in the ear. The DTH response that was induced by CT immunization was dependent on IL-17 and partially dependent on IFN-γ activity. These results indicate that both CT and CTB induce an efficient CD4(+) T-cell response to a co-administered antigen following ear immunization that is dependent on migrating DCs.

  12. Blockade of CCR7 leads to decreased dendritic cell migration to draining lymph nodes and promotes graft survival in low-risk corneal transplantation.

    PubMed

    Hos, D; Dörrie, J; Schaft, N; Bock, F; Notara, M; Kruse, F E; Krautwald, S; Cursiefen, C; Bachmann, B O

    2016-05-01

    The chemokine receptor CCR7 is essential for migration of mature dendritic cells (DCs) to the regional lymph nodes, and it has been shown that blocking of CCR7 improves graft survival after high-risk corneal transplantation in vascularized recipient corneas. However, it is so far unknown whether blocking of CCR7 reduces migration of DCs from the avascular cornea to the draining lymph nodes and whether this leads to improved graft survival also in the low-risk setting of corneal transplantation, which accounts for the majority of perforating transplantations performed. Therefore, in this study, pellets containing Freund's adjuvant and bovine serum albumin (BSA) conjugated to Alexa488 fluorescent dye were implanted into the corneal stroma of BALB/c mice to analyze antigen uptake by corneal DCs and their migration to the regional lymph nodes. After pellet implantation, mice were either treated by local administration of a CCR7 blocking fusion protein that consisted of CCL19 fused to the Fc part of human IgG1 or a control-IgG. In vivo fluorescence microscopy showed uptake of Alexa488-conjugated BSA by corneal DCs within 8 h. Furthermore, analysis of single cell suspensions of draining lymph nodes prepared after 48 h revealed that 2.1 ± 0.3% of CD11c(+) cells were also Alexa488(+). Importantly, DC migration was significantly reduced after topical administration of CCL19-IgG (1.2 ± 0.2%; p < 0.05). To test the effect of CCR7 blockade on graft rejection after allogeneic low-risk keratoplasty, corneal transplantations were performed using C57BL/6-mice as donors and BALB/c-mice as recipients. Treatment mice received two intraperitoneal loading doses of CCL19-IgG prior to transplantation, followed by local treatment with CCL19-IgG containing eye drops for the first two weeks after transplantation. Control mice received same amounts of control-IgG. Kaplan-Meier survival analysis showed that in the CCL19-IgG treated group, 76% of the grafts survived through the end

  13. Plasmin Promotes Keratinocyte Migration and Phagocytic-killing Accompanied by Suppression of Cell Proliferation which may Facilitate Re-epithelialization of Wound Beds

    PubMed Central

    Szabo, Imre; Simon, Miklos; Hunyadi, Janos

    2004-01-01

    Abstract Keratinocytes were shown to induce the activation of plasminogen activator resulting in the formation of plasmin and the initiation of proteolysis in vitro. Activation of surface bound plasminogen may localize protease activity in the pericellular microenvironment and play a role in inducing both a conformational change and cell locomotion. Plasmin, however, can induce non-proteolytic effects on certain cell functions in a variety of cell lineages. In the present study we examined the effects of plasmin on keratinocytes with a focus on its role in the process of re-epithelialization, which included studies of cell migration, phagocytic-killing and cell proliferation. Migration of freshly isolated human epidermal keratinocytes was analyzed utilizing the agarose gel assay in the presence of 10% human serum. Plasmin at the concentration of 25 U/l induced a 160% increase in the chemotactic migration of keratinocytes that was completely blocked by the plasmin inhibitor α2-antiplasmin (Serpin). In the absence of serum, plasmin also induced a reversible chemotactic migration of HaCaT keratinocytes as determined utilizing the microchemotaxis assay. Dose-response analysis showed a bi-phasic effect of plasmin with a maximum increase of 52% in keratinocyte chemotaxis at a concentration of 25 U/l. HaCaT cells on the other hand, showed no detectable in vitro chemokinesis by plasmin. Phagocytic-killing of Candida albicans by freshly isolated epidermal keratinocytes was enhanced in the presence of 25 U/l plasmin which was also reversible by the addition of Serpin. Spontaneous proliferation of HaCaT keratinocytes as determined by 3H-Thymidine uptake on the other hand, was reduced by 47 and 13% in cultures with 25 U/l plasmin for 24 and 48 h respectively, in a Serpin reversible manner. These data suggest that plasmin-induced chemotactic migration of epidermal keratinocytes is accompanied by enhanced phagocytic-killing coupled with suppression of proliferation of these

  14. Single chain fragment variable antibodies developed by using as target the 3rd fibronectin type III homologous repeat fragment of human neural cell adhesion molecule L1 promote cell migration and neuritogenesis.

    PubMed

    Tang, Dan-Yang; Yu, Yang; Zhao, Xuan-Jun; Schachner, Melitta; Zhao, Wei-Jiang

    2015-01-15

    L1CAM plays important roles during ontogeny, including promotion of neuronal cell migration and neuritogenesis, and stimulation of axonal outgrowth, fasciculation and myelination. These functions are at least partially exerted through a 16-mer amino acid sequence in the third fibronectin type III-like repeat of L1, which associates with several interaction partners, including integrins, other adhesion molecules and growth factor receptors. Here, using the Tomlinson I library for phage display, we obtained two single-chain variable fragment antibodies (scFvs) against this peptide sequence of human L1, hereafter called H3 peptide. Both scFvs recognize the H3 peptide and the extracellular domain of L1, as tested by enzyme-linked immunosorbent assay (ELISA), Western blot analysis and immunofluorescence staining of L1 expresssing cells. Furthermore, both scFvs reduce U-87 MG cell adhesion to fibronectin, while stimulating cell migration. Application of scFvs to human neuroblastoma SK-N-SH cells promote process outgrowth. Similar to triggering of endogenous L1 functions at the cell surface, both scFvs activate the signal transducers Erk and Src in these cells. Our results indicate that scFvs against a functionally pivotal domain in L1 trigger its regeneration-beneficial functions in vitro, encouraging thoughts on therapy of neurodegenerative diseases in the hope to ameliorate human nervous system diseases. PMID:25447207

  15. IL-21-Induced MHC Class II+ NK Cells Promote the Expansion of Human Uncommitted CD4+ Central Memory T Cells in a Macrophage Migration Inhibitory Factor-Dependent Manner.

    PubMed

    Loyon, Romain; Picard, Emilie; Mauvais, Olivier; Queiroz, Lise; Mougey, Virginie; Pallandre, Jean-René; Galaine, Jeanne; Mercier-Letondal, Patricia; Kellerman, Guillaume; Chaput, Nathalie; Wijdenes, John; Adotévi, Olivier; Ferrand, Christophe; Romero, Pedro; Godet, Yann; Borg, Christophe

    2016-07-01

    NK cells are critical for innate immunity-mediated protection. The main roles of NK cells rely on their cytotoxic functions or depend on the tuning of Th1 adaptive immunity by IFN-γ. However, the precise influence of inflammatory cytokines on NK cell and CD4 T lymphocyte interactions was never investigated. In this study, we provide evidence that IL-21, a cytokine produced during chronic inflammation or infectious diseases, promotes the differentiation of a specific subset of NK cells coexpressing CD86 and HLA-DR and lacking NKp44. More importantly, IL-21-propagated HLA-DR(+) NK cells produce macrophage migration inhibitory factor and provide costimulatory signaling during naive CD4(+) T cell priming inducing the differentiation of uncommitted central memory T cells. Central memory T cells expanded in the presence of HLA-DR(+) NK cells are CXCR3(+)CCR6(-)CCR4(-)CXCR5(-) and produce IL-2, as well as low levels of TNF-α. Costimulation of CD4(+) T cells by HLA-DR(+) NK cells prevents the acquisition of effector memory phenotype induced by IL-2. Moreover, we identified this population of NK HLA-DR(+) macrophage migration inhibitory factor(+) cells in inflammatory human appendix. Collectively, these results demonstrate a novel function for IL-21 in tuning NK and CD4(+) T cell interactions promoting a specific expansion of central memory lymphocytes. PMID:27233967

  16. Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets.

    PubMed

    Sordi, Valeria; Malosio, Maria Luisa; Marchesi, Federica; Mercalli, Alessia; Melzi, Raffaella; Giordano, Tiziana; Belmonte, Nathalie; Ferrari, Giuliana; Leone, Biagio Eugenio; Bertuzzi, Federico; Zerbini, Gianpaolo; Allavena, Paola; Bonifacio, Ezio; Piemonti, Lorenzo

    2005-07-15

    Bone marrow-derived mesenchymal stem cells (BM-MSCs) are stromal cells with the ability to proliferate and differentiate into many tissues. Although they represent powerful tools for several therapeutic settings, mechanisms regulating their migration to peripheral tissues are still unknown. Here, we report chemokine receptor expression on human BM-MSCs and their role in mediating migration to tissues. A minority of BM-MSCs (2% to 25%) expressed a restricted set of chemokine receptors (CXC receptor 4 [CXCR4], CX3C receptor 1 [CX3CR1], CXCR6, CC chemokine receptor 1 [CCR1], CCR7) and, accordingly, showed appreciable chemotactic migration in response to the chemokines CXC ligand 12 (CXCL12), CX3CL1, CXCL16, CC chemokine ligand 3 (CCL3), and CCL19. Using human pancreatic islets as an in vitro model of peripheral tissue, we showed that islet supernatants released factors able to attract BM-MSCs in vitro, and this attraction was principally mediated by CX3CL1 and CXCL12. Moreover, cells with features of BM-MSCs were detected within the pancreatic islets of mice injected with green fluorescent protein (GFP)-positive BM. A population of bona fide MSCs that also expressed CXCR4, CXCR6, CCR1, and CCR7 could be isolated from normal adult human pancreas. This study defines the chemokine receptor repertoire of human BM-MSCs that determines their migratory activity. Modulation of homing capacity may be instrumental for harnessing the therapeutic potential of BM-MSCs. PMID:15784733

  17. Novel FTS-diamine/cinnamic acid hybrids inhibit tumor cell proliferation and migration and promote apoptosis via blocking Ras-related signaling in vitro.

    PubMed

    Ling, Yong; Zhao, Xinmei; Li, Xianghua; Wang, Xuemin; Yang, Yang; Wang, Zhiqiang; Wang, Xinyang; Zhang, Jie; Zhang, Yihua

    2015-02-01

    Novel FTS-diamine/cinnamic acid hybrids 7a-f were prepared, and their in vitro biological activities were evaluated. It was found that 7c showed the strongest anti-proliferation activities against cancer cells in vitro and significant growth inhibition of tumor in vivo, and more potential for inhibitory selectivity to tumor cells than intermediate 6 and FTS. Furthermore, the anti-proliferative effect of 7c in Lovo cell lines followed a similar pattern, which included a dose-dependent induction of cell apoptosis via the up-regulation of Bax as well as activated caspase-3 and down-regulation of Bcl-2, and the inhibition of cancer cells migration and invasion in a concentration-dependent way. More importantly, 7c could significantly block Ras-related signaling pathways, which may contribute to its pro-apoptotic induction of the cancer cell lines and its inhibition of carcinoma cell proliferation, migration, and invasion. Therefore, our novel findings may provide a new framework for the discovery of new FTS hybrids for the intervention of human carcinoma cells.

  18. Epithelial MUC1 promotes cell migration, reduces apoptosis and affects levels of mucosal modulators during acetylsalicylic acid (aspirin)-induced gastropathy.

    PubMed

    Banerjee, Debashish; Fernandez, Harvey Robert; Patil, Pradeep Bhatu; Premaratne, Pushpa; Quiding-Järbrink, Marianne; Lindén, Sara Katarina

    2015-02-01

    MUC1 is a transmembrane mucin highly expressed in the stomach. Although extensive research has uncovered many of its roles in cancer, knowledge about the functions of MUC1 in normal tissues is limited. In the present study, we showed that acetylsalicylic acid (ASA; aspirin) up-regulated MUC1/Muc1 expression in the gastric mucosa of humans and wild-type (WT) mice. ASA induced mucosal injury in all mice to a similar extent; however, WT animals and those chimaeras with Muc1 on the epithelia recovered faster than Muc1-knockout (KO) mice and chimaeras carrying Muc1 on haemopoietic but not epithelial cells. MUC1 enhanced proliferation and migration of the human gastric cell line MKN-7 and increased resistance to apoptosis. The repeated treatment regime used caused a reduction in cyclo-oxygenase-1 (Cox-1) expression, though WT animals returned faster towards pre-treatment levels and had increased Cox-2 and vascular endothelial growth factor levels during recovery. Thus we found that epithelial Muc1 is more important for the healing process than haemopoietic Muc1 and Muc1/MUC1 facilitates wound healing by enhancing cell migration and proliferation, protecting against apoptosis and mediating expression of mucosal modulators. Thus MUC1 plays essential roles during wound healing and development of treatment modalities targeting enhanced expression of MUC1 may be beneficial to treat mucosal wounds.

  19. Autocrine CCL5 signaling promotes invasion and migration of CD133+ ovarian cancer stem-like cells via NF-κB-mediated MMP-9 upregulation.

    PubMed

    Long, Haixia; Xie, Rongkai; Xiang, Tong; Zhao, Zhongquan; Lin, Sheng; Liang, Zhiqing; Chen, Zhengtang; Zhu, Bo

    2012-10-01

    The concept of cancer stem cells (CSCs) proposes that solely CSCs are capable of generating tumor metastases. However, how CSCs maintain their invasion and migration abilities, the most important properties of metastatic cells, still remains elusive. Here we used CD133 to mark a specific population from human ovarian cancer cell line and ovarian cancer tissue and determined its hyperactivity in migration and invasion. Therefore, we labeled this population as cancer stem-like cells (CSLCs). In comparison to CD133- non-CSLCs, chemokine CCL5 and its receptors, CCR1, CCR3, and CCR5, were consistently upregulated in CSLCs, and most importantly, blocking of CCL5, CCR1, or CCR3 effectively inhibits the invasive capacity of CSLCs. Mechanistically, we identified that this enhanced invasiveness is mediated through nuclear factor κB (NF-κB) activation and the consequently elevated MMP9 secretion. Our results suggested that the autocrine activation of CCR1 and CCR3 by CCL5 represents one of major mechanisms underlying the metastatic property of ovarian CSLCs. PMID:22887854

  20. Combination of cyclopamine and tamoxifen promotes survival and migration of mcf-7 breast cancer cells--interaction of hedgehog-gli and estrogen receptor signaling pathways.

    PubMed

    Sabol, Maja; Trnski, Diana; Uzarevic, Zvonimir; Ozretic, Petar; Musani, Vesna; Rafaj, Maja; Cindric, Mario; Levanat, Sonja

    2014-01-01

    Hedgehog-Gli (Hh-Gli) signaling pathway is one of the new molecular targets found upregulated in breast tumors. Estrogen receptor alpha (ERα) signaling has a key role in the development of hormone-dependent breast cancer. We aimed to investigate the effects of inhibiting both pathways simultaneously on breast cancer cell survival and the potential interactions between these two signaling pathways. ER-positive MCF-7 cells show decreased viability after treatment with cyclopamine, a Hh-Gli pathway inhibitor, as well as after tamoxifen (an ERα inhibitor) treatment. Simultaneous treatment with cyclopamine and tamoxifen on the other hand, causes short-term survival of cells, and increased migration. We found upregulated Hh-Gli signaling under these conditions and protein profiling revealed increased expression of proteins involved in cell proliferation and migration. Therefore, even though Hh-Gli signaling seems to be a good potential target for breast cancer therapy, caution must be advised, especially when combining therapies. In addition, we also show a potential direct interaction between the Shh protein and ERα in MCF-7 cells. Our data suggest that the Shh protein is able to activate ERα independently of the canonical Hh-Gli signaling pathway. Therefore, this may present an additional boost for ER-positive cells that express Shh, even in the absence of estrogen.

  1. Combination of Cyclopamine and Tamoxifen Promotes Survival and Migration of MCF-7 Breast Cancer Cells – Interaction of Hedgehog-Gli and Estrogen Receptor Signaling Pathways

    PubMed Central

    Uzarevic, Zvonimir; Ozretic, Petar; Musani, Vesna; Rafaj, Maja; Cindric, Mario; Levanat, Sonja

    2014-01-01

    Hedgehog-Gli (Hh-Gli) signaling pathway is one of the new molecular targets found upregulated in breast tumors. Estrogen receptor alpha (ERα) signaling has a key role in the development of hormone-dependent breast cancer. We aimed to investigate the effects of inhibiting both pathways simultaneously on breast cancer cell survival and the potential interactions between these two signaling pathways. ER-positive MCF-7 cells show decreased viability after treatment with cyclopamine, a Hh-Gli pathway inhibitor, as well as after tamoxifen (an ERα inhibitor) treatment. Simultaneous treatment with cyclopamine and tamoxifen on the other hand, causes short-term survival of cells, and increased migration. We found upregulated Hh-Gli signaling under these conditions and protein profiling revealed increased expression of proteins involved in cell proliferation and migration. Therefore, even though Hh-Gli signaling seems to be a good potential target for breast cancer therapy, caution must be advised, especially when combining therapies. In addition, we also show a potential direct interaction between the Shh protein and ERα in MCF-7 cells. Our data suggest that the Shh protein is able to activate ERα independently of the canonical Hh-Gli signaling pathway. Therefore, this may present an additional boost for ER-positive cells that express Shh, even in the absence of estrogen. PMID:25503972

  2. [Internal migration].

    PubMed

    Borisovna, L

    1991-06-01

    Very few studies have been conducted that truly permit explanation of internal migration and it repercussions on social and economic structure. It is clear however that a profound knowledge of the determinants and consequences of internal migration will be required as a basis for economic policy decisions that advance the goal of improving the level of living of the population. the basic supposition of most studies of the relationship of population and development is that socioeconomic development conditions demographic dynamics. The process of development in Mexico, which can be characterized by great heterogeneity, consequently produces great regional disparities. At the national level various studies have estimated the volume of internal migration in Mexico, but they have usually been limited to interstate migration because the main source of data, the census, is classified by states. But given the great heterogeneity within states in all the elements related to internal migration, it is clear that studies of internal migration within states are also needed. Such studies are almost nonexistent because of their technical difficulty. National level studies show that interstate migration increased significantly between 1940-80. The proportion of Mexicans living outside their states of birth increased by 558% in those years, compared to the 342% increase in the total Mexican population. Although Puebla has a high rate of increase, migration has kept it below Mexico's national growth rate. Migration between Puebla and other states and within Puebla has led to an increasing unevenness of spatial distribution. Between 1970-80, 57 of Puebla's municipios had growth rates above the state average of 2.8%/year, 6 had growth rates equal to the average, and 129 had growth rates that were below the average but not negative. 25 states with negative growth rates that were considered strongly expulsive. In 1980, 51.7% of the population was concentrated in the 57 municipios

  3. 17β-estradiol promotes the invasion and migration of nuclear estrogen receptor-negative breast cancer cells through cross-talk between GPER1 and CXCR1.

    PubMed

    Jiang, Qi-Feng; Wu, Ting-Ting; Yang, Jun-Yan; Dong, Chao-Ran; Wang, Ni; Liu, Xiao-Hua; Liu, Zhi-Min

    2013-11-01

    G protein-coupled estrogen receptor 1 (GPER1) is widely expressed in human breast cancers correlating with increased tumor size and malignancy. Although estrogen signaling via GPER1 was extensively studied in recent years, the underlying molecular mechanism of GPER1-associated metastasis of breast cancer still remains unclear. In this study, the main aims were focused on the potential role of GPER1 in regulating migration and invasion of nuclear estrogen receptor (ER)-negative breast cancer cells upon 17β-estradiol (E2) stimulation and the involved signaling pathway. Key events in estrogen signaling were chosen for our studies, such as the activation of ERK and AKT, nuclear translocation of NF-κB and secretion of Interleukin-8 (IL-8). The migration and invasion activities upon E2 stimulation were also examined in ER-negative SKBR3 and BT-20 breast cancer cells. Compared with ER-positive MCF-7 breast cancer cells, both SKBR3 and BT-20 cells had very similar expression of GPER1, but relatively high expression of CXC receptor-1 (CXCR1), which is considered as an active regulator for cancer metastasis upon binding IL-8. Results showed that E2 facilitated the activation of ERK, AKT and NF-κB, which could be significantly attenuated by GPER1 blockage or knock-down in both SKBR3 and BT-20 cells. Moreover, increased secretion of IL-8 induced by E2 was also inhibited either by specific inhibitors for GPER1, ERK, AKT, and NF-κB, or by knock-down for GPER1. Furthermore, E2 could activate the migration and invasion of both SKBR3 and BT-20 cells, which in turn could also be inhibited by blocking GPER1, ERK, AKT, NF-κB, and CXCR1, respectively, or knock-down for GPER1 and CXCR1. In conclusion, we demonstrated that estrogen signaling via GPER1 associated with the metastasis of breast cancer, which might be through GPER1/ERK&AKT/NF-κB/IL-8/CXCR1 cascade. The cross-talk between GPER1 and CXCR1 could be another potential target for the therapy of metastatic breast cancer.

  4. Elevated expression of Fn14 in non-small cell lung cancer correlates with activated EGFR and promotes tumor cell migration and invasion.

    PubMed

    Whitsett, Timothy G; Cheng, Emily; Inge, Landon; Asrani, Kaushal; Jameson, Nathan M; Hostetter, Galen; Weiss, Glen J; Kingsley, Christopher B; Loftus, Joseph C; Bremner, Ross; Tran, Nhan L; Winkles, Jeffrey A

    2012-07-01

    Lung cancer is the leading cause of cancer deaths worldwide; approximately 85% of these cancers are non-small cell lung cancer (NSCLC). Patients with NSCLC frequently have tumors harboring somatic mutations in the epidermal growth factor receptor (EGFR) gene that cause constitutive receptor activation. These patients have the best clinical response to EGFR tyrosine kinase inhibitors (TKIs). Herein, we show that fibroblast growth factor-inducible 14 (Fn14; TNFRSF12A) is frequently overexpressed in NSCLC tumors, and Fn14 levels correlate with p-EGFR expression. We also report that NSCLC cell lines that contain EGFR-activating mutations show high levels of Fn14 protein expression. EGFR TKI treatment of EGFR-mutant HCC827 cells decreased Fn14 protein levels, whereas EGF stimulation of EGFR wild-type A549 cells transiently increased Fn14 expression. Furthermore, Fn14 is highly expressed in EGFR-mutant H1975 cells that also contain an EGFR TKI-resistance mutation, and high TKI doses are necessary to reduce Fn14 levels. Constructs encoding EGFRs with activating mutations induced Fn14 expression when expressed in rat lung epithelial cells. We also report that short hairpin RNA-mediated Fn14 knockdown reduced NSCLC cell migration and invasion in vitro. Finally, Fn14 overexpression enhanced NSCLC cell migration and invasion in vitro and increased experimental lung metastases in vivo. Thus, Fn14 may be a novel therapeutic target for patients with NSCLC, in particular for those with EGFR-driven tumors who have either primary or acquired resistance to EGFR TKIs. PMID:22634180

  5. Overexpression of ST3Gal-I promotes migration and invasion of HCCLM3 in vitro and poor prognosis in human hepatocellular carcinoma

    PubMed Central

    Wu, Han; Shi, Xue-Liang; Zhang, Hai-Jian; Song, Qing-Jie; Yang, Xiao-Bing; Hu, Wei-Dong; Mei, Guang-Lin; Chen, Xi; Mao, Qin-Sheng; Chen, Zhong

    2016-01-01

    Purpose Excessive ST3Gal-I levels predict a poor outcome for patients with several types of tumors. This study aims to investigate the role of ST3Gal-I in determining the invasive and metastatic potential of human hepatocellular carcinoma (HCC) and clinical prognosis for patients with HCC. Methods We compared the expression of ST3Gal-I in various HCC cell lines and in 20 pairs of tumor and peritumor tissue samples using Western blot analysis. Changes in the degree of invasiveness and migration were determined before and after small interfering RNA-induced knockdown of ST3Gal-I using a Transwell matrigel invasion assay and scratch wound assay. The correlation between ST3Gal-I expression and prognosis was determined in a large HCC patient cohort (n=273). Results ST3Gal-I expression was higher in metastatic HCCLM3 cells and tumor tissue compared with normal adjacent tissue. Following the ST3Gal-I knockdown, the invasiveness and migration of HCCLM3 cells were markedly reduced. ST3Gal-I expression in HCC correlated closely with tumor thrombus (P<0.001), tumor size (>5.0 cm, P=0.032), tumor node metastasis stages II–III (P=0.002), and Barcelona Clinic Liver Cancer stages B–C (P<0.001). Cox regression analysis demonstrated that ST3Gal-I is an independent predictor of prognosis in patients with HCC, and related to disease-free survival (hazard ratio =1.464, P=0.037) and overall survival (hazard ratio =1.662, P=0.012). Conclusion ST3Gal-I might contribute to the invasiveness and metastatic nature of HCC and, thus, could be an independent predictor of recurrence and a suitable pharmaceutical target in patients with HCC. PMID:27143918

  6. MiR-181b-5p Downregulates NOVA1 to Suppress Proliferation, Migration and Invasion and Promote Apoptosis in Astrocytoma

    PubMed Central

    Shao, Naiyuan; Wang, Rong; Xue, Lian; Wang, Suinuan; Xia, Xiwei; Yang, Yilin

    2014-01-01

    MicroRNAs (miRNAs) are small, short noncoding RNAs that modulate the expression of numerous genes by targeting their mRNA. Numerous abnormal miRNA expression patterns are observed in various human malignancies, and certain miRNAs can act as oncogenes or tumor suppressors. Astrocytoma, the most common neuroepithelial cancer, represents the majority of malignant brain tumors in humans. In our previous studies, we found that the downregulation of miR-181b-5p in astrocytomas is associated with a poor prognosis. The aim of the present study was to investigate the functional role of miR-181b-5p and its possible target genes. miR-181b-5p was significantly downregulated in astrocytoma specimens, and the reduced expression of miR-181b-5p was inversely correlated with the clinical stage. The ectopic expression of miR-181b-5p inhibited proliferation, migration and invasion and induced apoptosis in astrocytoma cancer cells in vitro. The NOVA1 (neuro-oncological ventral antigen 1) gene was further identified as a novel direct target of miR-181b-5p. Specifically, miR-181b-5p bound directly to the 3'-untranslated region (UTR) of NOVA1 and suppressed its expression. In clinical specimens, NOVA1 was overexpressed, and its protein levels were inversely correlated with miR-181b-5p expression. Furthermore, the changing level of NOVA1 was significantly associated with a poor survival outcome. Similar to restoring miR-181b-5p expression, downregulating NOVA1 inhibited cell growth, migration and invasion. Overexpression of NOVA1 reversed the inhibitory effects of miR-181b-5p. Our results indicate that miR-181b-5p is a tumor suppressor in astrocytoma that inhibits tumor progression by targeting NOVA1. These findings suggest that miR-181b-5p may serve as a novel therapeutic target for astrocytoma. PMID:25299073

  7. 17β-Estradiol regulates cell proliferation, colony formation, migration, invasion and promotes apoptosis by upregulating miR-9 and thus degrades MALAT-1 in osteosarcoma cell MG-63 in an estrogen receptor-independent manner

    SciTech Connect

    Fang, Dengfeng; Yang, Hui; Lin, Jing; Teng, Yi; Jiang, Yingying; Chen, Jiao; Li, Yu

    2015-02-20

    In bone, different concentration of estrogen leads to various of physiological processes in osteoblast, such as the proliferation, migration, and apoptosis in an estrogen receptor-dependent manner. But little was known about the estrogen effects on osteosarcoma (OS). In this study, OS cell MG-63 was treated with low (1 nM) or high (100 nM) dose of 17β-Estradiol (E2) with the presence or absence of estrogen receptor α (ERα), for evaluating the E2 effects on proliferation, migration, invasion, colony formation and apoptosis. Consistent with a previous study, high dose of E2 treatment dramatically downregulated expressing level of long non-coding RNA metastasis associated lung adenocarcinoma transcript 1 (MALAT-1). The observation of upregulation of miR-9 after a high dose of E2 treatment indicated the cause of MALAT-1 reduction. Downregulation of MALAT-1 promoted the combination of SFPQ/PTBP2 complex. It was also observed that the proliferation, migration, invasion, colony formation and apoptosis of OS cells were remarkably affected by high dose of E2 treatment, but not by low dose, in an ERα independent manner. Furthermore, the abolishment of the effects on these physiological processes caused by ectopic expression of miR-9 ASOs suggested the necessity of miR-9 in MALAT-1 regulation. Here we found that the high dose of E2 treatment upregulated miR-9 thus posttranscriptionally regulated MALAT-1 RNA level in OS cells, and then the downregulation of MALAT-1 inhibited cell proliferation, migration, invasion and epithelial–mesenchymal transition (EMT) processes in the E2-dose dependent and ER-independent ways. - Highlights: • E2 affects osteosarcoma cell MG-63 in an Estrogen receptor-independent way. • High dose of E2 treatment upregulates miR-9 which target to MALAT-1 RNA. • Upregulated miR-9 degrades MALAT-1 and thus affects combination of SFPQ/PTBP2. • E2 treatment block cell proliferation, colony formation, mobility, and enhance apoptosis.

  8. FAM19A4 is a novel cytokine ligand of formyl peptide receptor 1 (FPR1) and is able to promote the migration and phagocytosis of macrophages

    PubMed Central

    Wang, Wenyan; Li, Ting; Wang, Xiaolin; Yuan, Wanxiong; Cheng, Yingying; Zhang, Heyu; Xu, Enquan; Zhang, Yingmei; Shi, Shuang; Ma, Dalong; Han, Wenling

    2015-01-01

    FAM19A4 is an abbreviation for family with sequence similarity 19 (chemokine (C–C motif)-like) member A4, which is a secretory protein expressed in low levels in normal tissues. The biological functions of FAM19A4 remain to be determined, and its potential receptor(s) is unclarified. In this study, we demonstrated that FAM19A4 was a classical secretory protein and we verified for the first time that its mature protein is composed of 95 amino acids. We found that the expression of this novel cytokine was upregulated in lipopolysaccharide (LPS)-stimulated monocytes and macrophages and was typically in polarized M1. FAM19A4 shows chemotactic activities on macrophages and enhances the macrophage phagocytosis of zymosan both in vitro and in vivo with noticeable increases of the phosphorylation of protein kinase B (Akt). FAM19A4 can also increase the release of reactive oxygen species (ROS) upon zymosan stimulation. Furthermore, based on receptor internalization, radio ligand binding assays and receptor blockage, we demonstrated for the first time that FAM19A4 is a novel ligand of formyl peptide receptor 1 (FPR1). The above data indicate that upon inflammatory stimulation, monocyte/macrophage-derived FAM19A4 may play a crucial role in the migration and activation of macrophages during pathogenic infections. PMID:25109685

  9. Heregulin-HER3-HER2 signaling promotes matrix metalloproteinase-dependent blood-brain-barrier transendothelial migration of human breast cancer cell lines.

    PubMed

    Momeny, Majid; Saunus, Jodi M; Marturana, Flavia; McCart Reed, Amy E; Black, Debra; Sala, Gianluca; Iacobelli, Stefano; Holland, Jane D; Yu, Dihua; Da Silva, Leonard; Simpson, Peter T; Khanna, Kum Kum; Chenevix-Trench, Georgia; Lakhani, Sunil R

    2015-02-28

    HER2-positive breast tumors are associated with a high risk of brain relapse. HER3 is thought to be an indispensible signaling substrate for HER2 (encoded by ERBB2) and is induced in breast cancer-brain metastases, though the molecular mechanisms by which this oncogenic dimer promotes the development of brain metastases are still elusive. We studied the effects of the HER3-HER2 ligand, heregulin (neuregulin-1, broadly expressed in the brain), on luminal breast cancer cell lines in vitro. Treatment of SKBr3 (ERBB2-amplified), MDA-MB-361 (ERBB2-amplified, metastatic brain tumor-derived) and MCF7 (HER2-positive, not ERBB2-amplified) cells with exogenous heregulin increased proliferation and adhesive potential, concomitant with induction of cyclin D1 and ICAM-1, and suppression of p27. All three cell lines invaded through matrigel toward a heregulin chemotactic signal in transwell experiments, associated with activation of extracellular cathepsin B and matrix metalloproteinase-9 (MMP-9). Moreover, heregulin induced breast cancer cell transmigration across a tight barrier of primary human brain microvascular endothelia. This was dependent on the activity of HER2, HER3 and MMPs, and was completely abrogated by combination HER2-HER3 blockade using Herceptin® and the humanized HER3 monoclonal antibody, EV20. Collectively these data suggest mechanisms by which the HER3-HER2 dimer promotes development of metastatic tumors in the heregulin-rich brain microenvironment.

  10. Association of tuberculosis and polymorphisms in the promoter region of macrophage migration inhibitory factor (MIF) in a Southwestern China Han population.

    PubMed

    Li, Yanlin; Yuan, Tao; Lu, Weiping; Chen, Ming; Cheng, Xiaoxing; Deng, Shaoli

    2012-10-01

    The macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that plays an important role in the pathogenesis of immune diseases. High levels of MIF have been detected in the sera of patients with tuberculosis (TB), and it has been proposed that MIF gene polymorphisms may influence the risk of developing TB. The aim of this study was to evaluate the potential relationship between functional polymorphisms of MIF and TB in a Han population from Southwestern China. TB patients (n=215) and healthy unrelated controls (n=245) were recruited for this study. Genomic DNA was isolated from all the participants. The MIF-173 G/C SNP was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The MIF-794 CATT(5-8) microsatellite was evaluated by direct sequencing of the subsequent PCR products. Association analysis of the two polymorphisms showed that the frequency of -173 (GC+CC) in TB patients and controls was 49.3% and 31.4%, respectively, which was statistically significant (OR=2.12, 95% CI=1.45-3.10, P<0.001); the frequencies of -794 (7/X+8/X) were 56.7% and 45.3%, respectively, also statistically significant between the TB and healthy controls (OR=1.58, 95% CI=1.10-2.29, P=0.015). In summary, Genetic variation in the MIF gene is closely associated with tuberculosis. Both the 173 (GC+CC) SNP and -794 (7/X+8/X) microsatellite increased the risk of Chinese Han developing TB.

  11. S100A4 expression is increased in stricture fibroblasts from patients with fibrostenosing Crohn's disease and promotes intestinal fibroblast migration.

    PubMed

    Cunningham, Michael F; Docherty, Neil G; Burke, John P; O'Connell, P Ronan

    2010-08-01

    Fibroblasts represent the key cell type in fibrostenosing Crohn's disease (FCD) pathogenesis. S100A4 is an EF-hand calcium-binding protein family member, implicated in epithelial-mesenchymal transition and as a marker of activated T lymphocytes and fibroblasts in chronic tissue remodeling. The aim of this study was to examine the expression profile of S100A4 in the resected ileum of patients with FCD. Mucosa, seromuscular explants, and transmural biopsies were harvested from diseased and proximal, macroscopically normal margins of ileocecal resections from patients with FCD. Samples were processed for histochemistry, immunohistochemistry, real-time RT-PCR, Western blotting, and transmission electron microscopy. Primary explant cultures of seromuscular fibroblasts were exposed to transforming growth factor (TGF)-beta1 (1 ng/ml), and S100A4 expression and scratch wound-healing activity were assessed at 24 h. CCD-18Co fibroblasts were transfected with S100A4 small interfering RNA, treated with TGF-beta1 (1 ng/ml) for 30 min or 24 h, and then assessed for S100A4 and Smad3 expression and scratch wound-healing activity. S100A4 expression was increased in stricture mucosa, in the lamina propria, and in CD3-positive intraepithelial CD3-positive T lymphocytes. Fibroblastic S100A4 staining was observed in seromuscular scar tissue. Stricture fibroblast explant culture showed significant upregulation of S100A4 expression. TGF-beta1 increased S100A4 expression in cultured ileal fibroblasts. In CCD-18Co fibroblasts, S100A4 small interfering RNA inhibited scratch wound healing and modestly inhibited Smad3 activation. S100A4 expression is increased in fibroblasts, as well as immune cells, in Crohn's disease stricture and induced by TGF-beta1. Results from knockdown experiments indicate a potential role for S100A4 in mediating intestinal fibroblast migration. PMID:20489045

  12. Plasticity of Migrating CD1b+ and CD1b- Lymph Dendritic Cells in the Promotion of Th1, Th2 and Th17 in Response to Salmonella and Helminth Secretions

    PubMed Central

    Olivier, Michel; Foret, Benjamin; Le Vern, Yves; Kerboeuf, Dominique; Guilloteau, Laurence A.

    2013-01-01

    Dendritic cells (DCs) are pivotal in the development of specific T-cell responses to control pathogens, as they govern both the initiation and the polarization of adaptive immunity. To investigate the capacities of migrating DCs to respond to pathogens, we used physiologically generated lymph DCs (L-DCs). The flexible polarization of L-DCs was analysed in response to Salmonella or helminth secretions known to induce different T cell responses. Mature conventional CD1b+ L-DCs showed a predisposition to promote pro-inflammatory (IL-6), pro-Th1 (IL-12p40) and anti-inflammatory (IL-10) responses which were amplified by Salmonella, and limited to only IL-6 induction by helminth secretions. The other major population of L-DCs did not express the CD1b molecule and displayed phenotypic features of immaturity compared to CD1b+ L-DCs. Salmonella infection reduced the constitutive expression of TNF-α and IL-4 mRNA in CD1b- L-DCs, whereas this expression was not affected by helminth secretions. The cytokine response of T cells promoted by L-DCs was analysed in T cell subsets after co-culture with Salmonella or helminth secretion-driven CD1b+ or CD1b- L-DCs. T cells preferentially expressed the IL-17 gene, and to a lesser extent the IFN-γ and IL-10 genes, in response to Salmonella-driven CD1b+ L-DCs, whereas a preferential IL-10, IFN-γ and IL-17 gene expression was observed in response to Salmonella-driven CD1b- L-DCs. In contrast, a predominant IL-4 and IL-13 gene expression by CD4+ and CD8+ T cells was observed after stimulation of CD1b+ and CD1b- L-DCs with helminth secretions. These results show that mature conventional CD1b+ L-DCs maintain a flexible capacity to respond differently to pathogens, that the predisposition of CD1b- L-DCs to promote a Th2 response can be oriented towards other Th responses, and finally that the modulation of migrating L-DCs responses is controlled more by the pathogen encountered than the L-DC subsets. PMID:24223964

  13. miR-130a acts as a potential diagnostic biomarker and promotes gastric cancer migration, invasion and proliferation by targeting RUNX3.

    PubMed

    Jiang, Hong; Yu, Wei-Wei; Wang, Lu-Lu; Peng, Yang

    2015-09-01

    MicroRNAs (miRNAs) are abnormally expressed in various types of cancer. miR-130a expression and function in gastric cancer has yet to be elucidated. The aim of the present study was to identify the miR-130a expression and function in gastric cancer. miR-130a expression was examined in gastric cancer cell lines and tissues by RT-qPCR. The diagnostic and prognostic significance of miR-130a in gastric cancer was analyzed by receiver-operating characteristic (ROC) curve and Kaplan-Meier analysis. miR130a expression was identified and the diagnostic significance in the serum of gastric cancer patients and healthy controls was analyzed using RT-qPCR and ROC curves, respectively. A target gene for miR-130a was identified using luciferase reporter assays, and gastric cancer tumorigenesis ability was examined by 3-(4,5-dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Transwell assays. The results showed that miR‑130a was upregulated in gastric cancer. The low-miR-130a group had significantly improved overall survival compared to the high-miR-130a group. Furthermore, the expression of miR‑130a in plasma in gastric cancer patients was upregulated and diagnostic value for gastric cancer of miR-130a is more effective than the tumor markers carcinoembryonic antigen (CEA) and CA-199. miR-130a directly targeted runt‑related transcription factor 3 (RUNX3) and promoted gastric cancer tumorigenesis by targeting RUNX3. miR-130a may therefore be a useful marker for the diagnosis and prognosis of gastric cancer. Additionally, miR-130a was identified as an oncogene that promotes gastric cancer tumorigenesis by targeting RUNX3. PMID:26134263

  14. Simvastatin mobilizes bone marrow stromal cells migrating to injured areas and promotes functional recovery after spinal cord injury in the rat.

    PubMed

    Han, Xiaoguang; Yang, Ning; Cui, Yueyi; Xu, Yingsheng; Dang, Gengting; Song, Chunli

    2012-07-19

    This study investigated the therapeutic effects of simvastatin administered by subarachnoid injection after spinal cord injury (SCI) in rats; explored the underlying mechanism from the perspective of mobilization, migration and homing of bone marrow stromal cells (BMSCs) to the injured area induced by simvastatin. Green fluorescence protein labeled-bone marrow stromal cells (GFP-BMSCs) were transplanted into rats through the tail vein for stem cell tracing. Twenty-four hours after transplantation, spinal cord injury (SCI) was produced using weight-drop method (10g 4cm) at the T10 level. Simvastatin (5mg/kg) or vehicle was administered by subarachnoid injection at lumbar level 4 after SCI. Locomotor functional recovery was assessed in the 4 weeks following surgery using the open-field test and inclined-plane test. At the end of the study, MRI was used to evaluate the reparation of the injured spinal cord. Animals were then euthanized, histological evaluation was used to measure lesion cavity volumes. Immunofluorescence for GFP and cell lineage markers (NeuN and GFAP) was used to evaluate simvastatin-mediated mobilization and differentiation of transplanted BMSCs. Western blot and immunohistochemistry were used to assess the expression of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF). Simvastatin-treated animals showed significantly better locomotor recovery, less signal abnormality in MRI and a smaller cavity volume compared to the control group. Immunofluorescence revealed that simvastatin increased the number of GFP-positive cells in the injured spinal cord, and the number of cells double positive for GFP/NeuN or GFP/GFAP was larger in the simvastatin treated group than the control group. Western blot and immunohistochemistry showed higher expression of BDNF and VEGF in the simvastatin treated group than the control group. In conclusion, simvastatin can help to repair spinal cord injury in rat, where the underlying

  15. Sulfated polysaccharide isolated from the sea cucumber Stichopus japonicas promotes the SDF-1α/CXCR4 axis-induced NSC migration via the PI3K/Akt/FOXO3a, ERK/MAPK, and NF-κB signaling pathways.

    PubMed

    Cui, Chao; Wang, Peng; Cui, Ningshan; Song, Shuliang; Liang, Hao; Ji, Aiguo

    2016-03-11

    The present study describes a positive regulatory loop between SJP and the SDF-1α/CXCR4 axis in NSC migration. The treatment of NSCs with SJP and SDF-1α increases the cell migration capacity and promotes cell migration from the neurospheres. These effects are accompanied by the up-regulation of Nestin, N-cadherin, TLR4, TNF-α, Cyclin D1, EGFR, Alpha 6 integrin, MMP-2, MMP-9, and iNOS, including SDF-1α and CXCR4 themselves. However, these effects are blocked by AMD3100, LY294002, U0126, and PDTC. SJP enhances the SDF-1α/CXCR4 axis-induced MMP-2 and MMP-9 secretion and NO release. Results demonstrate that interaction of SJP with the SDF-1α/CXCR4 axis regulates NSC migration via the PI3K/Akt/FOXO3a, ERK-MAPK, and NF-κB signaling pathways. PMID:26827717

  16. Sulfated polysaccharide isolated from the sea cucumber Stichopus japonicas promotes the SDF-1α/CXCR4 axis-induced NSC migration via the PI3K/Akt/FOXO3a, ERK/MAPK, and NF-κB signaling pathways.

    PubMed

    Cui, Chao; Wang, Peng; Cui, Ningshan; Song, Shuliang; Liang, Hao; Ji, Aiguo

    2016-03-11

    The present study describes a positive regulatory loop between SJP and the SDF-1α/CXCR4 axis in NSC migration. The treatment of NSCs with SJP and SDF-1α increases the cell migration capacity and promotes cell migration from the neurospheres. These effects are accompanied by the up-regulation of Nestin, N-cadherin, TLR4, TNF-α, Cyclin D1, EGFR, Alpha 6 integrin, MMP-2, MMP-9, and iNOS, including SDF-1α and CXCR4 themselves. However, these effects are blocked by AMD3100, LY294002, U0126, and PDTC. SJP enhances the SDF-1α/CXCR4 axis-induced MMP-2 and MMP-9 secretion and NO release. Results demonstrate that interaction of SJP with the SDF-1α/CXCR4 axis regulates NSC migration via the PI3K/Akt/FOXO3a, ERK-MAPK, and NF-κB signaling pathways.

  17. MicroRNA-20b (miR-20b) Promotes the Proliferation, Migration, Invasion, and Tumorigenicity in Esophageal Cancer Cells via the Regulation of Phosphatase and Tensin Homologue Expression

    PubMed Central

    Xiao, Bin

    2016-01-01

    Increasing evidence has indicated that many microRNAs participate in the development and progression of esophageal cancer and gene expression regulation. MicroRNA-20b (miR-20b) has been reported to be aberrantly expressed in various cancers, but its exact role in esophageal cancer cells remains unclear so far. Therefore, we detected the levels of miR-20b in esophageal tumor tissues and their adjacent normal tissues, and various esophageal cancer cell lines by qRT-PCR. We also explored the effects of miR-20b on cell proliferation, migration, invasion and tumorigenicity of esophageal carcinoma cells through transfection with miR-20b mimics or inhibitor to upregulate or downregulate miR-20b expression in the esophageal cancer cells Eca-109 and KYSE-150, respectively. Additionally, the 3'-untranslated region (3'-UTR) of phosphatase and tensin homologue (PTEN) binding with miR-20b was analyzed by dual-luciferase reporter assays. The results indicated that miR-20b expression level in esophageal tumor tissues was significantly increased compared with their neighboring normal tissues, but its expression was inverse with PTEN protein expression. Luciferase assays confirmed that the 3'-UTR of PTEN was a target of miR-20b in esophageal cancer cells. MiR-20b upregulation promoted cell proliferation, migration, invasiveness, and tumor growth, and decreased apoptosis, and reduced PTEN protein level but not mRNA expression in Eca-109 cells. Conversely, downregulation of miR-20b suppressed these processes in KYSE-150 cells, and enhanced PTEN protein expression. These data indicate that miR-20b plays important roles in tumorigenesis of esophageal cancer possibly via regulation of PTEN expression, and it may be a potential therapeutic target for esophageal cancer treatment. PMID:27701465

  18. Vulnerable to HIV / AIDS. Migration.

    PubMed

    Fernandez, I

    1998-01-01

    This special report discusses the impact of globalization, patterns of migration in Southeast Asia, gender issues in migration, the links between migration and HIV/AIDS, and spatial mobility and social networks. Migrants are particularly marginalized in countries that blame migrants for transmission of infectious and communicable diseases and other social ills. Effective control of HIV/AIDS among migrant and native populations requires a multisectoral approach. Programs should critically review the privatization of health care services and challenge economic models that polarize the rich and the poor, men and women, North and South, and migrant and native. Programs should recognize the equality between locals and migrants in receipt of health services. Countermeasures should have input from migrants in order to reduce the conditions that increase vulnerability to HIV/AIDS. Gender-oriented research is needed to understand women's role in migration. Rapid assessment has obscured the human dimension of migrants' vulnerability to HIV. Condom promotion is not enough. Migration is a major consequence of globalization, which holds the promise, real or imagined, of prosperity for all. Mass migration can be fueled by explosive regional developments. In Southeast Asia, migration has been part of the process of economic development. The potential to emigrate increases with greater per capita income. "Tiger" economies have been labor importers. Safe sex is not practiced in many Asian countries because risk is not taken seriously. Migrants tend to be used as economic tools, without consideration of social adjustment and sex behavior among singles.

  19. Urbanism, Migration, and Tolerance: A Reassessment.

    ERIC Educational Resources Information Center

    Wilson, Thomas C.

    1991-01-01

    Urbanism's impact on the personality may be stronger than previously thought. Finds that urban residence has a strong positive effect on tolerance. Migration also promotes tolerance, regardless of the size of the destination community. (DM)

  20. [Theories on migration and migration policy].

    PubMed

    Waldrauch, H

    1995-01-01

    "In its first part the article gives a short historical overview of theories on migration.... The author tries to clarify the term[s]...'migration policy' and...'migration' itself and assesses the usefulness of various migration typologies. The final chapter analyses determinants and trends of migration policies in Europe in the 1990s: the continuing pressures for migration in developing countries, the end of numerous barriers to emigration, the revival of nationalistic concepts of immigration and exclusionary tendencies founded on culturalistic arguments, the process of harmonizing control mechanisms in the European Union, and the influence of international human rights declarations on the formulation of migration policies." (SUMMARY IN ENG AND FRE)

  1. Γ-Ionizing radiation-induced activation of the EGFR-p38/ERK-STAT3/CREB-1-EMT pathway promotes the migration/invasion of non-small cell lung cancer cells and is inhibited by podophyllotoxin acetate.

    PubMed

    Cho, Jeong Hyun; Hong, Wan Gi; Jung, Yu-Jin; Lee, Jaeseok; Lee, Eunah; Hwang, Sang-Gu; Um, Hong-Duck; Park, Jong Kuk

    2016-06-01

    Here, we report a new intracellular signaling pathway involved in γ-ionizing radiation (IR)-induced migration/invasion and show that podophyllotoxin acetate (PA) inhibits the IR-induced invasion and migration of A549 cells (a non-small cell lung cancer (NSCLC) cell line). Our results revealed that IR increased the invasion/migration of A549 cells, and this effect was decreased by 10 nM PA treatment. PA also inhibited the expressions/activities of matrix metalloprotase (MMP) -2, MMP-9, and vimentin, suggesting that PA could block the IR-induced epithelial-mesenchymal transition (EMT). The IR-induced increases in invasion/migration were associated with the activation of EGFR-AKT, and PA inhibited this effect. P38 and p44/42 ERK were also involved in IR-induced invasion/migration, and combined treatments with PA plus inhibitors of each MAPK synergistically blocked this invasion/migration. In terms of transcription factors (TFs), IR-induced increases in cyclic AMP response element-binding protein-1 (CREB-1) and signal transducer and activator of transcription 3 (STAT3) increased invasion/migration and EMT. PA also inhibited these transcription factors and then blocked IR-induced invasion/migration. Collectively, these results indicate that IR induces cancer cell invasion/migration by activating the EGFR-p38/ERK-CREB-1/STAT3-EMT pathway and that PA blocks this pathway to inhibit IR-induced invasion/migration.

  2. Multiscale Cues Drive Collective Cell Migration

    NASA Astrophysics Data System (ADS)

    Nam, Ki-Hwan; Kim, Peter; Wood, David K.; Kwon, Sunghoon; Provenzano, Paolo P.; Kim, Deok-Ho

    2016-07-01

    To investigate complex biophysical relationships driving directed cell migration, we developed a biomimetic platform that allows perturbation of microscale geometric constraints with concomitant nanoscale contact guidance architectures. This permits us to elucidate the influence, and parse out the relative contribution, of multiscale features, and define how these physical inputs are jointly processed with oncogenic signaling. We demonstrate that collective cell migration is profoundly enhanced by the addition of contract guidance cues when not otherwise constrained. However, while nanoscale cues promoted migration in all cases, microscale directed migration cues are dominant as the geometric constraint narrows, a behavior that is well explained by stochastic diffusion anisotropy modeling. Further, oncogene activation (i.e. mutant PIK3CA) resulted in profoundly increased migration where extracellular multiscale directed migration cues and intrinsic signaling synergistically conspire to greatly outperform normal cells or any extracellular guidance cues in isolation.

  3. Multiscale Cues Drive Collective Cell Migration

    PubMed Central

    Nam, Ki-Hwan; Kim, Peter; Wood, David K.; Kwon, Sunghoon; Provenzano, Paolo P.; Kim, Deok-Ho

    2016-01-01

    To investigate complex biophysical relationships driving directed cell migration, we developed a biomimetic platform that allows perturbation of microscale geometric constraints with concomitant nanoscale contact guidance architectures. This permits us to elucidate the influence, and parse out the relative contribution, of multiscale features, and define how these physical inputs are jointly processed with oncogenic signaling. We demonstrate that collective cell migration is profoundly enhanced by the addition of contract guidance cues when not otherwise constrained. However, while nanoscale cues promoted migration in all cases, microscale directed migration cues are dominant as the geometric constraint narrows, a behavior that is well explained by stochastic diffusion anisotropy modeling. Further, oncogene activation (i.e. mutant PIK3CA) resulted in profoundly increased migration where extracellular multiscale directed migration cues and intrinsic signaling synergistically conspire to greatly outperform normal cells or any extracellular guidance cues in isolation. PMID:27460294

  4. Internationalization and migration pressure.

    PubMed

    Kultalahti, O

    1994-01-01

    The author first develops the concept of migration pressure, which is defined as the growth in the number of people wishing to migrate and the barriers preventing them from so doing. Both macro- and micro-level factors affecting migration pressure are identified. Historical trends in migration pressure in Finland are then discussed. The author then applies this concept to the analysis of current Finnish migration trends. The primary focus is on international migration.

  5. ILO - International Migration Programme.

    PubMed

    Boudraa, Miriam

    2011-01-01

    In a wide International Context characterised not only by the economical development but also by the social, cultural, political and individual development, we witness more and more to a exchange between the developed and the developing countries, which can be translated especially in the migration of the work force. In theory, all countries are either countries of origin either countries of transit or destination, and they are all responsible for the rights of migrant workers by promoting the rights, by monitoring and by preventing the abusive conditions. The process of migration of the workforce can be divided into three stages: the first coincides with the period prior to departure, the second is represented by the aftermath of the departure and the period of stay in the country of destination, the third stage corresponds to the return in the country of origin. The workers must be protected throughout this process by the international organizations that perform the catalytic role of communication and exchange between countries, for the only purpose of protecting the rights of immigrant and/or immigrants workers. The responsibility for the protection of workers is divided among the various players in the International Labour Organisation. Every country has to apply measures according to the international standards regarding workers' rights, standards that guide the various countries in the formulation and implementation of their policies and legislation. These standards are suggested by International Conventions, the ILO Conventions and other international instruments such as the human rights instrument. There has been a big step forward once the ILO Fundamental Conventions and Conventions on Migrant Workers where implemented and this implementation represented the use of the Guidelines "ILO Multilateral Framework on Labour Migration".

  6. ILO - International Migration Programme.

    PubMed

    Boudraa, Miriam

    2011-01-01

    In a wide International Context characterised not only by the economical development but also by the social, cultural, political and individual development, we witness more and more to a exchange between the developed and the developing countries, which can be translated especially in the migration of the work force. In theory, all countries are either countries of origin either countries of transit or destination, and they are all responsible for the rights of migrant workers by promoting the rights, by monitoring and by preventing the abusive conditions. The process of migration of the workforce can be divided into three stages: the first coincides with the period prior to departure, the second is represented by the aftermath of the departure and the period of stay in the country of destination, the third stage corresponds to the return in the country of origin. The workers must be protected throughout this process by the international organizations that perform the catalytic role of communication and exchange between countries, for the only purpose of protecting the rights of immigrant and/or immigrants workers. The responsibility for the protection of workers is divided among the various players in the International Labour Organisation. Every country has to apply measures according to the international standards regarding workers' rights, standards that guide the various countries in the formulation and implementation of their policies and legislation. These standards are suggested by International Conventions, the ILO Conventions and other international instruments such as the human rights instrument. There has been a big step forward once the ILO Fundamental Conventions and Conventions on Migrant Workers where implemented and this implementation represented the use of the Guidelines "ILO Multilateral Framework on Labour Migration". PMID:22073693

  7. Migration issues important -- Mongolia.

    PubMed

    1999-01-01

    Migration and urbanization are issues that require increasing attention in Mongolia. Mr. Sodov Sonin, Minister of Health and Social Welfare, stated at the Forum that fertility has declined, but mortality, in particular the mortality of children and mothers, is still too high. In addition, there is a significant gap between the knowledge of and behaviors concerning reproductive health, which is one of the causes of the country's high abortion rates. However, on the positive side, literacy is high among women--70% of the students in Mongolia's higher educational institutions are female and the State recognizes equal rights for women. Moreover, programs that promote health and education, including the National Program on Reproductive Health, are being implemented; but despite all these, Mongolia still lacks the human and financial resources to implement the ICPD Program of Action satisfactorily. The country also needs dramatic changes in mind-set and in terms of capacity building, given its ongoing socioeconomic transition. PMID:12295512

  8. Seasonal Survival Probabilities Suggest Low Migration Mortality in Migrating Bats

    PubMed Central

    Giavi, Simone; Moretti, Marco; Bontadina, Fabio; Zambelli, Nicola; Schaub, Michael

    2014-01-01

    Migration is adaptive if survival benefits are larger than costs of residency. Many aspects of bat migration ecology such as migratory costs, stopover site use and fidelity are largely unknown. Since many migrating bats are endangered, such information is urgently needed to promote conservation. We selected the migrating Leisler's bat (Nyctalus leisleri) as model species and collected capture-recapture data in southern Switzerland year round during 6 years. We estimated seasonal survival and site fidelity with Cormack-Jolly-Seber models that accounted for the presence of transients fitted with Bayesian methods and assessed differences between sexes and seasons. Activity peaked in autumn and spring, whereas very few individuals were caught during summer. We hypothesize that the study site is a migratory stopover site used during fall and spring migration for most individuals, but there is also evidence for wintering. Additionally, we found strong clues for mating during fall. Summer survival that included two major migratory journeys was identical to winter survival in males and slightly higher in females, suggesting that the migratory journeys did not bear significant costs in terms of survival. Transience probability was in both seasons higher in males than in females. Our results suggest that, similarly to birds, Leisler's bat also use stopover sites during migration with high site fidelity. In contrast to most birds, the stopover site was also used for mating and migratory costs in terms of survival seemed to be low. Transients' analyses highlighted strong individual variation in site use which makes particularly challenging the study and modelling of their populations as well as their conservation. PMID:24454906

  9. Seasonal survival probabilities suggest low migration mortality in migrating bats.

    PubMed

    Giavi, Simone; Moretti, Marco; Bontadina, Fabio; Zambelli, Nicola; Schaub, Michael

    2014-01-01

    Migration is adaptive if survival benefits are larger than costs of residency. Many aspects of bat migration ecology such as migratory costs, stopover site use and fidelity are largely unknown. Since many migrating bats are endangered, such information is urgently needed to promote conservation. We selected the migrating Leisler's bat (Nyctalus leisleri) as model species and collected capture-recapture data in southern Switzerland year round during 6 years. We estimated seasonal survival and site fidelity with Cormack-Jolly-Seber models that accounted for the presence of transients fitted with Bayesian methods and assessed differences between sexes and seasons. Activity peaked in autumn and spring, whereas very few individuals were caught during summer. We hypothesize that the study site is a migratory stopover site used during fall and spring migration for most individuals, but there is also evidence for wintering. Additionally, we found strong clues for mating during fall. Summer survival that included two major migratory journeys was identical to winter survival in males and slightly higher in females, suggesting that the migratory journeys did not bear significant costs in terms of survival. Transience probability was in both seasons higher in males than in females. Our results suggest that, similarly to birds, Leisler's bat also use stopover sites during migration with high site fidelity. In contrast to most birds, the stopover site was also used for mating and migratory costs in terms of survival seemed to be low. Transients' analyses highlighted strong individual variation in site use which makes particularly challenging the study and modelling of their populations as well as their conservation.

  10. Cyclin D1 functions in cell migration.

    PubMed

    Li, Zhiping; Wang, Chenguang; Prendergast, George C; Pestell, Richard G

    2006-11-01

    Cell migration is essential for developmental morphogenesis, tissue repair, and tumor metastasis. A recent study reveals that cyclin D1 acts to promote cell migration by inhibiting Rho/ROCK signaling and expression of thrombospondin-1 (TSP-1), an extracellular matrix protein that regulates cell migration in many settings including cancer. Given the frequent overexpression of cyclin D1 in cancer cells, due to its upregulation by Ras, Rho, Src, and other genes that drive malignant development, the new findings suggest that cyclin D1 may have a central role in mediating invasion and metastasis of cancer cells by controlling Rho/ROCK signaling and matrix deposition of TSP-1.

  11. Control of cortical neuronal migration by glutamate and GABA

    PubMed Central

    Luhmann, Heiko J.; Fukuda, A.; Kilb, W.

    2015-01-01

    Neuronal migration in the cortex is controlled by the paracrine action of the classical neurotransmitters glutamate and GABA. Glutamate controls radial migration of pyramidal neurons by acting primarily on NMDA receptors and regulates tangential migration of inhibitory interneurons by activating non-NMDA and NMDA receptors. GABA, acting on ionotropic GABAA-rho and GABAA receptors, has a dichotomic action on radially migrating neurons by acting as a GO signal in lower layers and as a STOP signal in upper cortical plate (CP), respectively. Metabotropic GABAB receptors promote radial migration into the CP and tangential migration of interneurons. Besides GABA, the endogenous GABAergic agonist taurine is a relevant agonist controlling radial migration. To a smaller extent glycine receptor activation can also influence radial and tangential migration. Activation of glutamate and GABA receptors causes increases in intracellular Ca2+ transients, which promote neuronal migration by acting on the cytoskeleton. Pharmacological or genetic manipulation of glutamate or GABA receptors during early corticogenesis induce heterotopic cell clusters in upper layers and loss of cortical lamination, i.e., neuronal migration disorders which can be associated with neurological or neuropsychiatric diseases. The pivotal role of NMDA and ionotropic GABA receptors in cortical neuronal migration is of major clinical relevance, since a number of drugs acting on these receptors (e.g., anti-epileptics, anesthetics, alcohol) may disturb the normal migration pattern when present during early corticogenesis. PMID:25688185

  12. Control of cortical neuronal migration by glutamate and GABA.

    PubMed

    Luhmann, Heiko J; Fukuda, A; Kilb, W

    2015-01-01

    Neuronal migration in the cortex is controlled by the paracrine action of the classical neurotransmitters glutamate and GABA. Glutamate controls radial migration of pyramidal neurons by acting primarily on NMDA receptors and regulates tangential migration of inhibitory interneurons by activating non-NMDA and NMDA receptors. GABA, acting on ionotropic GABAA-rho and GABAA receptors, has a dichotomic action on radially migrating neurons by acting as a GO signal in lower layers and as a STOP signal in upper cortical plate (CP), respectively. Metabotropic GABAB receptors promote radial migration into the CP and tangential migration of interneurons. Besides GABA, the endogenous GABAergic agonist taurine is a relevant agonist controlling radial migration. To a smaller extent glycine receptor activation can also influence radial and tangential migration. Activation of glutamate and GABA receptors causes increases in intracellular Ca(2+) transients, which promote neuronal migration by acting on the cytoskeleton. Pharmacological or genetic manipulation of glutamate or GABA receptors during early corticogenesis induce heterotopic cell clusters in upper layers and loss of cortical lamination, i.e., neuronal migration disorders which can be associated with neurological or neuropsychiatric diseases. The pivotal role of NMDA and ionotropic GABA receptors in cortical neuronal migration is of major clinical relevance, since a number of drugs acting on these receptors (e.g., anti-epileptics, anesthetics, alcohol) may disturb the normal migration pattern when present during early corticogenesis.

  13. Return migration to Italy and labour migration.

    PubMed

    Calvaruso, C

    1983-01-01

    The problems caused by large-scale return migration to Italy in recent years are considered. The importance of the additional skills and capital acquired by these migrants while abroad is stressed. Extensive data on the volume of return migration in the 1970s are included.

  14. Population, migration and urbanization.

    PubMed

    1982-06-01

    Despite recent estimates that natural increase is becoming a more important component of urban growth than rural urban transfer (excess of inmigrants over outmigrants), the share of migration in the total population growth has been consistently increasing in both developed and developing countries. From a demographic perspective, the migration process involves 3 elements: an area of origin which the mover leaves and where he or she is considered an outmigrant; the destination or place of inmigration; and the period over which migration is measured. The 2 basic types of migration are internal and international. Internal migration consists of rural to urban migration, urban to urban migration, rural to rural migration, and urban to rural migration. Among these 4 types of migration various patterns or processes are followed. Migration may be direct when the migrant moves directly from the village to the city and stays there permanently. It can be circular migration, meaning that the migrant moves to the city when it is not planting season and returns to the village when he is needed on the farm. In stage migration the migrant makes a series of moves, each to a city closer to the largest or fastest growing city. Temporary migration may be 1 time or cyclical. The most dominant pattern of internal migration is rural urban. The contribution of migration to urbanization is evident. For example, the rapid urbanization and increase in urban growth from 1960-70 in the Republic of Korea can be attributed to net migration. In Asia the largest component of the population movement consists of individuals and groups moving from 1 rural location to another. Recently, because urban centers could no longer absorb the growing number of migrants from other places, there has been increased interest in the urban to rural population redistribution. This reverse migration also has come about due to slower rates of employment growth in the urban centers and improved economic opportunities

  15. Migration and Adult Education

    ERIC Educational Resources Information Center

    Gois, William

    2007-01-01

    The objective of this paper is to highlight the role of adult education as a tool in addressing labour migration issues, specifically those concerning the protection of migrant workers' rights and the transformation of the impact of migration into positive holistic developmental gains. The view of labour migration as a means to forge the economic…

  16. Proteomic analysis identifies an NADPH oxidase 1 (Nox1)-mediated role for actin-related protein 2/3 complex subunit 2 (ARPC2) in promoting smooth muscle cell migration.

    PubMed

    Al Ghouleh, Imad; Rodríguez, Andrés; Pagano, Patrick J; Csányi, Gábor

    2013-01-01

    A variety of vascular pathologies, including hypertension, restenosis and atherosclerosis, are characterized by vascular smooth muscle cell (VSMC) hypertrophy and migration. NADPH oxidase 1 (Nox1) plays a pivotal role in these phenotypes via distinct downstream signaling. However, the mediators differentiating these distinct phenotypes and their precise role in vascular disease are still not clear. The present study was designed to identify novel targets of VSMC Nox1 signaling using 2D Differential In-Gel Electrophoresis and Mass Spectrometry (2D-DIGE/MS). VSMC treatment with scrambled (Scrmb) or Nox1 siRNA and incubation with the oxidant hydrogen peroxide (H2O2; 50 µM, 3 h) followed by 2D-DIGE/MS on cell lysates identified 10 target proteins. Among these proteins, actin-related protein 2/3 complex subunit 2 (ARPC2) with no previous link to Nox isozymes, H2O2, or other reactive oxygen species (ROS), was identified and postulated to play an intermediary role in VSMC migration. Western blot confirmed that Nox1 mediates H2O2-induced ARPC2 expression in VSMC. Treatment with a p38 MAPK inhibitor (SB203580) resulted in reduced ARPC2 expression in H2O2-treated VSMC. Additionally, wound-healing "scratch" assay confirmed that H2O2 stimulates VSMC migration via Nox1. Importantly, gene silencing of ARPC2 suppressed H2O2-stimulated VSMC migration. These results demonstrate for the first time that Nox1-mediated VSMC migration involves ARPC2 as a downstream signaling target. PMID:24152438

  17. Receptor-interacting protein kinase 2 promotes triple-negative breast cancer cell migration and invasion via activation of nuclear factor-kappaB and c-Jun N-terminal kinase pathways

    PubMed Central

    2014-01-01

    Introduction Metastasis is the main cause of breast cancer morbidity and mortality. Processes that allow for tumor cell migration and invasion are important therapeutic targets. Here we demonstrate that receptor-interacting protein kinase 2 (RIP2), a kinase known to be involved in inflammatory processes, also has novel roles in cancer cell migration and invasion. Methods A total of six breast cancer expression databases, including The Cancer Genome Atlas, were assessed for RIP2 expression among various clinical subtypes and its role as a prognostic biomarker. mRNA fluorescence in situ hybridization (FISH) for RIP2 was performed on 17 stage III breast cancers to determine if there was a correlation between RIP2 expression and lymph node involvement. RNA-interference was used to knock-down RIP2 expression in MDA-MB-231, Htb126, SUM149PT, MCF7, T47D, and HCC1428 cells. Cell migration and invasion were measured in vitro by scratch/wound healing and transwell migration assays. A xenograft mouse model was used to assess tumor growth and chemosensitivity to docetaxel in vivo in MDA-MB-231 cells with and without RIP2 small hairpin RNA knockdown. Western blot and immunofluorescence imaging were used to evaluate protein expressions. Results Interrogation of expression databases showed that RIP2 expression is significantly over-expressed in triple-negative breast cancers (TNBC: estrogen-receptor (ER) negative, progesterone-receptor (PR) negative, Her2/neu- (Her2) negative), compared to other clinical subtypes. High RIP2 expression correlates with worse progression-free survival using a combined breast cancer expression array dataset consisting of 946 patients. Multivariate analysis shows RIP2 as an independent prognostic biomarker. Knock-down of RIP2 significantly decreases migration in both scratch/wound healing and transwell migration assays in MDA-MB-231, Htb126, SUM149PT, MCF7, and T47D cells and is correlated with decreased Nuclear Factor-kappaB and c-Jun N

  18. Individuality in bird migration: routes and timing.

    PubMed

    Vardanis, Yannis; Klaassen, Raymond H G; Strandberg, Roine; Alerstam, Thomas

    2011-08-23

    The exploration of animal migration has entered a new era with individual-based tracking during multiple years. Here, we investigated repeated migratory journeys of a long-distance migrating bird, the marsh harrier Circus aeruginosus, in order to analyse the variation within and between individuals with respect to routes and timing. We found that there was a stronger individual repeatability in time than in space. Thus, the annual timing of migration varied much less between repeated journeys of the same individual than between different individuals, while there was considerable variation in the routes of the same individual on repeated journeys. The overall contrast in repeatability between time and space was unexpected and may be owing to strong endogenous control of timing, while short-term variation in environmental conditions (weather and habitat) might promote route flexibility. The individual variation in migration routes indicates that the birds navigate mainly by other means than detailed route recapitulation based on landmark recognition.

  19. New directions for migration policy in Europe.

    PubMed Central

    Laczko, Frank

    2002-01-01

    There is a growing debate about the future direction of migration policy in Europe. After nearly 30 years of pursuing restrictive immigration and asylum policies, many European Union (EU) governments are beginning to re-assess their migration policies and to call for a new approach. For the first time in many years, several EU governments have begun to talk again about the benefits of labour migration and, even more significantly, have even begun to take action to recruit more migrants, especially skilled workers. This paper looks at the background to current calls for a new approach to migration in Europe and public reaction to these new initiatives. It first describes recent trends in migration in Europe and then briefly considers the demographic case for more migration. This is followed by a brief outline of some of the measures being considered by European governments to promote selective labour migration. The remainder of the paper is devoted to a discussion of some of the implications of this change in policy, focusing on two main issues: the likely consequences for sending countries, and the implications for the fight against the smuggling and trafficking of people. PMID:12028795

  20. New directions for migration policy in Europe.

    PubMed

    Laczko, Frank

    2002-04-29

    There is a growing debate about the future direction of migration policy in Europe. After nearly 30 years of pursuing restrictive immigration and asylum policies, many European Union (EU) governments are beginning to re-assess their migration policies and to call for a new approach. For the first time in many years, several EU governments have begun to talk again about the benefits of labour migration and, even more significantly, have even begun to take action to recruit more migrants, especially skilled workers. This paper looks at the background to current calls for a new approach to migration in Europe and public reaction to these new initiatives. It first describes recent trends in migration in Europe and then briefly considers the demographic case for more migration. This is followed by a brief outline of some of the measures being considered by European governments to promote selective labour migration. The remainder of the paper is devoted to a discussion of some of the implications of this change in policy, focusing on two main issues: the likely consequences for sending countries, and the implications for the fight against the smuggling and trafficking of people.

  1. Polycyclic aromatic hydrocarbon (PAH)-mediated upregulation of hepatic microRNA-181 family promotes cancer cell migration by targeting MAPK phosphatase-5, regulating the activation of p38 MAPK

    SciTech Connect

    Song, Mi-Kyung; Park, Yong-Keun; Ryu, Jae-Chun

    2013-11-15

    Growing evidence indicates that changes in microRNA (miRNA) expression in cancer induced by chemical carcinogens play an important role in cancer development and progression by regulating related genes. However, the mechanisms underlying miRNA involvement in hepatocarcinogenesis induced by polycyclic aromatic hydrocarbons (PAHs) remain unclear. Thus, the identification of aberrant miRNA expression during PAH-induced cancer cell migration will lead to a better understanding of the substantial role of miRNAs in cancer progression. In the present study, miRNA expression profiling showed significant upregulation of miR-181a, -181b, and -181d in human hepatocellular carcinoma cells (HepG2 line) exposed to benzo[a]anthracene (BA) and benzo[k]fluoranthene (BF). MAPK phosphatase-5 (MKP-5), a validated miR-181 target that deactivates MAPKs, was markedly suppressed while phosphorylation of p38 MAPK was increased after BA and BF exposure. The migration of HepG2 cells, observed using the scratch wound-healing assay, also increased in a dose-dependent manner. Depletion of miR-181 family members by miRNA inhibitors enhanced the expression of MKP-5 and suppressed the phosphorylation of p38 MAPK. Furthermore, the depletion of the miR-181 family inhibited cancer cell migration. Based on these results, we conclude that the miR-181 family plays a critical role in PAH-induced hepatocarcinogenesis by targeting MKP-5, resulting in the regulation of p38 MAPK activation. - Highlights: • We found significant upregulation of miR-181 family in HCC exposed to BA and BF. • We identified the MKP-5 as a putative target of miR-181 family. • MKP-5 was suppressed while p-P38 was increased after BA and BF exposure. • The migration of HepG2 cells increased in a dose-dependent manner.

  2. Aquaporins and cell migration.

    PubMed

    Papadopoulos, M C; Saadoun, S; Verkman, A S

    2008-07-01

    Aquaporin (AQP) water channels are expressed primarily in cell plasma membranes. In this paper, we review recent evidence that AQPs facilitate cell migration. AQP-dependent cell migration has been found in a variety of cell types in vitro and in mice in vivo. AQP1 deletion reduces endothelial cell migration, limiting tumor angiogenesis and growth. AQP4 deletion slows the migration of reactive astrocytes, impairing glial scarring after brain stab injury. AQP1-expressing tumor cells have enhanced metastatic potential and local infiltration. Impaired cell migration has also been seen in AQP1-deficient proximal tubule epithelial cells, and AQP3-deficient corneal epithelial cells, enterocytes, and skin keratinocytes. The mechanisms by which AQPs enhance cell migration are under investigation. We propose that, as a consequence of actin polymerization/depolymerization and transmembrane ionic fluxes, the cytoplasm adjacent to the leading edge of migrating cells undergoes rapid changes in osmolality. AQPs could thus facilitate osmotic water flow across the plasma membrane in cell protrusions that form during migration. AQP-dependent cell migration has potentially broad implications in angiogenesis, tumor metastasis, wound healing, glial scarring, and other events requiring rapid, directed cell movement. AQP inhibitors may thus have therapeutic potential in modulating these events, such as slowing tumor growth and spread, and reducing glial scarring after injury to allow neuronal regeneration. PMID:17968585

  3. Role of aspiration-induced migration in cooperation

    NASA Astrophysics Data System (ADS)

    Yang, Han-Xin; Wu, Zhi-Xi; Wang, Bing-Hong

    2010-06-01

    Both cooperation and migration are ubiquitous in human society and animal world. In this Rapid Communication, we propose an aspiration-induced migration in which individuals will migrate to new sites provided that their payoffs are below some aspiration level. It is found that moderate aspiration level can best favor cooperative behavior. In particular, moderate aspiration level enables cooperator clusters to maintain and expand whereas induces defector clusters to disintegrate, thus promoting the diffusion of cooperation among population. Our results provide insights into understanding the role played by migration in the emergence of cooperative behavior.

  4. Migration to Windows NT.

    ERIC Educational Resources Information Center

    Doles, Daniel T.

    In the constantly changing world of technology, migration is not only inevitable but many times necessary for survival, especially when the end result is simplicity for both users and IT support staff. This paper describes the migration at Franklin College (Indiana). It discusses the reasons for selecting Windows NT, the steps taken to complete…

  5. The Future of Migration.

    ERIC Educational Resources Information Center

    Organisation for Economic Cooperation and Development, Paris (France).

    This book comprises papers delivered at a conference of National Experts on Migration. The principle objective of the conference was twofold: to examine significant trends that will affect the future of migration in countries in the Organization for Economic Co-operation and Development (OCED), and to identify the relevant issues that will have to…

  6. The Great Migration.

    ERIC Educational Resources Information Center

    Trotter, Joe William, Jr.

    2002-01-01

    Describes the migration of African Americans in the United States and the reasons why African Americans migrated from the south. Focuses on issues, such as the effect of World War I, the opportunities offered in the north, and the emergence of a black industrial working class. (CMK)

  7. Migration and Environmental Hazards

    PubMed Central

    Hunter, Lori M.

    2011-01-01

    Losses due to natural hazards (e.g., earthquakes, hurricanes) and technological hazards (e.g., nuclear waste facilities, chemical spills) are both on the rise. One response to hazard-related losses is migration, with this paper offering a review of research examining the association between migration and environmental hazards. Using examples from both developed and developing regional contexts, the overview demonstrates that the association between migration and environmental hazards varies by setting, hazard types, and household characteristics. In many cases, however, results demonstrate that environmental factors play a role in shaping migration decisions, particularly among those most vulnerable. Research also suggests that risk perception acts as a mediating factor. Classic migration theory is reviewed to offer a foundation for examination of these associations. PMID:21886366

  8. Migration and Environmental Hazards.

    PubMed

    Hunter, Lori M

    2005-03-01

    Losses due to natural hazards (e.g., earthquakes, hurricanes) and technological hazards (e.g., nuclear waste facilities, chemical spills) are both on the rise. One response to hazard-related losses is migration, with this paper offering a review of research examining the association between migration and environmental hazards. Using examples from both developed and developing regional contexts, the overview demonstrates that the association between migration and environmental hazards varies by setting, hazard types, and household characteristics. In many cases, however, results demonstrate that environmental factors play a role in shaping migration decisions, particularly among those most vulnerable. Research also suggests that risk perception acts as a mediating factor. Classic migration theory is reviewed to offer a foundation for examination of these associations.

  9. Migration of health workers.

    PubMed

    Buchan, James

    2008-01-01

    The discussion and debate stimulated by these papers focused across a range of issues but there were four main areas of questioning: "measuring" and monitoring migration (issues related to comparability, completeness and accuracy of data sets on human resources); the impact of migration of health workers on health systems; the motivations of individual health workers to migrate (the "push" and "pull" factors) and the effect of policies designed either to reduce migration (e.g "self ufficiency") or to stimulate it (e.g active international recruitment). It was recognised that there was a critical need to examine migratory flows within the broader context of all health care labour market dynamics within a country, that increasing migration of health workers was an inevitable consequence of globalisation, and that there was a critical need to improve monitoring so as to better inform policy formulation and policy testing in this area. PMID:18561695

  10. Migration of health workers.

    PubMed

    Buchan, James

    2008-01-01

    The discussion and debate stimulated by these papers focused across a range of issues but there were four main areas of questioning: "measuring" and monitoring migration (issues related to comparability, completeness and accuracy of data sets on human resources); the impact of migration of health workers on health systems; the motivations of individual health workers to migrate (the "push" and "pull" factors) and the effect of policies designed either to reduce migration (e.g "self ufficiency") or to stimulate it (e.g active international recruitment). It was recognised that there was a critical need to examine migratory flows within the broader context of all health care labour market dynamics within a country, that increasing migration of health workers was an inevitable consequence of globalisation, and that there was a critical need to improve monitoring so as to better inform policy formulation and policy testing in this area.

  11. On marriage and migration.

    PubMed

    Stark, O

    1988-09-01

    Marriage, migration, and related phenomena such as marital stability, fertility, and investment in human capital may be better explained by studying marriage and migration jointly. This paper examines the role of migration in obtaining joint labor market and marriage market equilibrium. When broadly interpreted, marriage and migration share a number of common features. Both involve search and its resolution (pairing of mates in the former and matching of labor and firms in the latter). In both cases, success in finding a partner is sensitive to the availability of partners and to the distribution of their endowments and traits. Almost always, and along with separation and divorce, marriage mandates spatial relocation which may translate into migration. Both involve a movement that is associated with adjustment costs from 1 state into another. The decisions to enter marriage and undertake employment or the decisions to divorce and quit a job depend on exogenous parameters, some of which are determined by the marriage market and the labor market. Since both marriage and divorce take place in the context of broadly defined markets, they may and often are analyzed applying market concepts, theorems, and solutions. Yet the authors could not pinpoint 1 single, systematic attempt that checks through the interactions between marriage and migration, so this paper attempts to rectify this state of research. Essentially, this paper 1) discusses individual decision making pending possible migration prior to or following marriage, 2) examines whether it is easier for a married couple or a single person to migrate, and 3) considers whether marriage dissolution could cause migration when marriage is the only reason that has kept a spouse from moving. This integrated research agenda for both marriage and migration can delineate interesting new implications to examine.

  12. [Determinants of migration to Warsaw].

    PubMed

    Kucinski, K; Rakowski, W

    1990-01-01

    The authors examine trends and determinants of internal migration to Warsaw, Poland. Consideration is given to occupational and socioeconomic status of migrants, rural-urban migration, and effects of migration on marriage. (SUMMARY IN ENG AND RUS)

  13. Polydatin induces bone marrow stromal cells migration by activation of ERK1/2.

    PubMed

    Chen, ZhenQiu; Wei, QiuShi; Hong, GuoJu; Chen, Da; Liang, Jiang; He, Wei; Chen, Mei Hui

    2016-08-01

    Bone marrow stromal cells (BMSCs) have proven to be useful for the treatment of numerous human diseases. However, the reparative ability of BMSCs is limited by their poor migration. Polydatin, widely used in traditional Chinese remedies, has proven to exert protective effects to BMSCs. However, little is known about its role in BMSCs migration. In this study, we studied the effects of polydatin on rat BMSCs migration using the scratch wound healing and transwell migration assays. Our results showed polydatin could promote BMSCs migration. Further experiments showed activation of ERK 1/2, but not JNK, was required for polydatin-induced BMSCs migration, suggesting that polydatin may promote BMSCs migration via the ERK 1/2 signaling pathways. Taken together, our results indicate that polydatin might be beneficial for stem cell replacement therapy by improving BMSCs migration.

  14. Neuronal migration illuminated

    PubMed Central

    Trivedi, Niraj

    2011-01-01

    During vertebrate brain development, migration of neurons from the germinal zones to their final laminar positions is essential to establish functional neural circuits.1–3 Whereas key insights into neuronal migration initially came from landmark studies identifying the genes mutated in human cortical malformations,4 cell biology has recently greatly advanced our understanding of how cytoskeletal proteins and molecular motors drive the morphogenic cell movements that build the developing brain. This Commentary & View reviews recent studies examining the role of the molecular motors during neuronal migration and critically examines current models of acto-myosin function in the two-step neuronal migration cycle. Given the apparent emerging diversity of neuronal sub-type cytoskeletal organizations, we propose that two approaches must be taken to resolve differences between the current migration models: the mechanisms of radial and tangential migration must be compared, and the loci of tension generation, migration substrates and sites of adhesion dynamics must be precisely examined in an integrated manner. PMID:20935494

  15. Migration without migraines

    SciTech Connect

    Lines, L.; Burton, A.; Lu, H.X.

    1994-12-31

    Accurate velocity models are a necessity for reliable migration results. Velocity analysis generally involves the use of methods such as normal moveout analysis (NMO), seismic traveltime tomography, or iterative prestack migration. These techniques can be effective, and each has its own advantage or disadvantage. Conventional NMO methods are relatively inexpensive but basically require simplifying assumptions about geology. Tomography is a more general method but requires traveltime interpretation of prestack data. Iterative prestack depth migration is very general but is computationally expensive. In some cases, there is the opportunity to estimate vertical velocities by use of well information. The well information can be used to optimize poststack migrations, thereby eliminating some of the time and expense of iterative prestack migration. The optimized poststack migration procedure defined here computes the velocity model which minimizes the depth differences between seismic images and formation depths at the well by using a least squares inversion method. The optimization methods described in this paper will hopefully produce ``migrations without migraines.``

  16. Women in migration.

    PubMed

    Morokvasic, M

    1984-01-01

    This special issue reflects the belated but growing scholarly appreciation of the specificity and importance of women in migration. Aside from the sheer numerical significance of female migration documented in this issue, women migrants encounter problems and make special contributions which render comprehension of their specificity critical to an understanding of international migration in general. In an introductory essay, Morokvasic surveys the state of knowledge concerning women in migration. The focus then shifts, in Part II, to regional and national case studies which collectively elucidate the multifaceted dimensions of the women in migration research issue through time and space. In Part III, an international comparison of female immigrants and their labor market characteristics reveals striking similarities but also important differences. The US Canada and Australia can be discretely compared through 5 census-based quantitative analyses. The role of migrant women in the labor market is also the theme of Part IV. But the 5 studies comprising this section are based on survey research or on discernible global trends in migration and employment. Part V is devoted to the theme of female rural to urban migration in the Third World.

  17. Convergence of broad-scale migration strategies in terrestrial birds.

    PubMed

    La Sorte, Frank A; Fink, Daniel; Hochachka, Wesley M; Kelling, Steve

    2016-01-27

    Migration is a common strategy used by birds that breed in seasonal environments. Selection for greater migration efficiency is likely to be stronger for terrestrial species whose migration strategies require non-stop transoceanic crossings. If multiple species use the same transoceanic flyway, then we expect the migration strategies of these species to converge geographically towards the most optimal solution. We test this by examining population-level migration trajectories within the Western Hemisphere for 118 migratory species using occurrence information from eBird. Geographical convergence of migration strategies was evident within specific terrestrial regions where geomorphological features such as mountains or isthmuses constrained overland migration. Convergence was also evident for transoceanic migrants that crossed the Gulf of Mexico or Atlantic Ocean. Here, annual population-level movements were characterized by clockwise looped trajectories, which resulted in faster but more circuitous journeys in the spring and more direct journeys in the autumn. These findings suggest that the unique constraints and requirements associated with transoceanic migration have promoted the spatial convergence of migration strategies. The combination of seasonal atmospheric and environmental conditions that has facilitated the use of similar broad-scale migration strategies may be especially prone to disruption under climate and land-use change.

  18. Labor migration in Asia.

    PubMed

    Martin, P L

    1991-01-01

    "A recent conference sponsored by the United Nations Center for Regional Development (UNCRD) in Nagoya, Japan examined the growing importance of labor migration for four major Asian labor importers (Japan, Hong Kong, Malaysia, and Singapore) and five major labor exporters (Bangladesh, Korea, Pakistan, Philippines, and Thailand).... The conference concluded that international labor migration would increase within Asia because the tight labor markets and rising wages which have stimulated Japanese investment in other Asian nations, for example, have not been sufficient to eliminate migration push and pull forces...."

  19. Indonesia's migration transition.

    PubMed

    Hugo, G

    1995-01-01

    This article describes population movements in Indonesia in the context of rapid and marked social and economic change. Foreign investment in Indonesia is increasing, and global mass media is available to many households. Agriculture is being commercialized, and structural shifts are occurring in the economy. Educational levels are increasing, and women's role and status are shifting. Population migration has increased over the decades, both short and long distance, permanent and temporary, legal and illegal, and migration to and between urban areas. This article focuses specifically on rural-to-urban migration and international migration. Population settlements are dense in the agriculturally rich inner areas of Java, Bali, and Madura. Although the rate of growth of the gross domestic product was 6.8% annually during 1969-94, the World Bank ranked Indonesia as a low-income economy in 1992 because of the large population size. Income per capita is US $670. Indonesia is becoming a large exporter of labor to the Middle East, particularly women. The predominance of women as overseas contract workers is changing women's role and status in the family and is controversial due to the cases of mistreatment. Malaysia's high economic growth rate of over 8% per year means an additional 1.3 million foreign workers and technicians are needed. During the 1980s urban growth increased at a very rapid rate. Urban growth tended to occur along corridors and major transportation routes around urban areas. It is posited that most of the urban growth is due to rural-to-urban migration. Data limitations prevent an exact determination of the extent of rural-to-urban migration. More women are estimated to be involved in movements to cities during the 1980s compared to the 1970s. Recruiters and middlemen have played an important role in rural-to-urban migration and international migration. PMID:12347370

  20. Migration and malaria.

    PubMed

    Jitthai, Nigoon

    2013-01-01

    Migration is an important global issue as poorly managed migration can result in a diversity of problems, including an increase in the transmission of diseases such as malaria. There is evidence to suggest that malaria is no longer a forest-dependent disease and may largely be affected by population movements, mostly to agricultural areas. While internal and transnational migration has different legal implications in most countries, both types of migration occur for the same reasons; economic and/ or safety. Although migration in itself is not a definitive risk for malaria, several factors can put, migrants and local communities alike, in vulnerable situations. In particular, infrastructure and rural development, deforestation for logging and economic farming, political movements, and natural disasters are some of the major factors that push and pull people in and out of malaria-endemic areas. Therefore, understanding the changing socio-environmental situation as well as population movements and their associated risks for malaria infection, is critical for malaria control, containment, and elimination. Efforts to address these issues should include advocacy, mapping exercises and expanded/ strengthened surveillance to also include migrant health information systems. Malaria related information, prevention measures, and early diagnosis and appropriate treatment should be made easily accessible for migrants regardless of their migration status; not only to ensure that they are equipped with appropriate knowledge and devices to protect themselves, but also to ensure that they are properly diagnosed and treated, to prevent further transmission, and to ensure that they are captured by the surveillance system. PMID:24159832

  1. Timescales of DNAPL migration

    NASA Astrophysics Data System (ADS)

    Kueper, B.; Gerhard, J.; Reynolds, D.

    2003-04-01

    Dense, non-aqueous phase liquids such as chlorinated solvents, PCB oils, creosote, and coal tar are common soil and groundwater contaminants at sites throughout the world. Current source zone remediation approaches typically assume that the residual and pooled DNAPL of interest is no longer migrating. The motivation for partial mass removal from a DNAPL source zone varies from site to site, but is often motivated by the belief that mass removal will lead to shorter steady-state plumes, shorter longevity of the source zone, and possibly aquifer restoration in a reasonable period of time. This talk addresses the issue of DNAPL migration timescales, and illustrates that certain types of DNAPL in certain geological environments are likely still migrating at some sites. The implication of this is that remedial strategies may need to be aimed at source zone stabilization in the short term, not partial mass removal for the reasons outlined above. The timescales of DNAPL migration at a site are influenced by many factors, including fluid properties, capillary properties, relative permeability characteristics, boundary conditions, and the volume and nature of release. Accurate prediction of DNAPL migration timescales requires a model that properly accounts for both the entry and terminal pressures in the capillary pressure -- saturation constitutive relationship, and properly accounts for relative permeability characteristics. This talk will address the above issues, and will present the results of laboratory experiments and numerical simulations to illustrate the timescale of DNAPL migration in a variety of environments including fractured rock, fractured clay, and unconsolidated porous media.

  2. The Malaysian state's response to migration.

    PubMed

    Pillai, P

    1999-04-01

    This paper aims to provide a profile of migration trends in Malaysia since 1970 and to analyze public policy on migration in the context of economic growth and the labor market. The discussion centers on the impact of the Asian financial crisis. There is long history of immigration to Malaysia. The development strategy of the 1970s and 1980s was to create more jobs and restructure employment to meet equity goals. Labor shortages on plantations and construction booms led to a more organized, sustained effort to import labor. Recession in the mid-1980s led to unemployment, but many Malaysians were unwilling to work on plantations, in construction, or in low paying jobs. Economic growth during 1987-96 was very high, and labor shortages spread to service and manufacturing sectors. Migration policy has shifted over the decades. Both the market and the government's promotion of export-based industrialization require access to low cost migrant labor. Public and official recognition of the large number of migrants was not made until 1995. The financial crisis in 1998 led to enforcement of a new migration policy on illegal migrants and greater outflow of migrants. The economic crisis has increased job and income inequities in the region; this encourages continued migration. It is argued that it would be best for Malaysia to maximize short-term gains while minimizing long-term economic, social, and political costs.

  3. The Malaysian state's response to migration.

    PubMed

    Pillai, P

    1999-04-01

    This paper aims to provide a profile of migration trends in Malaysia since 1970 and to analyze public policy on migration in the context of economic growth and the labor market. The discussion centers on the impact of the Asian financial crisis. There is long history of immigration to Malaysia. The development strategy of the 1970s and 1980s was to create more jobs and restructure employment to meet equity goals. Labor shortages on plantations and construction booms led to a more organized, sustained effort to import labor. Recession in the mid-1980s led to unemployment, but many Malaysians were unwilling to work on plantations, in construction, or in low paying jobs. Economic growth during 1987-96 was very high, and labor shortages spread to service and manufacturing sectors. Migration policy has shifted over the decades. Both the market and the government's promotion of export-based industrialization require access to low cost migrant labor. Public and official recognition of the large number of migrants was not made until 1995. The financial crisis in 1998 led to enforcement of a new migration policy on illegal migrants and greater outflow of migrants. The economic crisis has increased job and income inequities in the region; this encourages continued migration. It is argued that it would be best for Malaysia to maximize short-term gains while minimizing long-term economic, social, and political costs. PMID:12295145

  4. Human rights and migration policies.

    PubMed

    Marmora, L

    1990-01-01

    This paper concerns the history of migration, migration policies, and the rights of migrants in Latin America from 1500 to the present. In the first part of the article, the author identifies and discusses the basic rights of migrants. In the second part, migration policies, migration flows, and the treatment of migrants are examined over time.

  5. Lamin A/C protein is overexpressed in tissue-invading prostate cancer and promotes prostate cancer cell growth, migration and invasion through the PI3K/AKT/PTEN pathway.

    PubMed

    Kong, Lu; Schäfer, Georg; Bu, Huajie; Zhang, Yong; Zhang, Yuxiang; Klocker, Helmut

    2012-04-01

    Prostate cancer (PC) remains the second most common cause of cancer-related death in Western countries. A previous proteomics study suggested that the nuclear membrane protein lamin A/C to be a maker to discriminate low- and high-Gleason score tumors and to identify high-risk cancers. To characterize its function in PC cells, we performed a detailed expression analysis in PC tissue and explored the consequences of down or upregulation of lamin A/C in PC cells. Our results confirm an increased lamin A/C protein expression in high-risk cancers and show association of expression with tumor cell formations at the invasion fronts of tumors and in invasion 'spearheading' tumor cell clusters. In the prostate tumor cell lines, LNCaP, DU145, and PC3 small hairpin RNA knockdown or overexpression of lamin A/C resulted in inhibition or stimulation, respectively, of cell growth, colony formation, migration and invasion. Further mechanism studies suggested that the lamin A/C-related malignant behavior is regulated through modulation of the phosphoinositide 3-kinase (PI3K)/AKT/PTEN signaling pathway. Western blot results indicated that knockdown or overexpression of lamin A/C decreased or increased, respectively, protein levels of the PI3K subunits p110 and p85 in all three cell lines; phosphor-AKT in the PTEN-negative cell lines LNCaP and PC3, and, increased or decreased, respectively, PTEN protein levels in PTEN-positive DU145 cells. Together, our data suggest that lamin A/C proteins are positively involved in malignant behavior of PC cells through the PI3K/AKT/PTEN pathway. Lamin A/C may represent a new oncogenic factor and a novel therapeutic target for PC.

  6. Environmental concerns and international migration.

    PubMed

    Hugo, G

    1996-01-01

    "This article focuses on international migration occurring as a result of environmental changes and processes. It briefly reviews attempts to conceptualize environment-related migration and then considers the extent to which environmental factors have been and may be significant in initiating migration. Following is an examination of migration as an independent variable in the migration-environment relationship. Finally, ethical and policy dimensions are addressed."

  7. Environmental concerns and international migration.

    PubMed

    Hugo, G

    1996-01-01

    "This article focuses on international migration occurring as a result of environmental changes and processes. It briefly reviews attempts to conceptualize environment-related migration and then considers the extent to which environmental factors have been and may be significant in initiating migration. Following is an examination of migration as an independent variable in the migration-environment relationship. Finally, ethical and policy dimensions are addressed." PMID:12291410

  8. Biometrics and international migration.

    PubMed

    Redpath, Jillyanne

    2007-01-01

    This paper will focus on the impact of the rapid expansion in the use of biometric systems in migration management on the rights of individuals; it seeks to highlight legal issues for consideration in implementing such systems, taking as the starting point that the security interests of the state and the rights of the individual are not, and should not be, mutually exclusive. The first part of this paper briefly describes the type of biometric applications available, how biometric systems function, and those used in migration management. The second part examines the potential offered by biometrics for greater security in migration management, and focuses on developments in the use of biometrics as a result of September 11. The third part discusses the impact of the use of biometrics in the management of migration on the individual's right to privacy and ability to move freely and lawfully. The paper highlights the increasing need for domestic and international frameworks to govern the use of biometric applications in the migration/security context, and proposes a number of issues that such frameworks could address. PMID:17536151

  9. Migration from Packaging Materials

    NASA Astrophysics Data System (ADS)

    Meulenaer, B. De

    Various chemical compounds can be present in foodstuffs which may induce health problems in humans. The origin of these compounds can be very diverse. Mathematical modeling can sometimes be used to predict the concentration of these chemicals in the food. Particularly for compounds which are produced in the food during, e.g., processing and for compounds which migrate from a food contact material this technique can be very fruitful. For the former type of compounds, classical chemical kinetics can be applied. In this contribution, the modeling of the migration from polymeric food contact materials is considered. This migration phenomenon can be modeled mathematically since the physical processes which govern this process are very well studied and understood. Therefore, initially some of these fundamentals will be discussed in more detail.

  10. More myths of migration.

    PubMed

    Basch, L; Lerner, G

    1986-01-01

    This paper discusses some of the myths of migration. The 5 myths presented are: 1) racism has little to do with the causes of migration and does not necessarily impede the adjustment or success of migrants; 2) in areas where there is a strong feminist movement and trade unions, migrant women receive their support and can count on the solidarity of these organizations; 3) transnational corporations are positive forces in the developing countries where they operate--not only do they provide these states with new sources of capital, but they also impart new industrial skills to the labor force; 4) migration today is essentially short-term in nature--it therefore does not have a strong impact on family life; and 5) most migrants cluster together in ethnic enclaves which provide a strong source of support and diminish dislocation inherent in the migrant process.

  11. [Migration, climate and health].

    PubMed

    Tellier, Siri; Carballo, Manuel; Calballo, Manuel

    2009-10-26

    Many tentative connections have been postulated between migration and climate. This article points to rural-urban migration, particularly into low elevation urban slums prone to flooding as an issue needing urgent attention by health professionals. It also notes the no-man's land in which environmental refugees find themselves and the consequences this may have. Finally, it points to the urgent need to reform health systems in both developing and developed countries to adapt to rapidly changing disease patterns and to become more responsive to them.

  12. What's driving migration?

    PubMed

    Kane, H

    1995-01-01

    During the 1990s investment in prevention of international or internal migration declined, and crisis intervention increased. The budgets of the UN High Commissioner for Refugees and the UN Development Program remained about the same. The operating assumption is that war, persecution, famine, and environmental and social disintegration are inevitable. Future efforts should be directed to stabilizing populations through investment in sanitation, public health, preventive medicine, land tenure, environmental protection, and literacy. Forces pushing migration are likely to increase in the future. Forces include depletion of natural resources, income disparities, population pressure, and political disruption. The causes of migration are not constant. In the past, migration occurred during conquests, settlement, intermarriage, or religious conversion and was a collective movement. Current migration involves mass movement of individuals and the struggle to survive. There is new pressure to leave poor squatter settlements and the scarcities in land, water, and food. The slave trade between the 1500s and the 1800s linked continents, and only 2-3 million voluntarily crossed national borders. Involuntary migration began in the early 1800s when European feudal systems were in a decline, and people sought freedom. Official refugees, who satisfy the strict 1951 UN definition, increased from 15 million in 1980 to 23 million in 1990 but remained a small proportion of international migrants. Much of the mass movement occurs between developing countries. Migration to developed countries is accompanied by growing intolerance, which is misinformed. China practices a form of "population transfer" in Tibet in order to dilute Tibetan nationalism. Colonization of countries is a new less expensive form of control over territory. Eviction of minorities is another popular strategy in Iraq. Public works projects supported by foreign aid displace millions annually. War and civil conflicts

  13. Migration strategies of insects.

    PubMed

    Dingle, H

    1972-03-24

    Physiological and ecological results from a variety of species are consistent with what seem to be valid general statements concerning insect migration. These are as follows: (i)During migration locomotory functions are enhanced and vegetative functions such as feeding and reproduction are suppressed. (ii) Migration usually occurs prereproductively in the life of the adult insect (the oogenesis-flight syndrome). (iii)Since migrant individuals are usually prereproductive, their reproductive values, and hence colonizing abilities, are at or near maximum. (iv) Migrants usually reside in temporary habitats. (v)Migrants have a high potential for population increase, r, which is also advantageous for colonizers. (vi)Both the physiological and ecological parameters of migration are modifiable by environmental factors (that is, phenotypically modifiable)to suit the prevailing conditions. Taken together, these criteria establish a comprehensive theory and adumbrate the basic strategy for migrant insects. This basic strategy is modified to suit the ecological requirements of individual species. Comparative studies of these modifications are of considerable theoretical and practical interest, the more so since most economically important insects are migrants. No satisfactory general statements can as yet be made with respect to the genotype and migration. Certainly we expect colonizing populiations to possess genotypes favoring a high r, but genotypic variation in r depends on the heritabilities of life table statistics, and such measurements are yet to be made (10, 53). The fact that flight duration can be increased by appropriate selection in Oncopeltus fasciatus, and the demonstration of additive genetic variance for this trait in Lygaeus kalmii, suggest that heritability studies of migratory behavior would also be worth pursuing. Most interesting of course, will be possible genetic correlations between migration and life history parameters. Also, migration often

  14. [Migration and health].

    PubMed

    Litvinjenko, S

    1997-01-01

    In the last decades of this century we are witnesses of frequent crises in different parts of the world produced by internal disturbance and wars. These crises, together with natural disasters, poverty and hunger, follow the history of mankind often forcing huge population groups to leave their homes. The harmful health consequences are among negative effects of migrations. While stable populations have well-tried routines for maintaining health, migrations mean abandoning such support systems. The increased exposure to harmful factors contributes more to the bad health condition of the migrant population. Setting of newcomers and local people together in the same homes, reduction in food and heating resources, drug shortage as well as importation of new infectious agents, may also endanger health of the native population. These observations have also been confirmed by Yugoslav experience. Depending on the fact whether a migration is elemental or organized i.e. dependent on its place in the large scale between these two extreme endpoints, the size of risk is also dependent on the consequences and degree of their difficulty. Mass health disturbances occur during migrations of the population from war regions, migrations from areas of natural disasters, mass pilgrimage, migrations of seasonal workers and migrations of armies during wars. However, even in these difficult times and conditions, a good organization can contribute to the mitigation of harmful consequences caused by these migrations. For instance, in 1942 there was an epidemic of typhus fever in Bosnia when many refugees crossed the Drina river on the way to Serbia escaping from Ustasha terrorism. At the Serbian side there were checkpoints where the refugees could taka a bath and where their laundry and clothing were depediculated with dry air, and after a two-week quarantine they could continue to Serbian provinces without making new foci of typhus fever. The most vulnerable and numerous group of refugees

  15. Charge migration in dicationic electrophiles and its application to the synthesis of aza-polycyclic aromatic compounds.

    PubMed

    Li, Ang; Kindelin, Patrick J; Klumpp, Douglas A

    2006-03-16

    [reaction: see text] Superacid-promoted reactions of dicationic electrophiles have been studied, and the positive charge centers are found to migrate apart in a predictable manner. Using isotopic labeling the charge migration is found in one system to occur through successive deprotonation-reprotonation steps. The charge migration chemistry is the basis for new general synthetic route to aza-polycyclic aromatic compounds.

  16. The Singapore state's response to migration.

    PubMed

    Yap, M T

    1999-04-01

    Migration trends in Singapore are traced since 1819. Immigration has been encouraged to advance economic development. Local and international factors fuel migration to Singapore. Singapore depends upon foreign labor. Population growth has been mainly due to migration from China, India, Malaysia, and countries surrounding Singapore. Independence in 1965 led to policies aimed at controlling high population growth. Policies became pronatalist after 1987. Foreigners in 1998 were over 18% of the total population, which was six times the number in 1970. About 2000 Singaporeans per year emigrated during the 1990s. Singapore is encouraging overseas industrial development. In 1997, the Prime Minister called for recruitment of foreign talent in order to meet the challenges of an increasingly globalized world, low fertility, and an aging society. Economic planners recommend short-term migration of unskilled foreign workers who would be a revolving pool to fill jobs natives do not want. Singapore is promoting arts and culture in order to keep people in Singapore. The government has issued assurances that natives will have first priority on jobs, education, and training. Singapore's ability to absorb workers will depend upon its economic performance.

  17. Method of migrating seismic records

    DOEpatents

    Ober, Curtis C.; Romero, Louis A.; Ghiglia, Dennis C.

    2000-01-01

    The present invention provides a method of migrating seismic records that retains the information in the seismic records and allows migration with significant reductions in computing cost. The present invention comprises phase encoding seismic records and combining the encoded seismic records before migration. Phase encoding can minimize the effect of unwanted cross terms while still allowing significant reductions in the cost to migrate a number of seismic records.

  18. The commercialization of migration.

    PubMed

    Abrera-mangahas, M A

    1989-01-01

    International migration is not new to the Philippines. In the recent outflow of contract workers to the Middle East, there is a shift from individual and family initiated migrations to the more organized, highly commercial variety. While profit-taking intermediaries have played some role in the past, the increase in the number and influence of these intermediaries has altered the story of migration decision-making. In 1975, the signing of the bilateral labor agreement between the governments of Iran and the Philippines signalled the rising demand for Filipino contract workers. From 1970 to 1975, the number of Asian migrant workers in the Gulf countries rose from about 120,000 to 370,000. These figures rose dramatically to 3.3 million in 1985. The growing share of organized and commercialized migration has altered migration decision making. Primarily, intermediaries are able to broaden access to foreign job and high wage opportunities. Commercialization effectively raises the transaction costs for contract migration. Studies on recruitment costs and fees show that self-solicited foreign employment costs less than employment obtained through recruitment agents and intermediaries. The difference in the 2 prices is due, not only to overhead costs of intermediation, but more importantly to the rent exacted by agents from having job information and placement rights. In the Philippines in October 1987 the average placement fee was P8000, greatly exceeding the mandated maximum fee level of P5000. This average is understated because the computation includes the 17% who do not pay any fees. The widespread and popular view of recruitment intermediaries is negative, dominated by images of abuses and victims. Private intermediaries and the government bureaucracy need each other. Intermediaries need government; their consistent demand for incentives and protection is indicative. On the other hand, government expands its supervision of control of overseas employment via the

  19. [Return migrations in the Italian migration system: a reexamination].

    PubMed

    Bonifazi, C; Heins, F

    1996-06-01

    The authors discuss trends in return migration in Italy, with a focus on regional differences. "On a regional level, the effects of return migration are very much connected with socio-economic structure. Only highly developed and autonomous regions can absorb productive investments and changes brought about by return migration. Several southern regions--especially those with greater migration experience--have shown in the last decades a very poor socio-economic development." The study is concerned with both internal and international migration. (SUMMARY IN ENG AND FRE)

  20. Investigating Delamination Migration in Composite Tape Laminates

    NASA Technical Reports Server (NTRS)

    Ratcliffe, James G.; DeCarvalho, Nelson V.

    2014-01-01

    A modification to a recently developed test specimen designed to investigate migration of a delamination between neighboring ply interfaces in tape laminates is presented. The specimen is a cross-ply laminated beam consisting of 40 plies with a polytetrafluoroethylene insert spanning part way along its length. The insert is located between a lower 0-degree ply (specimen length direction) and a stack of four 90-degree plies (specimen width direction). The modification involved a stacking sequence that promotes stable delamination growth prior to migration, and included a relocation of the insert from the specimen midplane to the interface between plies 14 and 15. Specimens were clamped at both ends onto a rigid baseplate and loaded on their upper surface via a piano hinge assembly, resulting in a predominantly flexural loading condition. Tests were conducted with the load-application point positioned at various locations along a specimen's span. This position affected the sequence of damage events during a test.

  1. Forced Migration: Refugee Populations

    PubMed Central

    Boyle, Joyceen S.

    2015-01-01

    Undocumented migration is a global phenomenon that manifests in various contexts. This article describes the impact of the movement of large numbers of people in several African countries, producing a unique type of migrant—the refugee. We describe issues that refugee movements create on fragile health care systems, situations that precipitate refugee movements, certain human rights violations that are of particular concern such as gender based violence (GBV) and child soldiers, and lastly, implications for nursing practice and policy. We use examples from several countries in Sub-Saharan Africa, including the Democratic Republic of the Congo, Rwanda, Liberia, Sierra Leone, and Mozambique. Drawing on key documents from the United Nations High Commissioner for Refugees, current literature, as well as the international experience of the authors, this article presents an overview of forced migration and discusses opportunities for nurses to impact research, practice and policy related to refugee health. PMID:25645484

  2. Migration with fiscal externalities.

    PubMed

    Hercowitz, Z; Pines, D

    1991-11-01

    "This paper analyses the distribution of a country's population among regions when migration involves fiscal externalities. The main question addressed is whether a decentralized decision making [by] regional governments can produce an optimal population distribution...or a centralized intervention is indispensable, as argued before in the literature.... It turns out that, while with costless mobility the fiscal externality is fully internalized by voluntary interregional transfers, with costly mobility, centrally coordinated transfers still remain indispensable for achieving the socially optimal allocation."

  3. IAPs and cell migration.

    PubMed

    Dubrez, Laurence; Rajalingam, Krishnaraj

    2015-03-01

    Inhibitors of apoptosis (IAPs) constitute a family of cell signaling regulators controlling several fundamental biological processes such as innate immunity, inflammation, cell death, cell proliferation, and cell differentiation. Increasing evidence from in vivo and in vitro studies indicate a function for IAPs in the modulation of invasive and migratory properties of cells. Here, we present and discuss the mechanisms whereby IAPs can control cell migration.

  4. Migration and stratification

    PubMed Central

    Jasso, Guillermina

    2011-01-01

    Migration and stratification are increasingly intertwined. One day soon it will be impossible to understand one without the other. Both focus on life chances. Stratification is about differential life chances - who gets what and why - and migration is about improving life chances - getting more of the good things of life. To examine the interconnections of migration and stratification, we address a mix of old and new questions, carrying out analyses newly enabled by a unique new data set on recent legal immigrants to the United States (the New Immigrant Survey). We look at immigrant processing and lost documents, depression due to the visa process, presentation of self, the race-ethnic composition of an immigrant cohort (made possible by the data for the first time since 1961), black immigration from Africa and the Americas, skin-color diversity among couples formed by U.S. citizen sponsors and immigrant spouses, and English fluency among children age 8–12 and their immigrant parents. We find, inter alia, that children of previously illegal parents are especially more likely to be fluent in English, that native-born U.S. citizen women tend to marry darker, that immigrant applicants who go through the visa process while already in the United States are more likely to have their documents lost and to suffer visa depression, and that immigration, by introducing accomplished black immigrants from Africa (notably via the visa lottery), threatens to overturn racial and skin color associations with skill. Our analyses show the mutual embeddedness of migration and stratification in the unfolding of the immigrants' and their children's life chances and the impacts on the stratification structure of the United States. PMID:26321771

  5. Pathologic tooth migration.

    PubMed

    Brunsvold, Michael A

    2005-06-01

    Pathologic tooth migration (PTM) is a common complication of moderate to severe periodontitis and is often the motivation for patients to seek periodontal therapy. In this review of the literature, available information concerning prevalence, etiology, treatment, and prevention of pathologic tooth migration is summarized. Prevalence of PTM among periodontal patients has been reported to range from 30.03% to 55.8%. A survey of the literature regarding chief complaints of periodontal patients support these high prevalence findings. The etiology of PTM appears to be multifactorial. Periodontal bone loss appears to be a major factor in the etiology of PTM. Many aspects of occlusion can contribute to abnormal migration of teeth, and more than one of those factors may be present in an individual patient. Soft tissue forces of the tongue, cheeks, and lips are known to cause tooth movement and in some situations can cause PTM. Also considered important in the etiology of PTM is pressure produced from inflammatory tissues within periodontal pockets. Because extrusion is a common form of PTM, clinical observations support the theory that eruption forces sometimes play a role in the etiology of PTM. Many oral habits have been associated with PTM which are often difficult for the therapist to detect. Most cases of severe PTM require a team approach to achieve success. Periodontal, orthodontic, and prosthodontic treatment are often required. Many patient variables enter into the selection of treatment for PTM. In early stages of PTM, spontaneous correction of migrated teeth sometimes occurs after periodontal therapy. Light intrusive forces are used successfully to treat extrusion and flaring forms of PTM. Based on the literature reviewed, it appears that many cases of PTM could be prevented through the early diagnosis and treatment of periodontal disease, occlusal contributing factors, gingival enlargement, and oral habits. PMID:15948679

  6. Gender and Migration from Albania

    PubMed Central

    STECKLOV, GUY; CARLETTO, CALOGERO; AZZARRI, CARLO; DAVIS, BENJAMIN

    2010-01-01

    This article examines the dynamics and causes of the shift in the gender composition of migration, and more particularly, in women’s access to migration opportunities and decision-making. Our analysis focuses on Albania, a natural laboratory for studying international migration where out-migration was essentially nonexistent from the end of World War II to the end of the 1980s. Interest in the Albanian case is heightened because of the complex layers of inequality existing at the time when migration began: relatively low levels of inequality within the labor market and educational system—a product of the Communist era—while household relations remained heavily steeped in tradition and patriarchy. We use micro-level data from the Albania 2005 Living Standards Measurement Study, including migration histories for family members since migration began. Based on discrete-time hazard models, the analysis shows a dramatic increase in male migration and a gradual and uneven expansion of the female proportion of this international migration. Female migration, which is shown to be strongly associated with education, wealth, and social capital, appears responsive to economic incentives and constraints. Using information on the dependency of female migration to the household demographic structure as well as the sensitivity of female migration to household-level shocks, we show how household-level constraints and incentives affect male and female migration differently. Throughout this period, however, women’s migration behavior appears more directly aligned with household-level factors, and there is little evidence to suggest that increased female migration signals rising behavioral independence among Albanian women. PMID:21308565

  7. Conservation physiology of animal migration.

    PubMed

    Lennox, Robert J; Chapman, Jacqueline M; Souliere, Christopher M; Tudorache, Christian; Wikelski, Martin; Metcalfe, Julian D; Cooke, Steven J

    2016-01-01

    Migration is a widespread phenomenon among many taxa. This complex behaviour enables animals to exploit many temporally productive and spatially discrete habitats to accrue various fitness benefits (e.g. growth, reproduction, predator avoidance). Human activities and global environmental change represent potential threats to migrating animals (from individuals to species), and research is underway to understand mechanisms that control migration and how migration responds to modern challenges. Focusing on behavioural and physiological aspects of migration can help to provide better understanding, management and conservation of migratory populations. Here, we highlight different physiological, behavioural and biomechanical aspects of animal migration that will help us to understand how migratory animals interact with current and future anthropogenic threats. We are in the early stages of a changing planet, and our understanding of how physiology is linked to the persistence of migratory animals is still developing; therefore, we regard the following questions as being central to the conservation physiology of animal migrations. Will climate change influence the energetic costs of migration? Will shifting temperatures change the annual clocks of migrating animals? Will anthropogenic influences have an effect on orientation during migration? Will increased anthropogenic alteration of migration stopover sites/migration corridors affect the stress physiology of migrating animals? Can physiological knowledge be used to identify strategies for facilitating the movement of animals? Our synthesis reveals that given the inherent challenges of migration, additional stressors derived from altered environments (e.g. climate change, physical habitat alteration, light pollution) or interaction with human infrastructure (e.g. wind or hydrokinetic turbines, dams) or activities (e.g. fisheries) could lead to long-term changes to migratory phenotypes. However, uncertainty remains

  8. Conservation physiology of animal migration

    PubMed Central

    Lennox, Robert J.; Chapman, Jacqueline M.; Souliere, Christopher M.; Tudorache, Christian; Wikelski, Martin; Metcalfe, Julian D.; Cooke, Steven J.

    2016-01-01

    Migration is a widespread phenomenon among many taxa. This complex behaviour enables animals to exploit many temporally productive and spatially discrete habitats to accrue various fitness benefits (e.g. growth, reproduction, predator avoidance). Human activities and global environmental change represent potential threats to migrating animals (from individuals to species), and research is underway to understand mechanisms that control migration and how migration responds to modern challenges. Focusing on behavioural and physiological aspects of migration can help to provide better understanding, management and conservation of migratory populations. Here, we highlight different physiological, behavioural and biomechanical aspects of animal migration that will help us to understand how migratory animals interact with current and future anthropogenic threats. We are in the early stages of a changing planet, and our understanding of how physiology is linked to the persistence of migratory animals is still developing; therefore, we regard the following questions as being central to the conservation physiology of animal migrations. Will climate change influence the energetic costs of migration? Will shifting temperatures change the annual clocks of migrating animals? Will anthropogenic influences have an effect on orientation during migration? Will increased anthropogenic alteration of migration stopover sites/migration corridors affect the stress physiology of migrating animals? Can physiological knowledge be used to identify strategies for facilitating the movement of animals? Our synthesis reveals that given the inherent challenges of migration, additional stressors derived from altered environments (e.g. climate change, physical habitat alteration, light pollution) or interaction with human infrastructure (e.g. wind or hydrokinetic turbines, dams) or activities (e.g. fisheries) could lead to long-term changes to migratory phenotypes. However, uncertainty remains

  9. Conservation physiology of animal migration.

    PubMed

    Lennox, Robert J; Chapman, Jacqueline M; Souliere, Christopher M; Tudorache, Christian; Wikelski, Martin; Metcalfe, Julian D; Cooke, Steven J

    2016-01-01

    Migration is a widespread phenomenon among many taxa. This complex behaviour enables animals to exploit many temporally productive and spatially discrete habitats to accrue various fitness benefits (e.g. growth, reproduction, predator avoidance). Human activities and global environmental change represent potential threats to migrating animals (from individuals to species), and research is underway to understand mechanisms that control migration and how migration responds to modern challenges. Focusing on behavioural and physiological aspects of migration can help to provide better understanding, management and conservation of migratory populations. Here, we highlight different physiological, behavioural and biomechanical aspects of animal migration that will help us to understand how migratory animals interact with current and future anthropogenic threats. We are in the early stages of a changing planet, and our understanding of how physiology is linked to the persistence of migratory animals is still developing; therefore, we regard the following questions as being central to the conservation physiology of animal migrations. Will climate change influence the energetic costs of migration? Will shifting temperatures change the annual clocks of migrating animals? Will anthropogenic influences have an effect on orientation during migration? Will increased anthropogenic alteration of migration stopover sites/migration corridors affect the stress physiology of migrating animals? Can physiological knowledge be used to identify strategies for facilitating the movement of animals? Our synthesis reveals that given the inherent challenges of migration, additional stressors derived from altered environments (e.g. climate change, physical habitat alteration, light pollution) or interaction with human infrastructure (e.g. wind or hydrokinetic turbines, dams) or activities (e.g. fisheries) could lead to long-term changes to migratory phenotypes. However, uncertainty remains

  10. Gender and migration from Albania.

    PubMed

    Stecklov, Guy; Carletto, Calogero; Azzarri, Carlo; Davis, Benjamin

    2010-11-01

    This article examines the dynamics and causes of the shift in the gender composition of migration, and more particularly, in women's access to migration opportunities and decision-making. Our analysis focuses on Albania, a natural laboratory for studying international migration where out-migration was essentially nonexistent from the end of World War II to the end of the 1980s. Interest in the Albanian case is heightened because of the complex layers of inequality existing at the time when migration began: relatively low levels of inequality within the labor market and educational system-a product of the Communist era-while household relations remained heavily steeped in tradition and patriarchy. We use micro-level data from the Albania 2005 Living Standards Measurement Study, including migration histories for family members since migration began. Based on discrete-time hazard models, the analysis shows a dramatic increase in male migration and a gradual and uneven expansion of the female proportion of this international migration. Female migration, which is shown to be strongly associated with education, wealth, and social capital, appears responsive to economic incentives and constraints. Using information on the dependency of female migration to the household demographic structure as well as the sensitivity of female migration to household-level shocks, we show how household-level constraints and incentives affect male and female migration differently. Throughout this period, however, women's migration behavior appears more directly aligned with household-level factors, and there is little evidence to suggest that increased female migration signals rising behavioral independence among Albanian women.

  11. Hydrodynamics of pronuclear migration

    NASA Astrophysics Data System (ADS)

    Nazockdast, Ehssan; Needleman, Daniel; Shelley, Michael

    2014-11-01

    Microtubule (MT) filaments play a key role in many processes involved in cell devision including spindle formation, chromosome segregation, and pronuclear positioning. We present a direct numerical technique to simulate MT dynamics in such processes. Our method includes hydrodynamically mediated interactions between MTs and other cytoskeletal objects, using singularity methods for Stokes flow. Long-ranged many-body hydrodynamic interactions are computed using a highly efficient and scalable fast multipole method, enabling the simulation of thousands of MTs. Our simulation method also takes into account the flexibility of MTs using Euler-Bernoulli beam theory as well as their dynamic instability. Using this technique, we simulate pronuclear migration in single-celled Caenorhabditis elegans embryos. Two different positioning mechanisms, based on the interactions of MTs with the motor proteins and the cell cortex, are explored: cytoplasmic pulling and cortical pushing. We find that although the pronuclear complex migrates towards the center of the cell in both models, the generated cytoplasmic flows are fundamentally different. This suggest that cytoplasmic flow visualization during pronuclear migration can be utilized to differentiate between the two mechanisms.

  12. Laboratory investigation of DNAPL migration in porous media.

    PubMed

    Luciano, Antonella; Viotti, Paolo; Papini, Marco Petrangeli

    2010-04-15

    Laboratory experiments have been carried out with and without groundwater flow in a two-dimensional laboratory-scale tank to assess the influence of layered media and hydraulic gradient on DNAPL infiltration and redistribution processes. Hydrofluoroether has been used as DNAPL and glass beads have been utilized as porous medium. An image analysis procedure has been used to determine saturation distribution during infiltration and redistribution processes. This method allows quantitative time dependent full fields mapping of the DNAPL saturation, as well as the monitoring of DNAPL saturation variation. By means of performed experiments important information were obtained about the migration and redistribution process, the infiltration and migration velocity, the characteristics of migration body. The experimental results show that the hydraulic gradient promotes the infiltration process, increasing the infiltration rate. It hampers DNAPL spread and fingering bringing to a reduction of residual DNAPL and it also promotes the DNAPL redistribution, and it reduces the amount remaining at residual saturation. Furthermore the hydraulic gradient promotes downward and down-gradient migration. DNAPL migration in the direction of water flow, can be considered important due to significant errors in the location of sources in the case of high gradients and high aquifer thicknesses, and for high water flow velocities, such as those which can be expected during pumping actions in water supply or in remediation activities.

  13. Brine migration in salt in a thermal gradient

    NASA Astrophysics Data System (ADS)

    Kang, M.; Lerche, M.; Lesher, C. E.

    2015-12-01

    Salt deposits have long been considered viable repositories for long-term storage of high-level nuclear waste. However, brine trapped in salt tends to migrate up thermal gradients, such as can develop around radioactive waste storage containers, potentially promoting corrosion of containment structures. Brine inclusions move up the temperature gradient through the three main steps: 1) the dissolution of salt at the hot side of the inclusion caused by increased salt solubility, 2) ordinary and thermal diffusion of dissolved salt ions within the inclusion, and 3) precipitation of salt at the cold side of the inclusion due to local supersaturation. This process of brine transport through salt under a thermal gradient is generally referred to as thermal migration. Here we investigated thermal migration of brine inclusion in salts for a wide range of mean temperatures (~ 50 °C to ~200 °C) and temperature gradients (~ 10 °C/cm to ~57 °C/cm). With time brine inclusions moving towards the heat source become elongated parallel to the thermal gradient. We quantified the rate of brine migration as a function of mean temperature and thermal gradient using time-lapse optical microscope. X -ray and neutron tomography were used to visualize and quantify 3D spatial distribution of brine inclusion in a salt crystal at different stages of thermal migration. Migration velocities are shown to increase with temperature, temperature gradient and size of inclusion. We find an abrupt increase in migration velocity at certain time steps of thermal migration. Migration velocities of brine inclusions ranged from 0.1 m/year to 30.7 m/year. Empirical equations at different velocity regions for brine inclusions were obtained by fitting exponential equations to the experimental data with high coefficient of determination values (R2> 0.94).The experimental results are in good agreement with the theoretical migration rates obtained using a previous analytical model.

  14. Glutamate involvement in calcium–dependent migration of astrocytoma cells

    PubMed Central

    2014-01-01

    Background Astrocytoma are known to have altered glutamate machinery that results in the release of large amounts of glutamate into the extracellular space but the precise role of glutamate in favoring cancer processes has not yet been fully established. Several studies suggested that glutamate might provoke active killing of neurons thereby producing space for cancer cells to proliferate and migrate. Previously, we observed that calcium promotes disassembly of integrin-containing focal adhesions in astrocytoma, thus providing a link between calcium signaling and cell migration. The aim of this study was to determine how calcium signaling and glutamate transmission cooperate to promote enhanced astrocytoma migration. Methods The wound-healing model was used to assay migration of human U87MG astrocytoma cells and allowed to monitor calcium signaling during the migration process. The effect of glutamate on calcium signaling was evaluated together with the amount of glutamate released by astrocytoma during cell migration. Results We observed that glutamate stimulates motility in serum-starved cells, whereas in the presence of serum, inhibitors of glutamate receptors reduce migration. Migration speed was also reduced in presence of an intracellular calcium chelator. During migration, cells displayed spontaneous Ca2+ transients. L-THA, an inhibitor of glutamate re-uptake increased the frequency of Ca2+ oscillations in oscillating cells and induced Ca2+ oscillations in quiescent cells. The frequency of migration-associated Ca2+ oscillations was reduced by prior incubation with glutamate receptor antagonists or with an anti-β1 integrin antibody. Application of glutamate induced increases in internal free Ca2+ concentration ([Ca2+]i). Finally we found that compounds known to increase [Ca2+]i in astrocytomas such as thapsigagin, ionomycin or the metabotropic glutamate receptor agonist t-ACPD, are able to induce glutamate release. Conclusion Our data demonstrate that

  15. Levels of fecal corticosterone in sandhill cranes during a human-led migration

    USGS Publications Warehouse

    Hartup, B.K.; Olsen, G.H.; Czekala, N.M.; Paul-Murphy, J.; Langenberg, J.A.

    2004-01-01

    Fourteen captive-reared greater sandhill cranes (Grus canadensis tabida) were conditioned to follow ultralight aircraft to promote migration between Wisconsin and Florida (U SA) after release. Fecal samples were collected throughout the training period in Wisconsin and during a 1,977-km human-led migration to Florida to determine fecal corticosterone (FC) concentrations by radioimmunoassay. The mean (?SE) FC concentration during the training period was 1O9.5?7.5 ng/g and was representative of baseline levels recorded previously from sandhill cranes. Fecal corticosterone concentrations increased in early migration compared to concentrations 1 mo prior to departure (P<0.01) but were not different from baseline concentrations at the end of the 6-wk migration period. The variability of FC concentrations in individual samples was greater throughout the migration than the training period. Increases in FC during migration were modest and generally consistent with normal corticosterone elevations observed in migrating birds.

  16. Population, desertification, and migration.

    PubMed

    Westing, A H

    1994-01-01

    When an imbalance develops between population numbers and the carrying capacity of the land, the persons thereby displaced are referred to as environmental refugees. The utilization of the land beyond sustainability leads to land degradation and ultimately, desertification. The social and political impacts of long-term environmental migration can be distinguished: a) at the site of origin of the displaced persons by the residual population; b) at rural sites of destination within the nation between the new arrivals and preestablished populations; c) in the cities within the nation; d) in the nonindustrialized foreign countries; and e) in the industrialized foreign countries. In the event that an area which had previously been devoted to pastoralism is converted to agriculture, the displaced pastoralists might respond through armed rebellion. In some instances, the disenchanted urban squatters become a politically restive and even a destabilizing force, as occurred in Sudan in the 1980s, especially in Khartoum and Port Sudan. The foreign countries to which many of the displaced persons are migrating are subjected to increasing levels of migrant-induced economic, cultural, and political strains. The growing problems associated with south-to-north migration across the Mediterranean Sea have recently led France, Italy, Portugal, and Spain to enter into a consultative arrangement with Algeria, Libya, Mauritania, Morocco, and Tunisia. All foreign aid to the nonindustrialized countries that attempts to ameliorate the problem of desertification must adopt integrated approaches that: a) address population issues; b) support environmental education; c) provide for the protection of biodiversity; d) encourage participatory forms of local and national government; e) provide opportunities for income generation outside the livestock sector; and f) foster political security and facilitate ecogeographical (subregional) cooperation.

  17. Physical view on migration modes

    PubMed Central

    Mierke, Claudia Tanja

    2015-01-01

    Cellular motility is essential for many processes such as embryonic development, wound healing processes, tissue assembly and regeneration, immune cell trafficing and diseases such as cancer. The migration efficiency and the migratory potential depend on the type of migration mode. The previously established migration modes such as epithelial (non-migratory) and mesenchymal (migratory) as well as amoeboid (squeezing motility) relay mainly on phenomenological criteria such as cell morphology and molecular biological criteria such as gene expression. However, the physical view on the migration modes is still not well understood. As the process of malignant cancer progression such as metastasis depends on the migration of single cancer cells and their migration mode, this review focuses on the different migration strategies and discusses which mechanical prerequisites are necessary to perform a special migration mode through a 3-dimensional microenvironment. In particular, this review discusses how cells can distinguish and finally switch between the migration modes and what impact do the physical properties of cells and their microenvironment have on the transition between the novel migration modes such as blebbing and protrusive motility. PMID:26192136

  18. Migration of Asteroidal Dust

    NASA Technical Reports Server (NTRS)

    Ipatov, S. I.; Mather, J. C.

    2003-01-01

    Using the Bulirsh Stoer method of integration, we investigated the migration of dust particles under the gravitational influence of all planets, radiation pressure, Poynting Robertson drag and solar wind drag for equal to 0.01, 0.05, 0.1, 0.25, and 0.4. For silicate particles such values of correspond to diameters equal to about 40, 9, 4, 2, and 1 microns, respectively [1]. The relative error per integration step was taken to be less than 10sup-8. Initial orbits of the particles were close to the orbits of the first numbered mainbelt asteroids.

  19. Visualizing T Cell Migration in situ

    PubMed Central

    Benechet, Alexandre P.; Menon, Manisha; Khanna, Kamal M.

    2014-01-01

    Mounting a protective immune response is critically dependent on the orchestrated movement of cells within lymphoid tissues. The structure of secondary lymphoid organs regulates immune responses by promoting optimal cell–cell and cell–extracellular matrix interactions. Naïve T cells are initially activated by antigen presenting cells in secondary lymphoid organs. Following priming, effector T cells migrate to the site of infection to exert their functions. Majority of the effector cells die while a small population of antigen-specific T cells persists as memory cells in distinct anatomical locations. The persistence and location of memory cells in lymphoid and non-lymphoid tissues is critical to protect the host from re-infection. The localization of memory T cells is carefully regulated by several factors including the highly organized secondary lymphoid structure, the cellular expression of chemokine receptors and compartmentalized secretion of their cognate ligands. This balance between the anatomy and the ordered expression of cell surface and soluble proteins regulates the subtle choreography of T cell migration. In recent years, our understanding of cellular dynamics of T cells has been advanced by the development of new imaging techniques allowing in situ visualization of T cell responses. Here, we review the past and more recent studies that have utilized sophisticated imaging technologies to investigate the migration dynamics of naïve, effector, and memory T cells. PMID:25120547

  20. Determinants of partial bird migration in the Amazon Basin.

    PubMed

    Jahn, Alex E; Levey, Douglas J; Hostetler, Jeffrey A; Mamani, Ana María

    2010-09-01

    1. Little is known about mechanisms that drive migration of birds at tropical latitudes. Because most migratory bird species in South America have populations that are present year-round, partial migration (in which only some individuals of a given population migrate at the end of the breeding season) is likely to be common, providing an opportunity to assess proximate mechanisms of migration. 2. Two non-mutually exclusive hypotheses explaining intraspecific variation in migratory behaviour were tested in a Tropical Kingbird Tyrannus melancholicus population in the southern Amazon Basin, where a dramatic dry season decrease in the abundance of insect food for kingbirds may promote migration of some individuals. 3. The Dominance hypothesis predicts sub-dominant individuals migrate at the end of the breeding season and dominant individuals do not, whereas the Body Size hypothesis predicts smaller individuals migrate and larger individuals do not. 4. Based on 4 years of data on individually-marked birds, strong support was found for occurrence of partial migration in the study population. 5. In the best model, the largest males (which are typically older and dominant to younger individuals) had the highest probability of migrating. Younger females (which are the smallest individuals in the population) were also more likely to migrate than other kingbirds, except the largest males. Thus, an individual's probability of migrating was associated with a more complex interaction of size, age and sex than predicted by current hypotheses. 6. These results suggest that determinants of migratory behaviour differ between North temperate and tropical latitudes. Most tests of partial migration theory have been conducted on granivores (e.g. emberizids) or omnivores (e.g. turdids and icterids) at North temperate latitudes, where seasonality is primarily defined by temperature cycles. In tropical South America, however, the most common long-distance migrants are primarily

  1. Determinants of partial bird migration in the Amazon Basin.

    PubMed

    Jahn, Alex E; Levey, Douglas J; Hostetler, Jeffrey A; Mamani, Ana María

    2010-09-01

    1. Little is known about mechanisms that drive migration of birds at tropical latitudes. Because most migratory bird species in South America have populations that are present year-round, partial migration (in which only some individuals of a given population migrate at the end of the breeding season) is likely to be common, providing an opportunity to assess proximate mechanisms of migration. 2. Two non-mutually exclusive hypotheses explaining intraspecific variation in migratory behaviour were tested in a Tropical Kingbird Tyrannus melancholicus population in the southern Amazon Basin, where a dramatic dry season decrease in the abundance of insect food for kingbirds may promote migration of some individuals. 3. The Dominance hypothesis predicts sub-dominant individuals migrate at the end of the breeding season and dominant individuals do not, whereas the Body Size hypothesis predicts smaller individuals migrate and larger individuals do not. 4. Based on 4 years of data on individually-marked birds, strong support was found for occurrence of partial migration in the study population. 5. In the best model, the largest males (which are typically older and dominant to younger individuals) had the highest probability of migrating. Younger females (which are the smallest individuals in the population) were also more likely to migrate than other kingbirds, except the largest males. Thus, an individual's probability of migrating was associated with a more complex interaction of size, age and sex than predicted by current hypotheses. 6. These results suggest that determinants of migratory behaviour differ between North temperate and tropical latitudes. Most tests of partial migration theory have been conducted on granivores (e.g. emberizids) or omnivores (e.g. turdids and icterids) at North temperate latitudes, where seasonality is primarily defined by temperature cycles. In tropical South America, however, the most common long-distance migrants are primarily

  2. Process migration in UNIX environments

    NASA Technical Reports Server (NTRS)

    Lu, Chin; Liu, J. W. S.

    1988-01-01

    To support process migration in UNIX environments, the main problem is how to encapsulate the location dependent features of the system in such a way that a host independent virtual environment is maintained by the migration handlers on the behalf of each migrated process. An object-oriented approach is used to describe the interaction between a process and its environment. More specifically, environmental objects were introduced in UNIX systems to carry out the user-environment interaction. The implementation of the migration handlers is based on both the state consistency criterion and the property consistency criterion.

  3. Women and migration: a public health issue.

    PubMed

    Carballo, M; Grocutt, M; Hadzihasanovic, A

    1996-01-01

    The need to migrate is usually a function of the complex interaction of economic, social, familial and political factors. Among the most important, however, are the denial of access to education, employment, goods and services and the lack of respect for basic human rights. Because in many societies women are marginalized from these rights, migration to more economically and educationally open societies can often help improve their personal situation and their professional opportunities. On the other hand, because the status of women is usually linked to their role and status within the family and is defined in relationship to their male partners, migration can place women in situations where they experience stress and anxiety due to the loss of their traditional social entourage and environment. Their social integration in new settings may be equally limited by their initial lack of education and occupational experience. The higher vulnerability of women to sexual abuse and violence also places them at risk of STDs, including HIV, and a range of post-traumatic stress disorders associated with sexual violence. Their reproductive health needs often go unnoticed and unprotected even in well organized refugee and migrant situations, and the insensitivity of health staff to the needs of women is often more pronounced in refugee and migrant contexts than it is in general. Health monitoring of women in all migration-related situations has to be given greater priority. Similarly, much more attention at a health policy level is called for if the rights of women refugees and migrants are to be protected, and their contribution to health and social development is to be acknowledged and promoted.

  4. Women and migration: a public health issue.

    PubMed

    Carballo, M; Grocutt, M; Hadzihasanovic, A

    1996-01-01

    The need to migrate is usually a function of the complex interaction of economic, social, familial and political factors. Among the most important, however, are the denial of access to education, employment, goods and services and the lack of respect for basic human rights. Because in many societies women are marginalized from these rights, migration to more economically and educationally open societies can often help improve their personal situation and their professional opportunities. On the other hand, because the status of women is usually linked to their role and status within the family and is defined in relationship to their male partners, migration can place women in situations where they experience stress and anxiety due to the loss of their traditional social entourage and environment. Their social integration in new settings may be equally limited by their initial lack of education and occupational experience. The higher vulnerability of women to sexual abuse and violence also places them at risk of STDs, including HIV, and a range of post-traumatic stress disorders associated with sexual violence. Their reproductive health needs often go unnoticed and unprotected even in well organized refugee and migrant situations, and the insensitivity of health staff to the needs of women is often more pronounced in refugee and migrant contexts than it is in general. Health monitoring of women in all migration-related situations has to be given greater priority. Similarly, much more attention at a health policy level is called for if the rights of women refugees and migrants are to be protected, and their contribution to health and social development is to be acknowledged and promoted. PMID:9050196

  5. Nonlinear permanent migration response to climatic variations but minimal response to disasters

    PubMed Central

    Bohra-Mishra, Pratikshya; Oppenheimer, Michael; Hsiang, Solomon M.

    2014-01-01

    We present a microlevel study to simultaneously investigate the effects of variations in temperature and precipitation along with sudden natural disasters to infer their relative influence on migration that is likely permanent. The study is made possible by the availability of household panel data from Indonesia with an exceptional tracking rate combined with frequent occurrence of natural disasters and significant climatic variations, thus providing a quasi-experiment to examine the influence of environment on migration. Using data on 7,185 households followed over 15 y, we analyze whole-household, province-to-province migration, which allows us to understand the effects of environmental factors on permanent moves that may differ from temporary migration. The results suggest that permanent migration is influenced by climatic variations, whereas episodic disasters tend to have much smaller or no impact on such migration. In particular, temperature has a nonlinear effect on migration such that above 25 °C, a rise in temperature is related to an increase in outmigration, potentially through its impact on economic conditions. We use these results to estimate the impact of projected temperature increases on future permanent migration. Though precipitation also has a similar nonlinear effect on migration, the effect is smaller than that of temperature, underscoring the importance of using an expanded set of climatic factors as predictors of migration. These findings on the minimal influence of natural disasters and precipitation on permanent moves supplement previous findings on the significant role of these variables in promoting temporary migration. PMID:24958887

  6. Nonlinear permanent migration response to climatic variations but minimal response to disasters.

    PubMed

    Bohra-Mishra, Pratikshya; Oppenheimer, Michael; Hsiang, Solomon M

    2014-07-01

    We present a microlevel study to simultaneously investigate the effects of variations in temperature and precipitation along with sudden natural disasters to infer their relative influence on migration that is likely permanent. The study is made possible by the availability of household panel data from Indonesia with an exceptional tracking rate combined with frequent occurrence of natural disasters and significant climatic variations, thus providing a quasi-experiment to examine the influence of environment on migration. Using data on 7,185 households followed over 15 y, we analyze whole-household, province-to-province migration, which allows us to understand the effects of environmental factors on permanent moves that may differ from temporary migration. The results suggest that permanent migration is influenced by climatic variations, whereas episodic disasters tend to have much smaller or no impact on such migration. In particular, temperature has a nonlinear effect on migration such that above 25 °C, a rise in temperature is related to an increase in outmigration, potentially through its impact on economic conditions. We use these results to estimate the impact of projected temperature increases on future permanent migration. Though precipitation also has a similar nonlinear effect on migration, the effect is smaller than that of temperature, underscoring the importance of using an expanded set of climatic factors as predictors of migration. These findings on the minimal influence of natural disasters and precipitation on permanent moves supplement previous findings on the significant role of these variables in promoting temporary migration. PMID:24958887

  7. Kirchhoff migration without phases

    NASA Astrophysics Data System (ADS)

    Bardsley, Patrick; Guevara Vasquez, Fernando

    2016-10-01

    We present a simple, frequency domain, preprocessing step to Kirchhoff migration that allows the method to image scatterers when the wave field phase information is lost at the receivers, and only intensities are measured. The resulting imaging method does not require knowing the phases of the probing field or manipulating the phase of the wave field at the receivers. In a regime where the scattered field is small compared to the probing field, the problem of recovering the full-waveform scattered field from intensity data can be formulated as an embarrassingly simple least-squares problem. Although this only recovers the projection (on a known subspace) of the full-waveform scattered field, we show that, for high frequencies, this projection gives Kirchhoff images asymptotically identical to the images obtained with full waveform data. Our method can also be used when the source is modulated by a Gaussian process and autocorrelations are measured at an array of receivers.

  8. Chandra Contaminant Migration Model

    NASA Technical Reports Server (NTRS)

    Swartz, Douglas A.; O'Dell, Steve L.

    2014-01-01

    High volatility cleans OBFs and low volatility produces a high build-up at OBF centers; only a narrow (factor of 2 or less) volatility range produces the observed spatial pattern. Simulations predict less accumulation above outer S-array CCDs; this may explain, in part, gratings/imaging C/MnL discrepancies. Simulations produce a change in center accumulation due solely to DH heater ON/OFF temperature change; but a 2nd contaminant and perhaps a change in source rate is also required. Emissivity E may depend on thickness; another model parameter. Additional physics, e.g., surface migration, is not warranted at this time. At t approx. 14 yrs, model produced 0.22 grams of contaminant, 0.085 grams remaining within ACIS cavity; 7 percent (6mg) on OBFs.

  9. Migration and women's health.

    PubMed

    Adanu, Richard M K; Johnson, Timothy R B

    2009-08-01

    Women have been migrating at similar rates to men for the past 40 years, and comprised about half of all migrants in 2005. Women and children are most affected by displacement as a result of wars and human trafficking. In some cases, the health of female migrants is improved via integration into better health systems in the host country. More often, however, the health of female migrants is affected negatively. Women are doubly disadvantaged because they are discriminated against as women and as migrants. Female migrants are also highly vulnerable to acts of sexual abuse, rape, and violence. This is especially true for women in refugee camps, whose reproductive health needs are often overlooked. To improve the health of female migrants it is important to develop and implement policies that recognize and insist on the respect of the rights of migrants. PMID:19539929

  10. Matrikine and matricellular regulators of EGF receptor signaling on cancer cell migration and invasion.

    PubMed

    Grahovac, Jelena; Wells, Alan

    2014-01-01

    Cancer invasion is a complex process requiring, among other events, extensive remodeling of the extracellular matrix including deposition of pro-migratory and pro-proliferative moieties. In recent years, it has been described that while invading through matrices cancer cells can change shape and adapt their migration strategies depending on the microenvironmental context. Although intracellular signaling pathways governing the mesenchymal to amoeboid migration shift and vice versa have been mostly elucidated, the extracellular signals promoting these shifts are largely unknown. In this review, we summarize findings that point to matrikines that bind specifically to the EGF receptor as matricellular molecules that enable cancer cell migrational plasticity and promote invasion.

  11. India: 'brain drain' or the migration of talent?

    PubMed

    Oommen, T K

    1989-09-01

    2 views on "brain drain" exist: 1) LDCs lose their enormous investments on higher education when skilled people migrate to other countries and 2) LDCs are exaggerating the problem and only a few skilled people migrate at 1 time. India does not completely lose its investment in education when professionals migrate, since the migrants still contribute to knowledge and also send remittances to relatives in India. Unemployed educated people would cause a greater drain on India's resources than educated migrants. The author prefers the phrase migration of talent to brain drain, since the former indicates a 2-way movement. Most migrants from LDCs are students. About 11,000 university graduates leave India every year for advanced study and/or work. A conservative estimate is that 2500 will remain abroad permanently. Most professionals who migrate go to the US and Canada. Factors promoting migration include 1) unemployment, 2) immigration rules, 3) colonial links, 4) financial incentives and material benefits, 5) pursuit of higher education, 6) improvement of working conditions and facilities, 7) avoidance of excessive bureaucratic procedures, and 8) compensation for the mismatch between Indian education and employment. Reasons for returning to India include 1) deference to wives who were unable to adjust to a foreign way of life, 2) contributing to Indian development, and 3) racial discrimination. It will probably not be possible to lure back migrants who left for material reasons. Attractive job offers could entice back those who left for advanced training. To encourage the return of those who left to pursue high quality research, India must 1) increase expenditure on research and development, possibly through the private industrial sector, 2) promote travel to other countries for professional enrichment, and 3) improve conditions of research work. The article concludes with an analysis of migration of talent from 3 perspectives: 1) the individual, 2) the nation

  12. Evolution of cooperation driven by social-welfare-based migration

    NASA Astrophysics Data System (ADS)

    Li, Yan; Ye, Hang; Zhang, Hong

    2016-03-01

    Individuals' migration behavior may play a significant role in the evolution of cooperation. In reality, individuals' migration behavior may depend on their perceptions of social welfare. To study the relationship between social-welfare-based migration and the evolution of cooperation, we consider an evolutionary prisoner's dilemma game (PDG) in which an individual's migration depends on social welfare but not on the individual's own payoff. By introducing three important social welfare functions (SWFs) that are commonly studied in social science, we find that social-welfare-based migration can promote cooperation under a wide range of parameter values. In addition, these three SWFs have different effects on cooperation, especially through the different spatial patterns formed by migration. Because the relative efficiency of the three SWFs will change if the parameter values are changed, we cannot determine which SWF is optimal for supporting cooperation. We also show that memory capacity, which is needed to evaluate individual welfare, may affect cooperation levels in opposite directions under different SWFs. Our work should be helpful for understanding the evolution of human cooperation and bridging the chasm between studies of social preferences and studies of social cooperation.

  13. Factors influencing the migration of West African health professionals

    PubMed Central

    Lowe, Mat; Chen, Duan-Rung

    2016-01-01

    Introduction The West African health sector is characterized by a human resource base lacking in numbers and specialized skills. Among the contributory factors to this lack of human resource for health workforce include but not limited to the migration of health professionals. Methods This cross-sectional survey targeted 118 young professionals who have participated in the Young Professional Internship Program (YPIP) of the West African Health Organization (WAHO), from (2005-2013). It inquired about their socio-demographic characteristics associated with migration and reasons for going to their preferred or most likely destinations through online survey. Results Of the 118 young professionals, 100 responded to the online survey, of which (28%) have migrated and (72%) did not migrate. Migration was more common among males and those (age≤31 years old), single with high dependency level and no previous work experience. Having a medical profession and being posted to urban or semi-urban area was also associated with their emigration. Their most important reasons for going to preferred or most likely destinations were to have fair level of workload, job promotion and limited occupational risks. Conclusion This finding suggests that the migration of health professionals is situation dependent, mediated by basic socio-demographic variables and work related conditions. These issues have implications for curbing the brain drain potential of health professionals in the West African health sector. PMID:27800092

  14. Cohort Size Effects and Migration.

    ERIC Educational Resources Information Center

    Wilson, Franklin D.

    1983-01-01

    Explores whether changes in the size of cohorts entering the labor force affected the propensity within the U.S. labor force to migrate and socioeconomic circumstances of migrants at destination within 1965-76. Suggests that a significant reduction in the volume of migration among members of the baby boom cohort was the primary adjustment…

  15. Migration in asymmetric, random environments

    NASA Astrophysics Data System (ADS)

    Deem, Michael; Wang, Dong

    Migration is a key mechanism for expansion of communities. As a population migrates, it experiences a changing environment. In heterogeneous environments, rapid adaption is key to the evolutionary success of the population. In the case of human migration, environmental heterogeneity is naturally asymmetric in the North-South and East-West directions. We here consider migration in random, asymmetric, modularly correlated environments. Knowledge about the environment determines the fitness of each individual. We find that the speed of migration is proportional to the inverse of environmental change, and in particular we find that North-South migration rates are lower than East-West migration rates. Fast communication within the population of pieces of knowledge between individuals, similar to horizontal gene transfer in genetic systems, can help to spread beneficial knowledge among individuals. We show that increased modularity of the relation between knowledge and fitness enhances the rate of evolution. We investigate the relation between optimal information exchange rate and modularity of the dependence of fitness on knowledge. These results for the dependence of migration rate on heterogeneity, asymmetry, and modularity are consistent with existing archaeological facts.

  16. Africa: Setting for Human Migration

    ERIC Educational Resources Information Center

    Buuba, Babacar Diop

    2007-01-01

    Analysis of African migrations can help to understand prehistoric, historical, ancient modern and contemporaneous migrations. Movements of populations were and continue to be so intense that, for some analysts, they constitute one of the dominant trends of the history and destiny of the very old continent. African and non-African states, whether…

  17. Merlin's wizardry guides cohesive migration.

    PubMed

    Zoch, Ansgar; Morrison, Helen

    2015-03-01

    Cells often migrate in tightly connected groups with coordinated movement and polarity. The collective migration of epithelial cell sheets is now shown to be mediated by a signalling axis that involves the merlin tumour-suppressor protein, the tight-junction-associated angiomotin-Rich1 complex and the Rac1 small GTPase. PMID:25720961

  18. Vinculin is required for cell polarization, migration, and extracellular matrix remodeling in 3D collagen.

    PubMed

    Thievessen, Ingo; Fakhri, Nikta; Steinwachs, Julian; Kraus, Viola; McIsaac, R Scott; Gao, Liang; Chen, Bi-Chang; Baird, Michelle A; Davidson, Michael W; Betzig, Eric; Oldenbourg, Rudolf; Waterman, Clare M; Fabry, Ben

    2015-11-01

    Vinculin is filamentous (F)-actin-binding protein enriched in integrin-based adhesions to the extracellular matrix (ECM). Whereas studies in 2-dimensional (2D) tissue culture models have suggested that vinculin negatively regulates cell migration by promoting cytoskeleton-ECM coupling to strengthen and stabilize adhesions, its role in regulating cell migration in more physiologic, 3-dimensional (3D) environments is unclear. To address the role of vinculin in 3D cell migration, we analyzed the morphodynamics, migration, and ECM remodeling of primary murine embryonic fibroblasts (MEFs) with cre/loxP-mediated vinculin gene disruption in 3D collagen I cultures. We found that vinculin promoted 3D cell migration by increasing directional persistence. Vinculin was necessary for persistent cell protrusion, cell elongation, and stable cell orientation in 3D collagen, but was dispensable for lamellipodia formation, suggesting that vinculin-mediated cell adhesion to