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Sample records for arsenic promotes progressive

  1. Low level arsenic promotes progressive inflammatory angiogenesis and liver blood vessel remodeling in mice

    SciTech Connect

    Straub, Adam C.; Stolz, Donna B.; Vin, Harina; Ross, Mark A.; Soucy, Nicole V.; Klei, Linda R.; Barchowsky, Aaron

    2007-08-01

    The vascular effects of arsenic in drinking water are global health concerns contributing to human disease worldwide. Arsenic targets the endothelial cells lining blood vessels, and endothelial cell activation or dysfunction may underlie the pathogenesis of both arsenic-induced vascular diseases and arsenic-enhanced tumorigenesis. The purpose of the current studies was to demonstrate that exposing mice to drinking water containing environmentally relevant levels of arsenic promoted endothelial cell dysfunction and pathologic vascular remodeling. Increased angiogenesis, neovascularization, and inflammatory cell infiltration were observed in Matrigel plugs implanted in C57BL/6 mice following 5-week exposures to 5-500 ppb arsenic [Soucy, N.V., Mayka, D., Klei, L.R., Nemec, A.A., Bauer, J.A., Barchowsky, A., 2005. Neovascularization and angiogenic gene expression following chronic arsenic exposure in mice. Cardiovasc.Toxicol 5, 29-42]. Therefore, functional in vivo effects of arsenic on endothelial cell function and vessel remodeling in an endogenous vascular bed were investigated in the liver. Liver sinusoidal endothelial cells (LSEC) became progressively defenestrated and underwent capillarization to decrease vessel porosity following exposure to 250 ppb arsenic for 2 weeks. Sinusoidal expression of PECAM-1 and laminin-1 proteins, a hallmark of capillarization, was also increased by 2 weeks of exposure. LSEC caveolin-1 protein and caveolae expression were induced after 2 weeks of exposure indicating a compensatory change. Likewise, CD45/CD68-positive inflammatory cells did not accumulate in the livers until after LSEC porosity was decreased, indicating that inflammation is a consequence and not a cause of the arsenic-induced LSEC phenotype. The data demonstrate that the liver vasculature is an early target of pathogenic arsenic effects and that the mouse liver vasculature is a sensitive model for investigating vascular health effects of arsenic.

  2. Low level arsenic promotes progressive inflammatory angiogenesis and liver blood vessel remodeling in mice

    PubMed Central

    Straub, Adam C.; Stolz, Donna B.; Vin, Harina; Ross, Mark A.; Soucy, Nicole V.; Klei, Linda R.; Barchowsky, Aaron

    2006-01-01

    The vascular effects of arsenic in drinking water are global health concerns contributing to human disease worldwide. Arsenic targets the endothelial cells lining blood vessels and endothelial cell activation or dysfunction may underlie the pathogenesis of both arsenic-induced vascular diseases and arsenic-enhanced tumorigenesis. The purpose of the current studies was to demonstrate that exposing mice to drinking water containing environmentally relevant levels of arsenic promoted endothelial cell dysfunction and pathologic vascular remodeling. Increased angiogenesis, neovascularization, and inflammatory cell infiltration was observed in Matrigel plugs implanted in C57BL/6 mice following 5 week exposures to 5-500 ppb arsenic (Soucy et al., 2005). Therefore, functional in vivo effects of arsenic on endothelial cell function and vessel remodeling in an endogenous vascular bed were investigated in the liver. Liver sinusoidal endothelial cells (LSEC) became progressively defenestrated and underwent capillarization to decrease vessel porosity following exposure to 250 ppb arsenic for 2 weeks. Sinusoidal expression of PECAM-1 and laminin-1 proteins, a hallmark of capillarization, was also increased by 2 weeks of exposure. LSEC caveolin-1 protein and caveolae expression were induced after 2 weeks of exposure indicating a compensatory change. Likewise, CD45/CD68 positive inflammatory cells did not accumulate in the livers until after LSEC porosity was decreased; indicating that inflammation is a consequence and not a cause of the arsenic-induced LSEC phenotype. The data demonstrate that the liver vasculature is an early target of pathogenic arsenic effects and that the mouse liver vasculature is a sensitive model for investigating vascular health effects of arsenic. PMID:17123562

  3. Environmentally relevant concentration of arsenic trioxide and humic acid promoted tumor progression of human cervical cancer cells: In vivo and in vitro studies.

    PubMed

    Tsai, Min-Ling; Yen, Cheng-Chieh; Lu, Fung-Jou; Ting, Hung-Chih; Chang, Horng-Rong

    2016-09-01

    In a previous study, treatment at higher concentrations of arsenic trioxide or co-exposure to arsenic trioxide and humic acid was found to be inhibited cell growth of cervical cancer cells (SiHa cells) by reactive oxygen species generation. However, treatment at lower concentrations slightly increased cell viability. Here, we investigate the enhancement of progression effects of environmentally relevant concentration of humic acid and arsenic trioxide in SiHa cell lines in vitro and in vivo by measuring cell proliferation, migration, invasion, and the carcinogenesis-related protein (MMP-2, MMP-9, and VEGF-A) expressions. SiHa cells treated with low concentrations of humic acid and arsenic trioxide alone or in co-exposure significantly increased reactive oxygen species, glutathione levels, cell proliferation, scratch wound-healing activities, migration abilities, and MMP-2 expression as compared to the untreated control. In vivo the tumor volume of either single drug (humic acid or arsenic trioxide) or combined drug-treated group was significantly larger than that of the control for an additional 45 days after tumor cell injection on the back of NOD/SCID mice. Levels of MMP-2, MMP-9, and VEGF-A, also significantly increased compared to the control. Histopathologic effects of all tumor cells appeared round in cell shape with high mitosis, focal hyperkeratosis and epidermal hyperplasia in the skin, and some tumor growth in the muscle were observed. Our results may indicate that exposure to low concentrations of arsenic trioxide and humic acid is associated with the progression of cervical cancer. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1121-1132, 2016. © 2015 Wiley Periodicals, Inc.

  4. Differential Methylation of the Arsenic (III) Methyltransferase Promoter According to Arsenic Exposure

    PubMed Central

    Gribble, Matthew O.; Tang, Wan-yee; Shang, Yan; Pollak, Jonathan; Umans, Jason G.; Francesconi, Kevin A.; Goessler, Walter; Silbergeld, Ellen K.; Guallar, Eliseo; Cole, Shelley A.; Fallin, M. Daniele; Navas-Acien, Ana

    2013-01-01

    Inorganic arsenic is methylated in the body by arsenic (III) methyltransferase. Arsenic methylation is thought to play a role in arsenic-related epigenetic phenomena including aberrant DNA and histone methylation. However, it is unclear whether the promoter of the AS3MT gene, which codes for arsenic (III) methyltransferase, is differentially methylated as a function of arsenic exposure. In this study we evaluated AS3MT promoter methylation according to exposure, assessed by urinary arsenic excretion in a stratified random sample of 48 participants from the Strong Heart Study who had urine arsenic measured at baseline and DNA available from 1989–1991 and 1998–1999. For this study, all data are from the 1989–1991 visit. We measured AS3MT promoter methylation at its 48 CpG loci by bisulphite sequencing. We compared mean % methylation at each CpG locus by arsenic exposure group using linear regression adjusted for study centre, age and sex. A hypomethylated region in the AS3MT promoter was associated with higher arsenic exposure. In vitro, arsenic induced AS3MT promoter hypomethylation and it increased AS3MT expression in human peripheral blood mononuclear cells. These findings may suggest that arsenic exposure influences the epigenetic regulation of a major arsenic metabolism gene. PMID:24154821

  5. Arsenic | Cancer Trends Progress Report

    Cancer.gov

    The Cancer Trends Progress Report, first issued in 2001, summarizes our nation's advances against cancer in relation to Healthy People targets set forth by the Department of Health and Human Services.

  6. Arsenic

    MedlinePlus

    ... and minerals. Arsenic compounds are used to preserve wood, as pesticides, and in some industries. Arsenic can ... Breathing sawdust or burning smoke from arsenic-treated wood Living in an area with high levels of ...

  7. Arsenic

    MedlinePlus

    ... lesions and skin cancer are the most characteristic effects. Drinking-water and food The greatest threat to public health from arsenic originates from contaminated groundwater. Inorganic arsenic ...

  8. Arsenic and human health: epidemiologic progress and public health implications.

    PubMed

    Argos, Maria; Ahsan, Habibul; Graziano, Joseph H

    2012-09-10

    Elevated concentrations of arsenic in groundwater pose a public health threat to millions of people worldwide, including severely affected populations in South and Southeast Asia. Although arsenic is an established human carcinogen and has been associated with a multitude of health outcomes in epidemiologic studies, a mode of action has yet to be determined for some aspects of arsenic toxicity. Herein, we emphasize the role of recent genetic and molecular epidemiologic investigations of arsenic toxicity. Additionally, we discuss considerations for the public health impacts of arsenic exposure through drinking water with respect to primary and secondary prevention efforts.

  9. Arsenic Biotransformation as a Cancer Promoting Factor by Inducing DNA Damage and Disruption of Repair Mechanisms

    PubMed Central

    Martinez, Victor D.; Vucic, Emily A.; Adonis, Marta; Gil, Lionel; Lam, Wan L.

    2011-01-01

    Chronic exposure to arsenic in drinking water poses a major global health concern. Populations exposed to high concentrations of arsenic-contaminated drinking water suffer serious health consequences, including alarming cancer incidence and death rates. Arsenic is biotransformed through sequential addition of methyl groups, acquired from s-adenosylmethionine (SAM). Metabolism of arsenic generates a variety of genotoxic and cytotoxic species, damaging DNA directly and indirectly, through the generation of reactive oxidative species and induction of DNA adducts, strand breaks and cross links, and inhibition of the DNA repair process itself. Since SAM is the methyl group donor used by DNA methyltransferases to maintain normal epigenetic patterns in all human cells, arsenic is also postulated to affect maintenance of normal DNA methylation patterns, chromatin structure, and genomic stability. The biological processes underlying the cancer promoting factors of arsenic metabolism, related to DNA damage and repair, will be discussed here. PMID:22091411

  10. [Study progress of adverse effects of arsenic on health].

    PubMed

    Kang, Jiaqi; Jin, Yinlong

    2004-05-01

    Adverse effects on health of high arsenic in drinking water and contaminated environment are currently of great concern. This review focuses on metabolism of arsenic and it's impairments to skin, blood circle system, nervous system, reproductive-and-urinary system, digestive system, respiratory system and immune system.

  11. Arsenicals Produce Stable Progressive Changes in DNA Methylation Patterns that are Linked to Malignant Transformation of Immortalized Urothelial Cells

    PubMed Central

    Jensen, Taylor J.; Novak, Petr; Wnek, Shawn M.; Gandolfi, A. Jay; Futscher, Bernard W.

    2009-01-01

    Aberrant DNA methylation participates in carcinogenesis and is a molecular hallmark of a tumor cell. Tumor cells generally exhibit a redistribution of DNA methylation resulting in global hypomethylation with regional hypermethylation; however, the speed in which these changes emerge has not been fully elucidated and may depend on the temporal location of the cell in the path from normal, finite lifespan to malignant transformation. We used a model of arsenical-induced malignant transformation of immortalized human urothelial cells and DNA methylation microarrays to examine the extent and temporal nature of changes in DNA methylation that occur during the transition from immortal to malignantly transformed. Our data presented herein suggest that during arsenical-induced malignant transformation, aberrant DNA methylation occurs non-randomly, progresses gradually at hundreds of gene promoters, alters expression of the associated gene, and these changes are coincident with the acquisition of malignant properties, such as anchorage independent growth and tumor formation in immunocompromised mice. The DNA methylation changes appear stable, since malignantly transformed cells removed from the transforming arsenical exhibited no reversion in DNA methylation levels, associated gene expression, or malignant phenotype. These data suggest that arsenicals act as epimutagens and directly link their ability to induce malignant transformation to their actions on the epigenome. PMID:19716837

  12. Arsenicals produce stable progressive changes in DNA methylation patterns that are linked to malignant transformation of immortalized urothelial cells

    SciTech Connect

    Jensen, Taylor J.; Novak, Petr; Wnek, Shawn M.; Gandolfi, A. Jay; Futscher, Bernard W.

    2009-12-01

    Aberrant DNA methylation participates in carcinogenesis and is a molecular hallmark of a tumor cell. Tumor cells generally exhibit a redistribution of DNA methylation resulting in global hypomethylation with regional hypermethylation; however, the speed in which these changes emerge has not been fully elucidated and may depend on the temporal location of the cell in the path from normal, finite lifespan to malignant transformation. We used a model of arsenical-induced malignant transformation of immortalized human urothelial cells and DNA methylation microarrays to examine the extent and temporal nature of changes in DNA methylation that occur during the transition from immortal to malignantly transformed. Our data presented herein suggest that during arsenical-induced malignant transformation, aberrant DNA methylation occurs non-randomly, progresses gradually at hundreds of gene promoters, and alters expression of the associated gene, and these changes are coincident with the acquisition of malignant properties, such as anchorage independent growth and tumor formation in immunocompromised mice. The DNA methylation changes appear stable, since malignantly transformed cells removed from the transforming arsenical exhibited no reversion in DNA methylation levels, associated gene expression, or malignant phenotype. These data suggest that arsenicals act as epimutagens and directly link their ability to induce malignant transformation to their actions on the epigenome.

  13. Arsenic

    MedlinePlus

    ... As a preservative in pressure-treated lumber In pesticides As a preservative in animal hides As an ... dust. Arsenic was a common ingredient in many pesticides and herbicides in the past. People who made, ...

  14. Arsenic induces structural and compositional colonic microbiome change and promotes host nitrogen and amino acid metabolism.

    PubMed

    Dheer, Rishu; Patterson, Jena; Dudash, Mark; Stachler, Elyse N; Bibby, Kyle J; Stolz, Donna B; Shiva, Sruti; Wang, Zeneng; Hazen, Stanley L; Barchowsky, Aaron; Stolz, John F

    2015-12-15

    Chronic exposure to arsenic in drinking water causes cancer and non-cancer diseases. However, mechanisms for chronic arsenic-induced pathogenesis, especially in response to lower exposure levels, are unclear. In addition, the importance of health impacts from xeniobiotic-promoted microbiome changes is just being realized and effects of arsenic on the microbiome with relation to disease promotion are unknown. To investigate impact of arsenic exposure on both microbiome and host metabolism, the stucture and composition of colonic microbiota, their metabolic phenotype, and host tissue and plasma metabolite levels were compared in mice exposed for 2, 5, or 10weeks to 0, 10 (low) or 250 (high) ppb arsenite (As(III)). Genotyping of colonic bacteria revealed time and arsenic concentration dependent shifts in community composition, particularly the Bacteroidetes and Firmicutes, relative to those seen in the time-matched controls. Arsenic-induced erosion of bacterial biofilms adjacent to the mucosal lining and changes in the diversity and abundance of morphologically distinct species indicated changes in microbial community structure. Bacterical spores increased in abundance and intracellular inclusions decreased with high dose arsenic. Interestingly, expression of arsenate reductase (arsA) and the As(III) exporter arsB, remained unchanged, while the dissimilatory nitrite reductase (nrfA) gene expression increased. In keeping with the change in nitrogen metabolism, colonic and liver nitrite and nitrate levels and ratios changed with time. In addition, there was a concomitant increase in pathogenic arginine metabolites in the mouse circulation. These data suggest that arsenic exposure impacts the microbiome and microbiome/host nitrogen metabolism to support disease enhancing pathogenic phenotypes.

  15. Arsenic induces structural and compositional colonic microbiome change and promotes host nitrogen and amino acid metabolism

    PubMed Central

    Dheer, Rishu; Patterson, Jena; Dudash, Mark; Stachler, Elyse N.; Bibby, Kyle J.; Stolz, Donna B.; Shiva, Sruti; Wang, Zeneng; Hazen, Stanley L.; Barchowsky, Aaron; Stolz, John F.

    2015-01-01

    Chronic exposure to arsenic in drinking water causes cancer and non-cancer diseases. However, mechanisms for chronic arsenic-induced pathogeneis, especially in response to lower exposure levels, are unclear. In addition, the importance of health impacts from xeniobiotic-promoted microbiome changes is just being realized and effects of arsenic on the microbiome with relation to disease promotion are unknown. To investigate impact of arsenic exposure on both microbiome and host metabolism, the stucture and composition of colonic microbiota, their metabolic phenotype, and host tissue and plasma metabolite levels were compared in mice exposed for 2, 5, or 10 weeks to 0, 10 (low) or 250 (high) ppb arsenite (As(III)). Genotyping of colonic bacteria revealed time and arsenic concentration dependent shifts in community composition, particularly the Bacteroidetes and Firmicutes, relative to those seen in the time-matched controls. Arsenic-induced erosion of bacterial biofilms adjacent to the mucosal lining and changes in the diversity and abundance of morphologically distinct species indicated changes in microbial community structure. Bacterical spores increased in abundance and intracellular inclusions decreased with high dose arsenic. Interestingly, expression of arsenate reductase (arsA) and the As(III) exporter arsB, remained unchanged, while the dissimilatory nitrite reductase (nrfA) gene expression increased. In keeping with the change in nitrogen metabolism, colonic and liver nitrite and nitrate levels and ratios changed with time. In addition, there was a concomitant increase in pathogenic arginine metabolites in the mouse circulation. These data suggest that arsenic exposure impacts the microbiome and microbiome/host nitrogen metabolism to support disease enhancing pathogenic phenotypes. PMID:26529668

  16. Arsenic Inhibits DNA Mismatch Repair by Promoting EGFR Expression and PCNA Phosphorylation*

    PubMed Central

    Tong, Dan; Ortega, Janice; Kim, Christine; Huang, Jian; Gu, Liya; Li, Guo-Min

    2015-01-01

    Both genotoxic and non-genotoxic chemicals can act as carcinogens. However, while genotoxic compounds lead directly to mutations that promote unregulated cell growth, the mechanism by which non-genotoxic carcinogens lead to cellular transformation is poorly understood. Using a model non-genotoxic carcinogen, arsenic, we show here that exposure to arsenic inhibits mismatch repair (MMR) in human cells, possibly through its ability to stimulate epidermal growth factor receptor (EGFR)-dependent tyrosine phosphorylation of proliferating cellular nuclear antigen (PCNA). HeLa cells exposed to exogenous arsenic demonstrate a dose- and time-dependent increase in the levels of EGFR and tyrosine 211-phosphorylated PCNA. Cell extracts derived from arsenic-treated HeLa cells are defective in MMR, and unphosphorylated recombinant PCNA restores normal MMR activity to these extracts. These results suggest a model in which arsenic induces expression of EGFR, which in turn phosphorylates PCNA, and phosphorylated PCNA then inhibits MMR, leading to increased susceptibility to carcinogenesis. This study suggests a putative novel mechanism of action for arsenic and other non-genotoxic carcinogens. PMID:25907674

  17. Tert-butylhydroquinone as a phenolic activator of Nrf2 antagonizes arsenic-induced oxidative cytotoxicity but promotes arsenic methylation and detoxication in human hepatocyte cell line.

    PubMed

    Duan, Xiaoxu; Liu, Dan; Xing, Xiaoyue; Li, Jinlong; Zhao, Shuo; Nie, Huifang; Zhang, Yang; Sun, Guifan; Li, Bing

    2014-08-01

    Oxidative stress plays crucial roles in exerting a variety of damages upon arsenic exposure. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a master transcriptional regulator protecting cells and tissues from oxidative injuries. The objective of this study was to test whether tert-butylhydroquinone (tBHQ), a well-known synthetic Nrf2 inducer, could protect human hepatocytes against arsenic-induced cytotoxicity and oxidative injuries. Our results showed that 5 and 25 μmol/l tBHQ pretreatment suppressed the arsenic-induced hepatocellular cytotoxicity, reactive oxygen species generation, and hepatic lipid peroxidation, while relieved the arsenic-induced disturbances of intracellular glutathione balance. In addition, we also observed that tBHQ treatment promoted the arsenic biomethylation process and upregulated Nrf2-regulated downstream heme oxygenase-1 and NADPH: quinine oxidoreductase 1 mRNA expressions. Collectively, we suspected that Nrf2 signaling pathway may be involved in the protective effects of tBHQ against arsenic invasion in hepatocytes. These data suggest that phenolic Nrf2 inducers, such as tBHQ, represent novel therapeutic or dietary candidates for the population at high risk of arsenic poisoning.

  18. Stimulatory Effects of Arsenic-Tolerant Soil Fungi on Plant Growth Promotion and Soil Properties

    PubMed Central

    Srivastava, Pankaj Kumar; Shenoy, Belle Damodara; Gupta, Manjul; Vaish, Aradhana; Mannan, Shivee; Singh, Nandita; Tewari, Shri Krishna; Tripathi, Rudra Deo

    2012-01-01

    Fifteen fungi were obtained from arsenic-contaminated agricultural fields in West Bengal, India and examined for their arsenic tolerance and removal ability in our previous study. Of these, the four best arsenic-remediating isolates were tested for plant growth promotion effects on rice and pea in the present study. A greenhouse-based pot experiment was conducted using soil inocula of individual fungi. The results indicated a significant (P<0.05) increase in plant growth and improvement of soil properties in inoculated soils compared to the control. A significant increase in plant growth was recorded in treated soils and varied from 16–293%. Soil chemical and enzymatic properties varied from 20–222% and 34–760%, respectively, in inoculated soil. Plants inoculated with inocula of Westerdykella and Trichoderma showed better stimulatory effects on plant growth and soil nutrient availability than Rhizopus and Lasiodiplodia. These fungi improved soil nutrient content and enhanced plant growth. These fungi may be used as bioinoculants for plant growth promotion and improved soil properties in arsenic-contaminated agricultural soils. PMID:23047145

  19. A patient with progressive multiple myeloma treated successfully with arsenic trioxide after allogeneic bone marrow transplantation.

    PubMed

    Gesundheit, B; Shapira, M Y; Ackerstein, A; Resnik, I B; Bitan, M; Or, R

    2007-01-01

    Multiple myeloma (MM) is an incurable progressive disease. Many therapeutic options are available to delay progression, including autologous and allogeneic bone marrow transplantation. At advanced stages, MM is often refractory to treatment. We report a heavily pretreated patient with graft-versus-host disease after bone marrow transplantations, treated at a terminal stage with a modified protocol for arsenic trioxide (ATO). This patient with poor clinical status tolerated the treatment very well. He had a remarkable clinical response and achieved complete remission. The mechanisms of ATO are presented and the potential role of ATO for MM is discussed.

  20. Curcumin attenuates arsenic-induced hepatic injuries and oxidative stress in experimental mice through activation of Nrf2 pathway, promotion of arsenic methylation and urinary excretion.

    PubMed

    Gao, Shuang; Duan, Xiaoxu; Wang, Xin; Dong, Dandan; Liu, Dan; Li, Xin; Sun, Guifan; Li, Bing

    2013-09-01

    Oxidative stress is one of the major mechanisms implicated in inorganic arsenic poisoning. Curcumin is a natural phenolic compound with impressive antioxidant properties. What's more, curcumin is recently proved to exert its chemopreventive effects partly through the activation of nuclear factor (erythroid-2 related) factor 2 (Nrf2) and its antioxidant and phase II detoxifying enzymes. In vivo, we investigated the protective effects of curcumin against arsenic-induced hepatotoxicity and oxidative injuries. Our results showed that arsenic-induced elevation of serum alanine amino transferase (ALT) and aspartate aminotransferase (AST) activities, augmentation of hepatic malonaldehyde (MDA), as well as the reduction of blood and hepatic glutathione (GSH) levels, were all consistently relieved by curcumin. We also observed the involvement of curcumin in promoting arsenic methylation and urinary elimination in vivo. Furthermore, both the hepatic Nrf2 protein and two typically recognized Nrf2 downstream genes, NADP(H) quinine oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1), were consistently up-regulated in curcumin-treated mice. Our study confirmed the antagonistic roles of curcumin to counteract inorganic arsenic-induced hepatic toxicity in vivo, and suggested that the potent Nrf2 activation capability might be valuable for the protective effects of curcumin against arsenic intoxication. This provides a potential useful chemopreventive dietary component for human populations. Copyright © 2013 Elsevier Ltd. All rights reserved.

  1. Arsenic Promotes NF-Kb-Mediated Fibroblast Dysfunction and Matrix Remodeling to Impair Muscle Stem Cell Function

    PubMed Central

    Zhang, Changqing; Ferrari, Ricardo; Beezhold, Kevin; Stearns-Reider, Kristen; D’Amore, Antonio; Haschak, Martin; Stolz, Donna; Robbins, Paul D.; Barchowsky, Aaron; Ambrosio, Fabrisia

    2016-01-01

    Arsenic is a global health hazard that impacts over 140 million individuals worldwide. Epidemiological studies reveal prominent muscle dysfunction and mobility declines following arsenic exposure; yet, mechanisms underlying such declines are unknown. The objective of this study was to test the novel hypothesis that arsenic drives a maladaptive fibroblast phenotype to promote pathogenic myomatrix remodeling and compromise the muscle stem (satellite) cell (MuSC) niche. Mice were exposed to environmentally relevant levels of arsenic in drinking water before receiving a local muscle injury. Arsenic-exposed muscles displayed pathogenic matrix remodeling, defective myofiber regeneration and impaired functional recovery, relative to controls. When naïve human MuSCs were seeded onto three-dimensional decellularized muscle constructs derived from arsenic-exposed muscles, cells displayed an increased fibrogenic conversion and decreased myogenicity, compared with cells seeded onto control constructs. Consistent with myomatrix alterations, fibroblasts isolated from arsenic-exposed muscle displayed sustained expression of matrix remodeling genes, the majority of which were mediated by NF-κB. Inhibition of NF-κB during arsenic exposure preserved normal myofiber structure and functional recovery after injury, suggesting that NF-κB signaling serves as an important mechanism of action for the deleterious effects of arsenic on tissue healing. Taken together, the results from this study implicate myomatrix biophysical and/or biochemical characteristics as culprits in arsenic-induced MuSC dysfunction and impaired muscle regeneration. It is anticipated that these findings may aid in the development of strategies to prevent or revert the effects of arsenic on tissue healing and, more broadly, provide insight into the influence of the native myomatrix on stem cell behavior. PMID:26537186

  2. Arsenic-resistant bacteria associated with roots of the wild Cirsium arvense (L.) plant from an arsenic polluted soil, and screening of potential plant growth-promoting characteristics.

    PubMed

    Cavalca, Lucia; Zanchi, Raffaella; Corsini, Anna; Colombo, Milena; Romagnoli, Cristina; Canzi, Enrica; Andreoni, Vincenza

    2010-04-01

    A rhizobacterial community, associated with the roots of wild thistle Cirsium arvense (L.) growing in an arsenic polluted soil, was studied by fluorescence in situ hybridization (FISH) analysis in conjunction with cultivation-based methods. In the bulk, rhizosphere, and rhizoplane fractions of the soil, the qualitative picture obtained by FISH analysis of the main phylogenetic bacterial groups was similar and was predominantly comprised of Alphaproteobacteria, Betaproteobacteria, and Gammaproteobacteria. The arsenic-resistant isolates belonged to 13 genera, the most abundant being those of Bacillus, Achromobacter, Brevundimonas, Microbacterium, and Ochrobactrum. Most bacteria grew in the presence of high arsenic concentrations (over 100mM arsenate and 10mM arsenite). Most strains possessed the ArsC, ArsB and ACR3 genes homologous to arsenate reductase and to the two classes of arsenite efflux pumps, respectively, peculiar to the ars operon of the arsenic detoxification system. ArsB and ACR3 were present simultaneously in highly resistant strains. An inconsistency between 16S rRNA phylogenetic affiliations and the arsenate reductase sequences of the strains was observed, indicating possible horizontal transfer of arsenic resistance genes in the soil bacterial community. Several isolates were able to reduce arsenate and to oxidise arsenite. In particular, Ancylobacter dichloromethanicum strain As3-1b possessed both characteristics, and arsenite oxidation occurred in the strain also under chemoautotrophic conditions. Some rhizobacteria produced siderophores, indole acetic acid and 1-amino-cyclopropane-1-carboxylic acid deaminase, thus possessing potential plant growth-promoting traits.

  3. Arsenic promotes angiogenesis in vitro via a heme oxygenase-1-dependent mechanism

    SciTech Connect

    Meng Dan; Wang Xin; Chang Qingshan; Hitron, Andrew; Zhang Zhuo; Xu Mei; Chen Gang; Luo Jia; Jiang Binghua; Fang Jing; Shi Xianglin

    2010-05-01

    Angiogenesis and vessel remodeling are fundamental to the pathogenesis of a number of diseases caused by environmental arsenic exposure, including tumorigenesis and cardiovascular diseases. Arsenic (AsIII) has been shown to stimulate angiogenesis and vascular remodeling in vivo. However, the exact molecular mechanisms accounting for arsenic-induced angiogenesis are not clear. The present study investigates the role of heme oxygenase-1 (HO-1) in sodium arsenite-mediated angiogenesis in vitro. Transwell assay, three-dimensional Matrigel assay, RT-PCR, ELISA and immunoblotting were used to determine cell migration, vascular tube formation, mRNA and protein expression. Chromatin immunoprecipitation and luciferase assay were applied to examine the DNA binding with protein and HO-1 transcriptional activity. Here, we report that low concentrations of arsenite (0.1-1 muM) stimulated cell migration and vascular tube formation in human microvascular endothelial cells (HMVEC). Arsenite induced HO-1 mRNA and protein expression. Knock down of HO-1 expression decreased arsenite-induced VEGF expression, cell migration, and tube formation. We showed that arsenite promoted dissociation of Bach1 (a transcriptional repressor) from the HO-1 enhancers and increased Nrf2 binding to these elements. Site directed mutagenesis assay identified that Bach1 cysteine residues 557 and 574 were essential for the induction of HO-1 gene in response to arsenite. These findings demonstrate a role for HO-1 in arsenite-mediated angiogenesis in vitro.

  4. Arsenic promotes centrosome abnormalities and cell colony formation in p53 compromised human lung cells

    SciTech Connect

    Liao Weiting; Lin Pinpin; Cheng, T.-S.; Yu, H.-S.; Chang, Louis W.

    2007-12-01

    Epidemiological evidence indicated that residents, especially cigarette smokers, in arseniasis areas had significantly higher lung cancer risk than those living in non-arseniasis areas. Thus, an interaction between arsenic and cigarette smoking in lung carcinogenesis was suspected. p53 dysfunction or mutation in lung epithelial cells was frequently observed in cigarette smokers. Our present study was to explore the differential effects by arsenic on H1355 cells (human lung adenocarcinoma cell line with mutation in p53), BEAS-2B (immortalized lung epithelial cell with functional p53) and pifithrin-{alpha}-treated BEAS-2B cells (p53-inhibited cells). These cells were treated with different doses of sodium arsenite (0, 0.1, 1, 5 and 10 {mu}M) for 48 h. A greater reduction in cell viability was observed in the BEAS-2B cells vs. p53 compromised cells (H1355 or p53-inhibited BEAS-2B). Similar observation was also made on 7-day cell survival (growth) study. TUNEL analysis confirmed that there was indeed a significantly reduced arsenite-induced apoptosis found in p53-compromised cells. Centrosomal abnormality has been attributed to eventual chromosomal missegregation, aneuploidy and tumorigenesis. In our present study, reduced p21 and Gadd45a expressions and increased centrosomal abnormality (atopic and multiple centrosomes) were observed in both arsenite-treated H1355 and p53-inhibited BEAS-2B cells as compared with similarly treated BEAS-2B cells. Increased anchorage-independent growth (colony formation) of BEAS-2B cells co-treated with pifithrin-{alpha} and 5 {mu}M sodium arsenite was also observed in soft agar. Our present investigation demonstrated that arsenic would act specifically on p53 compromised cells (either with p53 dysfunction or inhibited) to induce centrosomal abnormality and colony formation. These findings provided strong evidence on the carcinogenic promotional role of arsenic, especially under the condition of p53 dysfunction.

  5. Effect of applying an arsenic-resistant and plant growth-promoting rhizobacterium to enhance soil arsenic phytoremediation by Populus deltoides LH05-17.

    PubMed

    Wang, Q; Xiong, D; Zhao, P; Yu, X; Tu, B; Wang, G

    2011-11-01

    Bioremediation of highly arsenic (As)-contaminated soil is difficult because As is very toxic for plants and micro-organisms. The aim of this study was to investigate soil arsenic removal effects using poplar in combination with the inoculation of a plant growth-promoting rhizobacterium (PGPR). A rhizobacterium D14 was isolated and identified within Agrobacterium radiobacter. This strain was highly resistant to arsenic and produced indole acetic acid and siderophore. Greenhouse pot bioremediation experiments were performed for 5 months using poplar (Populus deltoides LH05-17) grown on As-amended soils, inoculated with strain D14. The results showed that P. deltoides was an efficient arsenic accumulator; however, high As concentrations (150 and 300 mg kg(-1)) inhibited its growth. With the bacterial inoculation, in the 300 mg kg(-1) As-amended soils, 54% As in the soil was removed, which was higher than the uninoculated treatments (43%), and As concentrations in roots, stems and leaves were significantly increased by 229, 113 and 291%, respectively. In addition, the As translocation ratio [(stems + leaves)/roots = 0·8] was significantly higher than the uninoculated treatments (0·5). About 45% As was translocated from roots to the above-ground tissues. The plant height and dry weight of roots, stems and leaves were all enhanced; the contents of chlorophyll and soluble sugar, and the activities of superoxide dismutase and catalase were all increased; and the content of a toxic compound malondialdehyde was decreased. The results indicated that the inoculation of strain D14 could contribute to the increase in the As tolerance of P. deltoides, promotion of the growth, increase in the uptake efficiency and enhancement of As translocation. The use of P. deltoides in combination with the inoculation of strain D14 provides a potential application for efficient soil arsenic bioremediation. © 2011 The Authors. Journal of Applied Microbiology ©2011 The Society for Applied

  6. Arsenic Mobilization from Contaminated Sediments: A Full-scale Experiment in Progress

    SciTech Connect

    O'Day, P A; Campbell, K; Dixit, S; Hering, J G

    2004-02-03

    The mobilization of arsenic was examined in a system where the deposition of iron and arsenic have been substantially modified by large-scale manipulations. This engineering practice was designed to decrease arsenic concentrations in water supplied to the City of Los Angeles. Accomplishing this objective, however, has resulted in significant accumulation of arsenic and iron in the sediments of a reservoir on the Los Angeles Aqueduct. Arsenic and iron are released into the porewater at depth in the sediment, consistent with reductive dissolution of iron(III) oxyhydroxides. Factors influencing the possible re-sorption of arsenic onto residual iron(III) oxyhydroxides solids have been examined. Reduction of As(V) to As(III) alone cannot account for arsenic mobilization since arsenic occurs in the solid phase as As(III) well above the depth at which it is released into the porewater. Competition from other porewater constituents could suppress re-sorption of arsenic released by reductive dissolution.

  7. Brevundimonas diminuta mediated alleviation of arsenic toxicity and plant growth promotion in Oryza sativa L.

    PubMed

    Singh, Namrata; Marwa, Naina; Mishra, Shashank K; Mishra, Jyoti; Verma, Praveen C; Rathaur, Sushma; Singh, Nandita

    2016-03-01

    Arsenic (As), a toxic metalloid adversely affects plant growth in polluted areas. In the present study, we investigated the possibility of improving phytostablization of arsenic through application of new isolated strain Brevundimonas diminuta (NBRI012) in rice plant [Oryza sativa (L.) Var. Sarju 52] at two different concentrations [10ppm (low toxic) and 50ppm (high toxic)] of As. The plant growth promoting traits of bacterial strains revealed the inherent ability of siderophores, phosphate solubilisation, indole acetic acid (IAA), 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase production which may be associated with increased biomass, chlorophyll and MDA content of rice and thereby promoting plant growth. The study also revealed the As accumulation property of NBRI012 strain which could play an important role in As removal from contaminated soil. Furthermore, NBRI012 inoculation significantly restored the hampered root epidermal and cortical cell growth of rice plant and root hair elimination. Altogether our study highlights the multifarious role of B. diminuta in mediating stress tolerance and modulating translocation of As in edible part of rice plant.

  8. A Phytoremediation Strategy for Arsenic

    SciTech Connect

    Meagher, Richard B.

    2005-06-01

    A Phytoremediation Strategy for Arsenic Progress Report May, 2005 Richard B. Meagher Principal Investigator Arsenic pollution affects the health of several hundred millions of people world wide, and an estimated 10 million Americans have unsafe levels of arsenic in their drinking water. However, few environmentally sound remedies for cleaning up arsenic contaminated soil and water have been proposed. Phytoremediation, the use of plants to extract and sequester environmental pollutants, is one new technology that offers an ecologically sound solution to a devastating problem. We propose that it is less disruptive to the environment to harvest and dispose of several thousand pounds per acre of contaminated aboveground plant material, than to excavate and dispose of 1 to 5 million pounds of contaminated soil per acre (assumes contamination runs 3 ft deep). Our objective is to develop a genetics-based phytoremediation strategy for arsenic removal that can be used in any plant species. This strategy requires the enhanced expression of several transgenes from diverse sources. Our working hypothesis is that organ-specific expression of several genes controlling the transport, electrochemical state, and binding of arsenic will result in the efficient extraction and hyperaccumulation of arsenic into aboveground plant tissues. This hypothesis is supported by theoretical arguments and strong preliminary data. We proposed six Specific Aims focused on testing and developing this arsenic phytoremediation strategy. During the first 18 months of the grant we made significant progress on five Specific Aims and began work on the sixth as summarized below. Specific Aim 1: Enhance plant arsenic resistance and greatly expand sinks for arsenite by expressing elevated levels of thiol-rich, arsenic-binding peptides. Hyperaccumulation of arsenic depends upon making plants that are both highly tolerant to arsenic and that have the capacity to store large amounts of arsenic aboveground

  9. Sustainable engineered processes to mitigate the global arsenic crisis in drinking water: challenges and progress.

    PubMed

    Sarkar, Sudipta; Greenleaf, John E; Gupta, Anirban; Uy, Davin; Sengupta, Arup K

    2012-01-01

    Millions of people around the world are currently living under the threat of developing serious health problems owing to ingestion of dangerous concentrations of arsenic through their drinking water. In many places, treatment of arsenic-contaminated water is an urgent necessity owing to a lack of safe alternative sources. Sustainable production of arsenic-safe water from an arsenic-contaminated raw water source is currently a challenge. Despite the successful development in the laboratory of technologies for arsenic remediation, few have been successful in the field. A sustainable arsenic-remediation technology should be robust, composed of local resources, and user-friendly as well as must attach special consideration to the social, economic, cultural, traditional, and environmental aspects of the target community. One such technology is in operation on the Indian subcontinent. Wide-scale replication of this technology with adequate improvisation can solve the arsenic crisis prevalent in the developing world.

  10. Epithelial to mesenchymal transition in arsenic-transformed cells promotes angiogenesis through activating β-catenin-vascular endothelial growth factor pathway

    PubMed Central

    Wang, Zhishan; Humphries, Brock; Xiao, Hua; Jiang, Yiguo; Yang, Chengfeng

    2013-01-01

    Arsenic exposure represents a major health concern increasing cancer risks, yet the mechanism of arsenic carcinogenesis has not been elucidated. We and others recently reported that cell malignant transformation by arsenic is accompanied by epithelial to mesenchymal transition (EMT). However, the role of EMT in arsenic carcinogenesis is not well understood. Although previous studies showed that short term exposure of endothelial cells to arsenic stimulated angiogenesis, it remains to be determined whether cells that were malignantly transformed by long term arsenic exposure have a pro-angiogenic effect. The objective of this study was to investigate the effect of arsenic-transformed human bronchial epithelial cells that underwent EMT on angiogenesis and the underlying mechanism. It was found that the conditioned medium from arsenic-transformed cells strongly stimulated tube formation by human umbilical vein endothelial cells (HUVECs). Moreover, enhanced angiogenesis was detected in mouse xenograft tumor tissues resulting from inoculation of arsenic-transformed cells. Mechanistic studies revealed that β-catenin was activated in arsenic-transformed cells up-regulating its target gene expression including angiogenic-stimulating vascular endothelial growth factor (VEGF). Stably expressing microRNA-200b in arsenic-transformed cells that reversed EMT inhibited β-catenin activation, decreased VEGF expression and reduced tube formation by HUVECs. SiRNA knockdown β-catenin decreased VEGF expression. Adding a VEGF neutralizing antibody into the conditioned medium from arsenic-transformed cells impaired tube formation by HUVECs. Reverse transcriptase-PCR analysis revealed that the mRNA levels of canonical Wnt ligands were not increased in arsenic-transformed cells. These findings suggest that EMT in arsenic-transformed cells promotes angiogenesis through activating β-catenin-VEGF pathway. PMID:23643801

  11. Epithelial to mesenchymal transition in arsenic-transformed cells promotes angiogenesis through activating β-catenin–vascular endothelial growth factor pathway

    SciTech Connect

    Wang, Zhishan; Humphries, Brock; Xiao, Hua; Jiang, Yiguo; Yang, Chengfeng

    2013-08-15

    Arsenic exposure represents a major health concern increasing cancer risks, yet the mechanism of arsenic carcinogenesis has not been elucidated. We and others recently reported that cell malignant transformation by arsenic is accompanied by epithelial to mesenchymal transition (EMT). However, the role of EMT in arsenic carcinogenesis is not well understood. Although previous studies showed that short term exposure of endothelial cells to arsenic stimulated angiogenesis, it remains to be determined whether cells that were malignantly transformed by long term arsenic exposure have a pro-angiogenic effect. The objective of this study was to investigate the effect of arsenic-transformed human bronchial epithelial cells that underwent EMT on angiogenesis and the underlying mechanism. It was found that the conditioned medium from arsenic-transformed cells strongly stimulated tube formation by human umbilical vein endothelial cells (HUVECs). Moreover, enhanced angiogenesis was detected in mouse xenograft tumor tissues resulting from inoculation of arsenic-transformed cells. Mechanistic studies revealed that β-catenin was activated in arsenic-transformed cells up-regulating its target gene expression including angiogenic-stimulating vascular endothelial growth factor (VEGF). Stably expressing microRNA-200b in arsenic-transformed cells that reversed EMT inhibited β-catenin activation, decreased VEGF expression and reduced tube formation by HUVECs. SiRNA knockdown β-catenin decreased VEGF expression. Adding a VEGF neutralizing antibody into the conditioned medium from arsenic-transformed cells impaired tube formation by HUVECs. Reverse transcriptase-PCR analysis revealed that the mRNA levels of canonical Wnt ligands were not increased in arsenic-transformed cells. These findings suggest that EMT in arsenic-transformed cells promotes angiogenesis through activating β-catenin–VEGF pathway. - Highlights: • Arsenic-transformed cells that underwent EMT displayed a pro

  12. Environmental Health Promotion: Progress and Future Opportunities

    ERIC Educational Resources Information Center

    Srinivasan, Shobha; Dearry, Allen

    2004-01-01

    Health promotion seeks to provide practitioners of medicine and public health as well as members of the public with the information, resources, and tools that they can use to improve health and well-being. This goal is consonant with that of the National Institutes of Health (NIH), namely, to improve public health outcomes via research,…

  13. Environmental Health Promotion: Progress and Future Opportunities

    ERIC Educational Resources Information Center

    Srinivasan, Shobha; Dearry, Allen

    2004-01-01

    Health promotion seeks to provide practitioners of medicine and public health as well as members of the public with the information, resources, and tools that they can use to improve health and well-being. This goal is consonant with that of the National Institutes of Health (NIH), namely, to improve public health outcomes via research,…

  14. Evidence of arsenic release promoted by disinfection by-products within drinking-water distribution systems.

    PubMed

    Andra, Syam S; Makris, Konstantinos C; Botsaris, George; Charisiadis, Pantelis; Kalyvas, Harris; Costa, Costas N

    2014-02-15

    Changes in disinfectant type could trigger a cascade of reactions releasing pipe-anchored metals/metalloids into finished water. However, the effect of pre-formed disinfection by-products on the release of sorbed contaminants (arsenic-As in particular) from drinking water distribution system pipe scales remains unexplored. A bench-scale study using a factorial experimental design was performed to evaluate the independent and interaction effects of trihalomethanes (TTHM) and haloacetic acids (HAA) on arsenic (As) release from either scales-only or scale-biofilm conglomerates (SBC) both anchored on asbestos/cement pipe coupons. A model biofilm (Pseudomonas aeruginosa) was allowed to grow on select pipe coupons prior experimentation. Either TTHM or HAA individual dosing did not promote As release from either scales only or SBC, detecting <6 μg AsL(-1) in finished water. In the case of scales-only coupons, the combination of the highest spike level of TTHM and HAA significantly (p<0.001) increased dissolved and total As concentrations to levels up to 16 and 95 μg L(-1), respectively. Similar treatments in the presence of biofilm (SBC) resulted in significant (p<0.001) increase in dissolved and total recoverable As up to 20 and 47 μg L(-1), respectively, exceeding the regulatory As limit. Whether or not, our laboratory-based results truly represent mechanisms operating in disinfected finished water in pipe networks remains to be investigated in the field. Copyright © 2013 Elsevier B.V. All rights reserved.

  15. Secondary Coronary Artery Vasospasm Promotes Cardiomyopathy Progression

    PubMed Central

    Wheeler, Matthew T.; Korcarz, Claudia E.; Collins, Keith A.; Lapidos, Karen A.; Hack, Andrew A.; Lyons, Matthew R.; Zarnegar, Sara; Earley, Judy U.; Lang, Roberto M.; McNally, Elizabeth M.

    2004-01-01

    Genetic defects in the plasma membrane-associated sarcoglycan complex produce cardiomyopathy characterized by focal degeneration. The infarct-like pattern of cardiac degeneration has led to the hypothesis that coronary artery vasospasm underlies cardiomyopathy in this disorder. We evaluated the coronary vasculature of γ-sarcoglycan mutant mice and found microvascular filling defects consistent with arterial vasospasm. However, the vascular smooth muscle sarcoglycan complex was intact in the coronary arteries of γ-sarcoglycan hearts with perturbation of the sarcoglycan complex only within the adjacent myocytes. Thus, in this model, coronary artery vasospasm derives from a vascular smooth muscle-cell extrinsic process. To reduce this secondary vasospasm, we treated γ-sarcoglycan-deficient mice with the calcium channel antagonist verapamil. Verapamil treatment eliminated evidence of vasospasm and ameliorated histological and functional evidence of cardiomyopathic progression. Echocardiography of verapamil-treated, γ-sarcoglycan-null mice showed an improvement in left ventricular fractional shortening (44.3 ± 13.3% treated versus 37.4 ± 15.3% untreated), maximal velocity at the aortic outflow tract (114.9 ± 27.9 cm/second versus 92.8 ± 22.7 cm/second), and cardiac index (1.06 ± 0.30 ml/minute/g versus 0.67 ± 0.16 ml/minute/g, P < 0.05). These data indicate that secondary vasospasm contributes to the development of cardiomyopathy and is an important therapeutic target to limit cardiomyopathy progression. PMID:14982859

  16. Arsenic in private well water part 2 of 3: Who benefits the most from traditional testing promotion?

    PubMed

    Flanagan, Sara V; Spayd, Steven E; Procopio, Nicholas A; Chillrud, Steven N; Ross, James; Braman, Stuart; Zheng, Yan

    2016-08-15

    Arsenic, a toxic element naturally found in groundwater, is a public health concern for households drinking from wells. Private well water is not regulated to meet the federal drinking water arsenic Maximum Contaminant Level (MCL) of 10μg/L, or the more protective 5μg/L New Jersey (NJ) state MCL. In the absence of consistent private well regulation, public health efforts have relied on promoting testing in affected communities to various degrees of success. Few interventions publish results, and more often focus on the outcome of tested wells rather than who completed a test, and more importantly, who did not. Through our survey of randomly selected addresses (n=670) in 17 NJ towns we find higher rates of arsenic testing in areas with a history of testing promotion. However, we also see a stronger correlation of testing behavior with income and education in high promotion areas, suggesting that community engagement activities may be exacerbating socioeconomic status (SES) testing disparities. Well owners with a bachelor's degree had ten times greater odds of participating in our direct mail testing intervention than those with less education when tests cost $40. After all households (n=255) were offered free tests to overcome many of the usual testing barriers - awareness, convenience, and cost - only 47% participated and those who chose to return water samples were of higher income and education than those who did not. Our findings highlight that while efforts to promote and provide arsenic testing succeed in testing more wells, community testing interventions risk increasing SES disparities if those with more education and resources are more likely to take advantage of testing programs. Therefore, testing interventions can benefit by better targeting socially vulnerable populations in an effort to overcome SES-patterned self-selection when individuals are left alone with the responsibility of managing their drinking water quality.

  17. Effective rhizoinoculation and biofilm formation by arsenic immobilizing halophilic plant growth promoting bacteria (PGPB) isolated from mangrove rhizosphere: A step towards arsenic rhizoremediation.

    PubMed

    Mallick, Ivy; Bhattacharyya, Chandrima; Mukherji, Shayantan; Dey, Dhritiman; Sarkar, Somesh Chandra; Mukhopadhyay, Ujjal Kumar; Ghosh, Abhrajyoti

    2017-08-25

    Arsenic (As) uptake by plants is largely influenced by the presence of microbial consortia and their interactions with As. In the coastal region of Bengal deltaic plain of Eastern India, the As-contaminated groundwater is frequently used for irrigation purposes resulting in an elevated level of soil As in agricultural lands. The health hazards associated with As necessitates development of cost-effective remediation strategies to reclaim contaminated agricultural lands. Among the available technologies developed in recent times, bioremediation using bacteria has been found to be the most propitious. In this study, two As-resistant halophilic bacterial strains Kocuria flava AB402 and Bacillus vietnamensis AB403 were isolated, identified and characterized from mangrove rhizosphere of Sundarban. The isolates, AB402 and AB403, could tolerate 35mM and 20mM of arsenite, respectively. The effect of As on the exopolysaccharide (EPS) synthesis, biofilm formation, and root association was evaluated for both the bacterial strains. Arsenic adsorption on the cell surfaces and intracellular accumulation in both the bacterial strains were promising under culture conditions. Moreover, both the strains when used as inoculum, not only promoted the growth of rice seedlings but also decreased As uptake and accumulation in plants. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Activation of Hedgehog signaling by the environmental toxicant arsenic may contribute to the etiology of arsenic induced tumors

    PubMed Central

    Fei, Dennis Liang; Li, Hua; Kozul, Courtney D.; Black, Kendall E.; Singh, Samer; Gosse, Julie A.; DiRenzo, James; Martin, Kathleen A.; Wang, Baolin; Hamilton, Joshua W.; Karagas, Margaret R.; Robbins, David J.

    2010-01-01

    Exposure to the environmental toxicant arsenic, through both contaminated water and food, contributes to significant health problems worldwide. In particular, arsenic exposure is thought to function as a carcinogen for lung, skin and bladder cancer, via mechanisms that remain largely unknown. More recently, the Hedgehog (HH) signaling pathway has also been implicated in the progression and maintenance of these same cancers. Based on these similarities, we tested the hypothesis that arsenic may act in part through activating HH signaling. Here, we show that arsenic is able to activate HH signaling in a number of primary and established tissue culture cells, as well as in vivo. Arsenic activates HH signaling by decreasing the stability of the repressor form of GLI3, one of the transcription factors that ultimately regulate HH activity. We also show, using tumor samples from a cohort of bladder cancer patients, that high levels of arsenic exposure are associated with high levels of HH activity. Given the important role HH signaling plays in the maintenance and progression of a variety of tumors, including bladder cancer, these results suggest that arsenic exposure may in part promote cancer through the activation of HH signaling. Thus, we provide an important insight into the etiology of arsenic induced human carcinogenesis, which may be relevant to millions of people exposed to high levels of arsenic worldwide. PMID:20179202

  19. Evaluation of the effectiveness of arsenic screening promotion in private wells: a quasi-experimental study.

    PubMed

    Renaud, Jolianne; Gagnon, Fabien; Michaud, Cécile; Boivin, Sonia

    2011-12-01

    The Eastern Townships (ETR) is a region in Québec (Canada) where the soil is naturally rich in arsenic (As). About a third of the people in the ETR obtain their water from a private well. A quasi-experimental design was used to compare two campaigns designed to promote As screening in well water: a mass-media campaign (MMC) followed or not by a community-based intervention (CBI). The MMC is based on a press release issued for the ETR, along with a leaflet on As made available on the Internet, and in strategic places. The CBI, formulated according to the factors of the Precede-Proceed model, was aimed at mobilizing local authorities and small media. It targets only one municipality; the intervention community (IC). Using a separate pre-post samples design, two population-based cross-sectional (pre-CBI and post-CBI) surveys were conducted by phone at 6-month intervals, by means of random samples. The samples counted, for the IC and the ETR, respectively, 87 and 156 well owners in pre-CBI, and 106 and 190 in post-CBI. The results in post-CBI showed that the proportion of well owners who had their water test increased by four times in the IC after (16% p = 0.004). When adjusting for age and gender among all the post-CBI respondents, As screening is related with intervention status (exposed to MMC and CBI; p ≤ 0.001) and on previous microbiological water analysis behavior (p ≤ 0.05), but is not related to knowledge. This study demonstrates the superiority of a community-based campaign over a MMC when environmental health is concerned.

  20. Barium inhibits arsenic-mediated apoptotic cell death in human squamous cell carcinoma cells.

    PubMed

    Yajima, Ichiro; Uemura, Noriyuki; Nizam, Saika; Khalequzzaman, Md; Thang, Nguyen D; Kumasaka, Mayuko Y; Akhand, Anwarul A; Shekhar, Hossain U; Nakajima, Tamie; Kato, Masashi

    2012-06-01

    Our fieldwork showed more than 1 μM (145.1 μg/L) barium in about 3 μM (210.7 μg/L) arsenic-polluted drinking well water (n = 72) in cancer-prone areas in Bangladesh, while the mean concentrations of nine other elements in the water were less than 3 μg/L. The types of cancer include squamous cell carcinomas (SCC). We hypothesized that barium modulates arsenic-mediated biological effects, and we examined the effect of barium (1 μM) on arsenic (3 μM)-mediated apoptotic cell death of human HSC-5 and A431 SCC cells in vitro. Arsenic promoted SCC apoptosis with increased reactive oxygen species (ROS) production and JNK1/2 and caspase-3 activation (apoptotic pathway). In contrast, arsenic also inhibited SCC apoptosis with increased NF-κB activity and X-linked inhibitor of apoptosis protein (XIAP) expression level and decreased JNK activity (antiapoptotic pathway). These results suggest that arsenic bidirectionally promotes apoptotic and antiapoptotic pathways in SCC cells. Interestingly, barium in the presence of arsenic increased NF-κB activity and XIAP expression and decreased JNK activity without affecting ROS production, resulting in the inhibition of the arsenic-mediated apoptotic pathway. Since the anticancer effect of arsenic is mainly dependent on cancer apoptosis, barium-mediated inhibition of arsenic-induced apoptosis may promote progression of SCC in patients in Bangladesh who keep drinking barium and arsenic-polluted water after the development of cancer. Thus, we newly showed that barium in the presence of arsenic might inhibit arsenic-mediated cancer apoptosis with the modulation of the balance between arsenic-mediated promotive and suppressive apoptotic pathways.

  1. GT-repeat polymorphism in the heme oxygenase-1 gene promoter and the risk of carotid atherosclerosis related to arsenic exposure

    PubMed Central

    2010-01-01

    Background Arsenic is a strong stimulus of heme oxygenase (HO)-1 expression in experimental studies in response to oxidative stress caused by a stimulus. A functional GT-repeat polymorphism in the HO-1 gene promoter was inversely correlated to the development of coronary artery disease in diabetics and development of restenosis following angioplasty in patients. The role of this potential vascular protective factor in carotid atherosclerosis remains unclear. We previously reported a graded association of arsenic exposure in drinking water with an increased risk of carotid atherosclerosis. In this study, we investigated the relationship between HO-1 genetic polymorphism and the risk of atherosclerosis related to arsenic. Methods Three-hundred and sixty-seven participants with an indication of carotid atherosclerosis and an additional 420 participants without the indication, which served as the controls, from two arsenic exposure areas in Taiwan, a low arsenic-exposed Lanyang cohort and a high arsenic-exposed LMN cohort, were studied. Carotid atherosclerosis was evaluated using a duplex ultrasonographic assessment of the extracranial carotid arteries. Allelic variants of (GT)n repeats in the 5'-flanking region of the HO-1 gene were identified and grouped into a short (S) allele (< 27 repeats) and long (L) allele (≥ 27 repeats). The association of atherosclerosis and the HO-1 genetic variants was assessed by a logistic regression analysis, adjusted for cardiovascular risk factors. Results Analysis results showed that arsenic's effect on carotid atherosclerosis differed between carriers of the class S allele (OR 1.39; 95% CI 0.86-2.25; p = 0.181) and non-carriers (OR 2.65; 95% CI 1.03-6.82; p = 0.044) in the high-exposure LMN cohort. At arsenic exposure levels exceeding 750 μg/L, difference in OR estimates between class S allele carriers and non-carriers was borderline significant (p = 0.051). In contrast, no such results were found in the low-exposure Lanyang

  2. Promotion of well-switching to mitigate the current arsenic crisis in Bangladesh.

    PubMed Central

    Van Geen, Alexander; Ahsan, Habibul; Horneman, Allan H.; Dhar, Ratan K.; Zheng, Yan; Hussain, Iftikhhar; Ahmed, Kazi Matin; Gelman, Andrew; Stute, Martin; Simpson, H. James; Wallace, Sean; Small, Christopher; Parvez, Faruque; Slavkovich, Vesna; Loiacono, Nancy J.; Becker, Marck; Cheng, Zhongqi; Momotaj, Hassina; Shahnewaz, Mohammad; Seddique, Ashraf Ali; Graziano, Joseph H.

    2002-01-01

    OBJECTIVE: To survey tube wells and households in Araihazar upazila, Bangladesh, to set the stage for a long-term epidemiological study of the consequences of chronic arsenic exposure. METHODS: Water samples and household data were collected over a period of 4 months in 2000 from 4997 contiguous tube wells serving a population of 55000, the position of each well being determined to within +/- 30 m using Global Positioning System receivers. Arsenic concentrations were determined by graphite-furnace atomic-absorption spectrometry. In addition, groundwater samples collected every 2 weeks for an entire year from six tube wells were analysed for arsenic by high-resolution inductively coupled plasma-mass spectrometry. FINDINGS: Half of the wells surveyed in Araihazar had been installed in the previous 5 years; 94% were privately owned. Only about 48% of the surveyed wells supplied water with an arsenic content below 50 micro g/l, the current Bangladesh standard for drinking-water. Similar to other regions of Bangladesh and West Bengal, India, the distribution of arsenic in Araihazar is spatially highly variable (range: 5-860 micro g/l) and therefore difficult to predict. Because of this variability, however, close to 90% of the inhabitants live within 100 m of a safe well. Monitoring of six tube wells currently meeting the 50 micro g/l standard showed no indication of a seasonal cycle in arsenic concentrations coupled to the hydrological cycle. This suggests that well-switching is a viable option in Araihazar, at least for the short term. CONCLUSIONS: Well-switching should be more systematically encouraged in Araihazar and many other parts of Bangladesh and West Bengal, India. Social barriers to well-switching need to be better understood and, if possible, overcome. PMID:12378292

  3. A cluster-based randomized controlled trial promoting community participation in arsenic mitigation efforts in Bangladesh

    PubMed Central

    2012-01-01

    Objective To reduce arsenic (As) exposure, we evaluated the effectiveness of training community members to perform water arsenic (WAs) testing and provide As education compared to sending representatives from outside communities to conduct these tasks. Methods We conducted a cluster based randomized controlled trial of 20 villages in Singair, Bangladesh. Fifty eligible respondents were randomly selected in each village. In 10 villages, a community member provided As education and WAs testing. In a second set of 10 villages an outside representative performed these tasks. Results Overall, 53% of respondents using As contaminated wells, relative to the Bangladesh As standard of 50 μg/L, at baseline switched after receiving the intervention. Further, when there was less than 60% arsenic contaminated wells in a village, the classification used by the Bangladeshi and UNICEF, 74% of study households in the community tester villages, and 72% of households in the outside tester villages reported switching to an As safe drinking water source . Switching was more common in the outside-tester (63%) versus community-tester villages (44%). However, after adjusting for the availability of arsenic safe drinking water sources, well switching did not differ significantly by type of As tester (Odds ratio =0.86[95% confidence interval 0.42-1.77). At follow-up, among those using As contaminated wells who switched to safe wells, average urinary As concentrations significantly decreased. Conclusion The overall intervention was effective in reducing As exposure provided there were As-safe drinking water sources available. However, there was not a significant difference observed in the ability of the community and outside testers to encourage study households to use As-safe water sources. The findings of this study suggest that As education and WAs testing programs provided by As testers, irrespective of their residence, could be used as an effective, low cost approach to reduce As

  4. Sharpin promotes hepatocellular carcinoma progression via transactivation of Versican expression

    PubMed Central

    Tanaka, Y; Tateishi, K; Nakatsuka, T; Kudo, Y; Takahashi, R; Miyabayashi, K; Yamamoto, K; Asaoka, Y; Ijichi, H; Tateishi, R; Shibahara, J; Fukayama, M; Ishizawa, T; Hasegawa, K; Kokudo, N; Koike, K

    2016-01-01

    Sharpin (Shank-associated RH domain-interacting protein, also known as SIPL1) is a multifunctional molecule that participates in various biological settings, including nuclear factor-κB signaling activation and tumor suppressor gene inhibition. Sharpin is upregulated in various types of cancers, including hepatocellular carcinoma (HCC), and is implicated in tumor progression. However, the exact roles of Sharpin in tumorigenesis and tumor progression remain largely unknown. Here we report novel mechanisms of HCC progression through Sharpin overexpression. In our study, Sharpin was upregulated in human HCC tissues. Increased Sharpin expression enhanced hepatoma cell invasion, whereas decrease in Sharpin expression by RNA interference inhibited invasion. Microarray analysis identified that Versican, a chondroitin sulfate proteoglycan that plays crucial roles in tumor progression and invasion, was also upregulated in Sharpin-expressing stable cells. Versican expression increased in the majority of HCC tissues and knocking down of Versican greatly attenuated hepatoma cell invasion. Sharpin expression resulted in a significant induction of Versican transcription synergistically with Wnt/β-catenin pathway activation. Furthermore, Sharpin-overexpressing cells had high tumorigenic properties in vivo. These results demonstrate that Sharpin promotes Versican expression synergistically with the Wnt/β-catenin pathway, potentially contributing to HCC development. A Sharpin/Versican axis could be an attractive therapeutic target for this currently untreatable cancer. PMID:27941932

  5. Chk1 promotes replication fork progression by controlling replication initiation.

    PubMed

    Petermann, Eva; Woodcock, Mick; Helleday, Thomas

    2010-09-14

    DNA replication starts at initiation sites termed replication origins. Metazoan cells contain many more potential origins than are activated (fired) during each S phase. Origin activation is controlled by the ATR checkpoint kinase and its downstream effector kinase Chk1, which suppresses origin firing in response to replication blocks and during normal S phase by inhibiting the cyclin-dependent kinase Cdk2. In addition to increased origin activation, cells deficient in Chk1 activity display reduced rates of replication fork progression. Here we investigate the causal relationship between increased origin firing and reduced replication fork progression. We use the Cdk inhibitor roscovitine or RNAi depletion of Cdc7 to inhibit origin firing in Chk1-inhibited or RNAi-depleted cells. We report that Cdk inhibition and depletion of Cdc7 can alleviate the slow replication fork speeds in Chk1-deficient cells. Our data suggest that increased replication initiation leads to slow replication fork progression and that Chk1 promotes replication fork progression during normal S phase by controlling replication origin activity.

  6. Progress in protecting, promoting, and supporting breastfeeding: 1984-2009.

    PubMed

    Grummer-Strawn, Laurence M; Shealy, Katherine R

    2009-10-01

    The 1984 Surgeon General's Workshop on Breastfeeding delineated six priority areas for action to protect, promote, and support breastfeeding. In this article, we examine trends in breastfeeding behaviors and recall key events and actions that shaped these behaviors over the past 25 years. We examine progress in breastfeeding support through workplaces, public education, professional education, health system changes, support services, and research. Rates of initiation of breastfeeding more than doubled from a nadir of only 26.5% in 1970 to 61.9% in 1982. Initiation fell to 51.5% in 1990, but has risen almost monotonically since then to 74.2% in 2005. Trends in breastfeeding at 6 months have paralleled initiation trends. Black-white disparities have narrowed for breastfeeding initiation but not for continuation to 6 months. Considerable progress in breastfeeding support has been seen over the past 25 years, with more employers allowing women time and space to express milk at work, more states enacting legislation to ensure that accommodations are made for employed women and protect the right to breastfeed in public, more opportunities for physician education on breastfeeding, expansion of professional lactation services, and substantial increases in the amount of research on breastfeeding. However, only 21.4% of babies are breastfed for a year, and only 11.9% exclusively breastfeed for 6 months. Only 2% of babies are born in facilities that meet international standards of care, and 74% of employers do not offer lactation rooms or accommodations for breastfeeding. Thus, in spite of considerable progress, significant gaps remain in protecting, promoting, and supporting breastfeeding.

  7. Cyr61 promotes breast tumorigenesis and cancer progression

    SciTech Connect

    Tsai, Miaw-Sheue; Bogart, Daphne F.; Castaneda, Jessica M.; Li, Patricia; Lupu, Ruth

    2002-01-16

    Cyr61, a member of the CCN family of genes, is an angiogenic factor. We have shown that it is overexpressed in invasive and metastatic human breast cancer cells and tissues. Here, we investigated whether Cyr61 is necessary and/or sufficient to bypass the ''normal'' estrogen (E2) requirements for breast cancer cell growth. Our results demonstrate that under E2-depleted condition, Cyr61 is sufficient to induce MCF-7 cells grow in the absence of E2. MCF-7 cells transfected with Cyr61 (MCF-7/Cyr61) became E2-independent but still E2-responsive. On the other hand, MCF-7/vector cells remain E2-dependent. MCF-7/Cyr61 cells acquire an antiestrogen-resistant phenotype, one of the most common clinical occurrences during breast cancer progression. MCF-7/Cyr61 cells are anchorage-independent and capable of forming Matrigel outgrowth patterns in the absence of E2. ERa expression in MCF-7/Cyr61 cells is decreased although still functional. Additionally, MCF-7/Cyr61 cells are tumorigenic in ovariectomized athymic nude mice. The tumors resemble human invasive carcinomas with increased vascularization and overexpression of vascular endothelial growth factor (VEGF). Our results demonstrate that Cyr61 is a tumor-promoting factor and a key regulator of breast cancer progression. This study provides evidence that Cyr61 is sufficient to induce E2-independence and anti-E2 resistance, and to promote invasiveness in vitro, and to induce tumorigenesis in vivo, all of which are characteristics of an aggressive breast cancer phenotype.

  8. Hypermutation of DPYD Deregulates Pyrimidine Metabolism and Promotes Malignant Progression.

    PubMed

    Edwards, Lauren; Gupta, Rohit; Filipp, Fabian Volker

    2016-02-01

    New strategies are needed to diagnose and target human melanoma. To this end, genomic analyses was performed to assess somatic mutations and gene expression signatures using a large cohort of human skin cutaneous melanoma (SKCM) patients from The Cancer Genome Atlas (TCGA) project to identify critical differences between primary and metastatic tumors. Interestingly, pyrimidine metabolism is one of the major pathways to be significantly enriched and deregulated at the transcriptional level in melanoma progression. In addition, dihydropyrimidine dehydrogenase (DPYD) and other important pyrimidine-related genes: DPYS, AK9, CAD, CANT1, ENTPD1, NME6, NT5C1A, POLE, POLQ, POLR3B, PRIM2, REV3L, and UPP2 are significantly enriched in somatic mutations relative to the background mutation rate. Structural analysis of the DPYD protein dimer reveals a potential hotspot of recurring somatic mutations in the ligand-binding sites as well as the interfaces of protein domains that mediated electron transfer. Somatic mutations of DPYD are associated with upregulation of pyrimidine degradation, nucleotide synthesis, and nucleic acid processing while salvage and nucleotide conversion is downregulated in TCGA SKCM. At a systems biology level, somatic mutations of DPYD cause a switch in pyrimidine metabolism and promote gene expression of pyrimidine enzymes toward malignant progression. ©2015 American Association for Cancer Research.

  9. SPINK1 promotes colorectal cancer progression by downregulating Metallothioneins expression

    PubMed Central

    Tiwari, R; Pandey, S K; Goel, S; Bhatia, V; Shukla, S; Jing, X; Dhanasekaran, S M; Ateeq, B

    2015-01-01

    Colorectal cancer (CRC) is the third most common cancer in the world, and second leading cause of cancer deaths in the US. Although, anti-EGFR therapy is commonly prescribed for CRC, patients harboring mutations in KRAS or BRAF show poor treatment response, indicating an ardent demand for new therapeutic targets discovery. SPINK1 (serine peptidase inhibitor, Kazal type 1) overexpression has been identified in many cancers including the colon, lung, breast and prostate. Our study demonstrates the functional significance of SPINK1 in CRC progression and metastases. Stable knockdown of SPINK1 significantly decreases cell proliferation, invasion and soft agar colony formation in the colon adenocarcinoma WiDr cells. Conversely, an increase in these oncogenic phenotypes was observed on stimulation with SPINK1-enriched conditioned media (CM) in multiple benign models such as murine colonic epithelial cell lines, MSIE and YAMC (SPINK3-negative). Mechanistically, SPINK1 promotes tumorigenic phenotype by activating phosphatidylinositol 3-kinase (PI3K/AKT) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways, and the SPINK1-positive WiDr cells are sensitive to AKT and MEK inhibitors. Importantly, SPINK1 silencing mediated upregulation of various Metallothionein isoforms, considered as tumor suppressors in CRC, confer sensitivity to doxorubicin, which strengthens the rationale for using the combinatorial treatment approach for the SPINK1-positive CRC patients. Furthermore, in vivo studies using chicken chorioallantoic membrane assay, murine xenograft studies and metastasis models further suggest a pivotal role of SPINK1 in CRC progression and metastasis. Taken together, our study demonstrates an important role for the overexpressed SPINK1 in CRC disease progression, a phenomenon that needs careful evaluation towards effective therapeutic target development. PMID:26258891

  10. Extracellular acidity strengthens mesenchymal stem cells to promote melanoma progression

    PubMed Central

    Peppicelli, Silvia; Bianchini, Francesca; Toti, Alessandra; Laurenzana, Anna; Fibbi, Gabriella; Calorini, Lido

    2015-01-01

    Mesenchymal stem cells (MSC) participate to tumor stroma development and several evidence suggests that they play a role in facilitating cancer progression. Because melanoma often shows extracellular pH low enough to influence host cell as tumor cell behavior, the aim of this study is to elucidate whether acidity affects cross talk between MSC and melanoma cells to disclose new liaisons promoting melanoma progression, and to offer new therapeutic opportunities. We found that MSC grown in a low pH medium (LpH-MSC) stimulate melanoma xenografts more than MSC grown in a standard pH medium. LpH-MSC express a higher level of TGFβ that is instrumental of epithelial-to-mesenchymal transition (EMT)-like phenotype induction in melanoma cells. LpH-MSC profile also shows a switching to an oxidative phosphorylation metabolism that was accompanied by a forced glycolytic pathway of melanoma cells grown in LpH-MSC-conditioned medium. Metformin, an inhibitor of mitochondrial respiratory chain was able to reconvert oxidative metabolism and abrogate TGFβ expression in LpH-MSC. In addition, esomeprazole, a proton pump inhibitor activated in acidosis, blocked TGFβ expression in LpH-MSC through the downregulation of IkB. Both agents, metformin and esomeprazole, inhibited EMT profile in melanoma cells grown in LpH-MSC medium, and reduced glycolytic markers. Thus, acidosis of tumor microenvironment potentiates the pro-tumoral activity of MSC and orchestrates for a new potential symbiosis, which could be target to limit melanoma progression. PMID:26496168

  11. Arsenic Promotes Ubiquitinylation and Lysosomal Degradation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Chloride Channels in Human Airway Epithelial Cells*

    PubMed Central

    Bomberger, Jennifer M.; Coutermarsh, Bonita A.; Barnaby, Roxanna L.; Stanton, Bruce A.

    2012-01-01

    Arsenic exposure significantly increases respiratory bacterial infections and reduces the ability of the innate immune system to eliminate bacterial infections. Recently, we observed in the gill of killifish, an environmental model organism, that arsenic exposure induced the ubiquitinylation and degradation of cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel that is essential for the mucociliary clearance of respiratory pathogens in humans. Accordingly, in this study, we tested the hypothesis that low dose arsenic exposure reduces the abundance and function of CFTR in human airway epithelial cells. Arsenic induced a time- and dose-dependent increase in multiubiquitinylated CFTR, which led to its lysosomal degradation, and a decrease in CFTR-mediated chloride secretion. Although arsenic had no effect on the abundance or activity of USP10, a deubiquitinylating enzyme, siRNA-mediated knockdown of c-Cbl, an E3 ubiquitin ligase, abolished the arsenic-stimulated degradation of CFTR. Arsenic enhanced the degradation of CFTR by increasing phosphorylated c-Cbl, which increased its interaction with CFTR, and subsequent ubiquitinylation of CFTR. Because epidemiological studies have shown that arsenic increases the incidence of respiratory infections, this study suggests that one potential mechanism of this effect involves arsenic-induced ubiquitinylation and degradation of CFTR, which decreases chloride secretion and airway surface liquid volume, effects that would be proposed to reduce mucociliary clearance of respiratory pathogens. PMID:22467879

  12. Arsenic promotes ubiquitinylation and lysosomal degradation of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels in human airway epithelial cells.

    PubMed

    Bomberger, Jennifer M; Coutermarsh, Bonita A; Barnaby, Roxanna L; Stanton, Bruce A

    2012-05-18

    Arsenic exposure significantly increases respiratory bacterial infections and reduces the ability of the innate immune system to eliminate bacterial infections. Recently, we observed in the gill of killifish, an environmental model organism, that arsenic exposure induced the ubiquitinylation and degradation of cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel that is essential for the mucociliary clearance of respiratory pathogens in humans. Accordingly, in this study, we tested the hypothesis that low dose arsenic exposure reduces the abundance and function of CFTR in human airway epithelial cells. Arsenic induced a time- and dose-dependent increase in multiubiquitinylated CFTR, which led to its lysosomal degradation, and a decrease in CFTR-mediated chloride secretion. Although arsenic had no effect on the abundance or activity of USP10, a deubiquitinylating enzyme, siRNA-mediated knockdown of c-Cbl, an E3 ubiquitin ligase, abolished the arsenic-stimulated degradation of CFTR. Arsenic enhanced the degradation of CFTR by increasing phosphorylated c-Cbl, which increased its interaction with CFTR, and subsequent ubiquitinylation of CFTR. Because epidemiological studies have shown that arsenic increases the incidence of respiratory infections, this study suggests that one potential mechanism of this effect involves arsenic-induced ubiquitinylation and degradation of CFTR, which decreases chloride secretion and airway surface liquid volume, effects that would be proposed to reduce mucociliary clearance of respiratory pathogens.

  13. RESEARCH TOWARD THE DEVELOPMENT OF A BIOLOGICALLY BASED DOSE RESPONSE ASSESSMENT FOR INORGANIC ARSENIC CARCINOGENICITY: A PROGRESS REPORT

    EPA Science Inventory

    Cancer risk assessments for inorganic arsenic have been based on human epidemiological data, assuming a linear dose-response below the range of observation of tumors. Part of the reason for the continued use of the linear approach in arsenic risk assessments is the lack of an ad...

  14. RESEARCH TOWARD THE DEVELOPMENT OF A BIOLOGICALLY BASED DOSE RESPONSE ASSESSMENT FOR INORGANIC ARSENIC CARCINOGENICITY: A PROGRESS REPORT

    EPA Science Inventory

    Cancer risk assessments for inorganic arsenic have been based on human epidemiological data, assuming a linear dose-response below the range of observation of tumors. Part of the reason for the continued use of the linear approach in arsenic risk assessments is the lack of an ad...

  15. Recent progress of arsenic adsorption on TiO2 in the presence of coexisting ions: A review.

    PubMed

    Yan, Li; Hu, Shan; Jing, Chuanyong

    2016-11-01

    Arsenic (As)-contaminated wastewater and groundwater pose a pressing environmental issue and worldwide concern. Adsorption of As using TiO2 materials, in combination with filtration, introduces a promising technology for the treatment of As-contaminated water. This review presents an overview on the recent progress of the application of TiO2 for removal of As from wastewater and groundwater. The main focus is on the following three pressing issues that limit the field applications of TiO2 for As removal: coexisting ions, simulation of breakthrough curves, and regeneration and reuse of spent TiO2 materials. We first examined how the coexisting ions in water, especially high concentrations of cations in industrial wastewater, affect the efficacy of As removal using the TiO2 materials. We then discussed As breakthrough curves and the effect of compounded ions on the breakthrough curves. We successfully simulated the breakthrough curves by PHREEQC after integrating the CD-MUSIC model. We further discussed challenges facing the regeneration and reuse of TiO2 media for practical applications. We offer our perspectives on remaining issues and future research needs.

  16. Long-term arsenic exposure induces histone H3 Lys9 dimethylation without altering DNA methylation in the promoter region of p16(INK4a) and down-regulates its expression in the liver of mice.

    PubMed

    Suzuki, Takehiro; Nohara, Keiko

    2013-09-01

    Long-term exposure of humans to high concentrations of arsenic is associated with an increased risk of cancer. Previous studies have suggested that arsenic exposure promotes tumorigenesis by inducing changes in the expression of tumor-related genes by dysregulating DNA methylation at tumor-related gene loci. However, the causal relationships between epigenetic changes and both arsenic exposure and tumorigenesis are still unclear. In the present study, we investigated whether arsenic can change the expression of tumor-related genes by inducing epigenetic modifications before tumorigenesis. We did so by investigating the effects of long-term arsenic exposure on representative epigenetic modifications, DNA methylation and histone modifications, in the tumor-free normal liver of C57Bl/6 mice. We focused on the tumor-related genes, p16(INK4a) , RASSF1A, Ha-ras and ER-α as target genes, because their expression and promoter methylation status in mice have been reported to be affected by long-term arsenic exposure. The results showed that long-term arsenic exposure induced a significant decrease in expression of p16(INK4a) associated with an increase in level of dimethylated histone H3 lysine 9 (H3K9), a transcription-suppressive histone modification, in the promoter region, but that DNA methylation of the promoter region was unaffected. The results also showed a significant increase in recruitment of H3K9 histone methyltransferase G9a to the promoter after arsenic exposure. These findings suggest that long-term arsenic exposure may induce down-regulation of p16(INK4a) by targeting recruitment of G9a and H3K9 dimethylation without altering DNA methylation before tumorigenesis in the liver. Copyright © 2012 John Wiley & Sons, Ltd.

  17. Filamin A phosphorylation by Akt promotes cell migration in response to arsenic

    PubMed Central

    Li, Lingzhi; Lu, Yongju; Stemmer, Paul M.; Chen, Fei

    2015-01-01

    We had previously reported that trivalent arsenic (As3+), a well-known environmental carcinogen, induces phosphorylation of several putative Akt substrates. In the present report, we characterized one of these substrates by immunoprecipitation and proteomics analysis. The results indicate that a cytoskeleton remodeling protein, filamin A, with a molecular weight around 280 kDa, is phosphorylated by Akt in HEK-293 cells treated with As3+, which was also confirmed in human bronchial epithelial cell line, BEAS-2B cells. Additional biochemical and biological studies revealed that serine 2152 (S2152) of filamin A is phosphorylated by activated Akt in the cells treated with As3+. To further confirm the importance of Akt-dependent filamin A S2152 phosphorylation in As3+-induced cell migration, we over-expressed either wild type filamin A or the mutated filamin A in which the S2152 was substituted with alanine (S2152A). The capability of cell migration was reduced significantly in the cells expressing the mutated filamin A (S2152A). Clinically, we found that increased expression of filamin A predicts poorer overall survival of the lung cancer patients with adenocarcinoma. Thus, these data suggest that Akt dependent filamin A phosphorylation is one of the key events in mediating As3+-induced carcinogenesis. Antagonizing Akt signaling can ameliorate As3+-induced filamin A phosphorylation and cell migration, which may serve as a molecular targeting strategy for malignancies associated with environmental As3+ exposure. PMID:25944616

  18. Filamin A phosphorylation by Akt promotes cell migration in response to arsenic.

    PubMed

    Li, Lingzhi; Lu, Yongju; Stemmer, Paul M; Chen, Fei

    2015-05-20

    We had previously reported that trivalent arsenic (As(3+)), a well-known environmental carcinogen, induces phosphorylation of several putative Akt substrates. In the present report, we characterized one of these substrates by immunoprecipitation and proteomics analysis. The results indicate that a cytoskeleton remodeling protein, filamin A, with a molecular weight around 280 kDa, is phosphorylated by Akt in HEK-293 cells treated with As(3+), which was also confirmed in human bronchial epithelial cell line, BEAS-2B cells. Additional biochemical and biological studies revealed that serine 2152 (S2152) of filamin A is phosphorylated by activated Akt in the cells treated with As(3+). To further confirm the importance of Akt-dependent filamin A S2152 phosphorylation in As(3+)-induced cell migration, we over-expressed either wild type filamin A or the mutated filamin A in which the S2152 was substituted with alanine (S2152A). The capability of cell migration was reduced significantly in the cells expressing the mutated filamin A (S2152A). Clinically, we found that increased expression of filamin A predicts poorer overall survival of the lung cancer patients with adenocarcinoma. Thus, these data suggest that Akt dependent filamin A phosphorylation is one of the key events in mediating As(3+)-induced carcinogenesis. Antagonizing Akt signaling can ameliorate As(3+)-induced filamin A phosphorylation and cell migration, which may serve as a molecular targeting strategy for malignancies associated with environmental As(3+) exposure.

  19. Endocrine fibroblast growth factor FGF19 promotes prostate cancer progression.

    PubMed

    Feng, Shu; Dakhova, Olga; Creighton, Chad J; Ittmann, Michael

    2013-04-15

    Prostate cancer is the most common visceral malignancy and the second leading cause of cancer deaths in US men. There is broad evidence that fibroblast growth factor (FGF) receptors are important in prostate cancer initiation and progression, but the contribution of particular FGFs in this disease is not fully understood. The FGF family members FGF19, FGF21, and FGF23 comprise a distinct subfamily that circulate in serum and act in an endocrine manner. These endocrine FGFs require α-Klotho (KL) and/or β-Klotho (KLB), two related single-pass transmembrane proteins restricted in their tissue distribution, to act as coreceptors along with classic FGF receptors (FGFR) to mediate potent biologic activity. Here we show that FGF19 is expressed in primary and metastatic prostate cancer tissues, where it functions as an autocrine growth factor. Exogenous FGF19 promoted the growth, invasion, adhesion, and colony formation of prostate cancer cells at low ligand concentrations. FGF19 silencing in prostate cancer cells expressing autocrine FGF19 decreased invasion and proliferation in vitro and tumor growth in vivo. Consistent with these observations, KL and/or KLB were expressed in prostate cancer cells in vitro and in vivo, raising the possibility that additional endocrine FGFs may also exert biologic effects in prostate cancer. Our findings support the concept that therapies targeting FGFR signaling may have efficacy in prostate cancer and highlight FGF19 as a relevant endocrine FGF in this setting.

  20. [Hormone risk factors during breast tumoral promotion, progression and prognosis].

    PubMed

    Esquivel, Edith Lucia Salazar; López, Adrián Paredes; Sánchez, Leobardo Calzada

    2004-11-01

    Several hormonal factors, as menstrual irregularities, early ovarian maturation and long estrogen stimulation during women's reproductive life, have been pointed out as risk factors in the breast cancer promotion. To study the various involved factors during breast cancer evolution. Hormonal and reproductive factors were studied in 200 women with breast cancer. The greater incidence was showed in postmenopausal patients (118 patients). Nulliparity was presented in 29% of the patients, while late menopause and early menarche were presented in 25 and 8%, respectively. Having the first child at age > 30 years and family history of breast cancer (8.5%) were risk factors presented in 40% of the patients. Thirty percent of the patients showed low risk factors such as: high parity (26%), low parity (15%) and first child at age < 20 years. On the other hand, the left mammary gland was the most affected. The lesion was mainly situated in the upper-outer quadrant and upper-inside quadrant (36 and 26% in 72 and 52 patients, respectively). The decade of highest incidence was 40 to 50 years. During the first six months, 60% of the patients showed tumour progression. Nulliparity, late menopause, early menarche, first child at age > 30 years and family history of breast cancer are risk factors for serious breast cancer prognostic.

  1. Effects of Arsenic Trioxide on Minor Progressive High-Grade Osteosarcoma of the Extremities Metastatic to the Lung: Results of 39 Patients Treated in a Single Institution

    PubMed Central

    Xie, Lu; Guo, Wei; Tang, Xiaodong; Yang, Yi; Xu, Jie

    2016-01-01

    Patients who mildly progressed after first-line chemotherapy were administered arsenic trioxide (ATO) 5–10 mg intravenously daily. Thirty-nine patients were finally enrolled in the study, of whom 19 patients received first-line chemotherapy with ATO infusion while 20 patients did not. Progression-free survival at 4 months was 89.2 and 62.7% (p = 0.043) for the ATO group and the control group, respectively, while the 2-year overall survival was 61 and 16.4% (p = 0.032). PMID:27920692

  2. GRK6 deficiency promotes angiogenesis, tumor progression and metastasis

    PubMed Central

    Raghuwanshi, Sandeep K.; Smith, Nikia; Rivers, Elizabeth, J.; Thomas, Ariel J.; Sutton, Natalie; Hu, Yuhui; Mukhopadhyay, Somnath; Chen, Xiaoxin L.; Leung, TinChung; Richardson, Ricardo M.

    2013-01-01

    G protein coupled receptor kinases (GRKs) phosphorylate the activated form of G protein coupled receptors (GPCRs) leading to receptor desensitization and down-regulation. We have recently shown that the chemokine receptor, CXCR2, couples to GRK6 to regulate cellular responses including chemotaxis, angiogenesis and wound healing. In this study, we investigate the role of GRK6 in tumorigenesis using murine models of human lung cancer. Mice deficient in GRK6 (GRK6−/−) exhibited a significant increase in Lewis lung cancer (LLC) growth and metastasis relative to control littermates (GRK6+/+). GRK6 deletion had no effect on the expression of proangiogenic chemokine or vascular endothelial growth factor (VEGF), but up-regulated matrix metalloproteinase (MMP)-2 and MMP-9 release, tumor-infiltrating PMNs and microvessel density. Since βarr2−/− mice exhibited increase LLC growth and metastasis similar to that of GRK6−/−we developed a double GRK6−/−/βarr2−/− mouse model. Surprisingly, GRK6−/−/βarr2−/− mice exhibited faster tumor growth relative to GRK6−/− or βarr2−/− mice. Treatment of the mice with anti-CXCR2 antibody inhibited tumor growth in both GRK6−/− and GRK6−/−/βarr2−/− animals. Altogether, the results indicate that CXCR2 couples to GRK6 to regulate angiogenesis, tumor progression and metastasis. Deletion of GRK6 increases the activity of the host CXCR2, resulting in greater PMN infiltration and MMP release in the tumor microenvironment thereby promoting angiogenesis and metastasis. Since GRK6−/−/βarr2−/− showed greater tumor growth relative to GRK6−/− or βarr2−/− mice, the data further suggest that CXCR2 couples to different mechanisms to mediate tumor progression and metastasis. PMID:23589623

  3. Effect of arsenic on tolerance mechanisms of two plant growth-promoting bacteria used as biological inoculants.

    PubMed

    Armendariz, Ana L; Talano, Melina A; Wevar Oller, Ana L; Medina, María I; Agostini, Elizabeth

    2015-07-01

    Bacterial ability to colonize the rhizosphere of plants in arsenic (As) contaminated soils is highly important for symbiotic and free-living plant growth-promoting rhizobacteria (PGPR) used as inoculants, since they can contribute to enhance plant As tolerance and limit metalloid uptake by plants. The aim of this work was to study the effect of As on growth, exopolysaccharide (EPS) production, biofilm formation and motility of two strains used as soybean inoculants, Bradyrhizobium japonicum E109 and Azospirillum brasilense Az39. The metabolism of arsenate (As(V)) and arsenite (As(III)) and their removal and/or possible accumulation were also evaluated. The behavior of both bacteria under As treatment was compared and discussed in relation to their potential for colonizing plant rhizosphere with high content of the metalloid. B. japonicum E109 growth was reduced with As(III) concentration from 10 μM while A. brasilense Az39 showed a reduction of growth with As(III) from 500 μM. EPS and biofilm production increased significantly under 25 μM As(III) for both strains. Moreover, this was more notorious for Azospirillum under 500 μM As(III), where motility was seriously affected. Both bacterial strains showed a similar ability to reduce As(V). However, Azospirillum was able to oxidize more As(III) (around 53%) than Bradyrhizobium (17%). In addition, both strains accumulated As in cell biomass. The behavior of Azospirillum under As treatments suggests that this strain would be able to colonize efficiently As contaminated soils. In this way, inoculation with A. brasilense Az39 would positively contribute to promoting growth of different plant species under As treatment.

  4. Promotion of arsenic phytoextraction efficiency in the fern Pteris vittata by the inoculation of As-resistant bacteria: a soil bioremediation perspective

    PubMed Central

    Lampis, Silvia; Santi, Chiara; Ciurli, Adriana; Andreolli, Marco; Vallini, Giovanni

    2015-01-01

    A greenhouse pot experiment was carried out to evaluate the efficiency of arsenic phytoextraction by the fern Pteris vittata growing in arsenic-contaminated soil, with or without the addition of selected rhizobacteria isolated from the polluted site. The bacterial strains were selected for arsenic resistance, the ability to reduce arsenate to arsenite, and the ability to promote plant growth. P. vittata plants were cultivated for 4 months in a contaminated substrate consisting of arsenopyrite cinders and mature compost. Four different experimental conditions were tested: (i) non-inoculated plants; (ii) plants inoculated with the siderophore-producing and arsenate-reducing bacteria Pseudomonas sp. P1III2 and Delftia sp. P2III5 (A); (iii) plants inoculated with the siderophore and indoleacetic acid-producing bacteria Bacillus sp. MPV12, Variovorax sp. P4III4, and Pseudoxanthomonas sp. P4V6 (B), and (iv) plants inoculated with all five bacterial strains (AB). The presence of growth-promoting rhizobacteria increased plant biomass by up to 45% and increased As removal efficiency from 13% without bacteria to 35% in the presence of the mixed inoculum. Molecular analysis confirmed the persistence of the introduced bacterial strains in the soil and resulted in a significant impact on the structure of the bacterial community. PMID:25741356

  5. GT-repeat polymorphism in the heme oxygenase-1 gene promoter is associated with cardiovascular mortality risk in an arsenic-exposed population in northeastern Taiwan

    SciTech Connect

    Wu, Meei-Maan; Chiou, Hung-Yi; Chen, Chi-Ling; Wang, Yuan-Hung; Hsieh, Yi-Chen; Lien, Li-Ming; Lee, Te-Chang; Chen, Chien-Jen

    2010-11-01

    Inorganic arsenic has been associated with increased risk of atherosclerotic vascular disease and mortality in humans. A functional GT-repeat polymorphism in the heme oxygenase-1 (HO-1) gene promoter is inversely correlated with the development of coronary artery disease and restenosis after clinical angioplasty. The relationship of HO-1 genotype with arsenic-associated cardiovascular disease has not been studied. In this study, we evaluated the relationship between the HO-1 GT-repeat polymorphism and cardiovascular mortality in an arsenic-exposed population. A total of 504 study participants were followed up for a median of 10.7 years for occurrence of cardiovascular deaths (coronary heart disease, cerebrovascular disease, and peripheral arterial disease). Cardiovascular risk factors and DNA samples for determination of HO-1 GT repeats were obtained at recruitment. GT repeats variants were grouped into the S (< 27 repeats) or L allele ({>=} 27 repeats). Relative mortality risk was estimated using Cox regression analysis, adjusted for competing risk of cancer and other causes. For the L/L, L/S, and S/S genotype groups, the crude mortalities for cardiovascular disease were 8.42, 3.10, and 2.85 cases/1000 person-years, respectively. After adjusting for conventional cardiovascular risk factors and competing risk of cancer and other causes, carriers with class S allele (L/S or S/S genotypes) had a significantly reduced risk of cardiovascular mortality compared to non-carriers (L/L genotype) [OR, 0.38; 95% CI, 0.16-0.90]. In contrast, no significant association was observed between HO-1 genotype and cancer mortality or mortality from other causes. Shorter (GT)n repeats in the HO-1 gene promoter may confer protective effects against cardiovascular mortality related to arsenic exposure.

  6. Correlation of Breastmilk Arsenic With Maternal, Infant Urinary Arsenic and Drinking Water Arsenic in an Arsenic Affected Area of Bangladesh

    NASA Astrophysics Data System (ADS)

    Alauddin, M.; Islam, M. R.; Milton, A. H.; Alauddin, S. T.; Mouly, T.; Behri, E.; Ayesha, A.; Akter, S.; Islam, M. M.

    2016-12-01

    About 97% of population in Bangladesh depend on groundwater as the principle source of drinking water and this water is highly contaminated with inorganic arsenic. Consumption of arsenic contaminated drinking water by pregnant women raises the prospect of early life exposure to inorganic arsenic for newborn which may be lead to adverse health effect in later life. This work was carried out in parts of Gopalganj district in Bangladesh, a region affected by arsenic contamination in groundwater. The objective of the work was to assess potential early life exposure to arsenic for infants through breastfeeding by mothers who were drinking water with arsenic levels ranging from 100 to 300 µg/l. A cohort of 30 mother-baby pairs were selected for the current study. Breastmilk samples from mothers, urine samples from each pair of subjects at 1, 6 and 9 month age of infant were collected and total arsenic were determined in these samples. In addition speciation of urinary arsenic and metabolites were carried out in 12 mother-baby pairs. Median level for breastmilk arsenic were 0.50 µg/l. Urinary arsenic of infants did not correlate with breastmilk arsenic with progressing age of infants. Maternal and infant urinary total arsenic at 1 month age of infant showed some positive correlation (r = 0.39). In infant urine major metabolite were dimethyl arsenic acid (DMA) (approximately 70%) indicating good methylating capacity for infants at 1 and 6 months of age. In conclusion, infants were not exposed to arsenic through breastfeeding even though mothers were exposed to significant levels of arsenic through drinking water.

  7. Technology transfer: Promoting irrigation progress and best management practices

    USDA-ARS?s Scientific Manuscript database

    Educational efforts promoting irrigation best management practices are designed to increase adoption of these practices and increase public understanding of the importance of irrigation. They increase visibility and the impact of the Ogallala Aquifer Program and promote affiliated research and exten...

  8. High incidence of activating TERT promoter mutations in meningiomas undergoing malignant progression.

    PubMed

    Goutagny, Stéphane; Nault, Jean C; Mallet, Maxime; Henin, Dominique; Rossi, Jessica Z; Kalamarides, Michel

    2014-03-01

    Meningiomas are common central nervous system tumors. The World Health Organization (WHO) defines three grades, predictive of the risk of recurrence. These tumors can relapse frequently and sometimes undergo malignant transformation. Maintenance of telomere length is a key process in malignant progression, and mutations in TERT promoter have recently been identified in various types of cancer. We sequenced the TERT promoter in 85 meningiomas from 73 patients. We found a high incidence of TERT promoter mutations in patients with meningiomas undergoing malignant histological progression (28%, n = 5/18 patients). In this subset of patients with histological progression, TERT promoter mutations were found in both the lowest and the highest grade tumors, and in both NF2-mutated and nonmutated samples. In contrast, one mutation was identified in 35 meningiomas without recurrence or progression, belonging to various histological grades. This sample was an aggressive meningioma in a patient who died shortly after surgery. Interestingly, tumors showing relapse without histological progression were not mutated for TERT promoter (n = 20). Finally, TERT promoter mutations were associated with a marked increase in TERT expression. Thus, TERT promoter mutations are pivotal genetic alterations involved in malignant progression of meningiomas and could be used as a biomarker to identify meningiomas at risk of malignant transformation. © 2013 International Society of Neuropathology.

  9. Promoting Student Progressions in Science Classrooms: A Video Study

    ERIC Educational Resources Information Center

    Jin, Hui; Johnson, Michele E.; Shin, Hyo Jeong; Anderson, Charles W.

    2017-01-01

    This study was conducted in a large-scale environmental literacy project. In the project, we developed a Learning Progression Framework (LPF) for matter and energy in social-ecological systems; the LPF contains four achievement levels. Based on the LPF, we designed a Plant Unit to help Levels 2 and 3 students advance to Level 4 of the LPF. In the…

  10. Recent Progress in Promoting Gender Equality for Japanese Scientists

    NASA Astrophysics Data System (ADS)

    Tajima, Setsuko; Nishitani-Gamo, Mikka

    2009-04-01

    The last three years have been an epoch-making period in promoting gender equality in the Japanese science community. Motivated by recommendations we made on the basis of a large-scale survey, the Japanese government started several projects in 2006 for supporting women scientists and attracting girls to science and technology. In spite of these efforts, we see only very slow increase in the number of women researchers in professional positions.

  11. Arsenic Methyltransferase

    EPA Science Inventory

    The metalloid arsenic enters the environment by natural processes (volcanic activity, weathering of rocks) and by human activity (mining, smelting, herbicides and pesticides). Although arsenic has been exploited for homicidal and suicidal purposes since antiquity, its significan...

  12. Arsenic Methyltransferase

    EPA Science Inventory

    The metalloid arsenic enters the environment by natural processes (volcanic activity, weathering of rocks) and by human activity (mining, smelting, herbicides and pesticides). Although arsenic has been exploited for homicidal and suicidal purposes since antiquity, its significan...

  13. Occupational therapists' experiences of career progression following promotion.

    PubMed

    Nelson, Helen; Giles, Susan; McInnes, Heather; Hitch, Danielle

    2015-12-01

    The recruitment and retention of a skilled occupational therapy workforce is highlighted as a key issue for the profession, and yet there have been relatively few studies into the career progression of occupational therapists. A qualitative, naturalistic approach was adopted to answer the research question, using semi-structured interviews to gather data. Eleven purposefully selected participants at an Australian health service were interviewed as part of this study. Categories representing the most common themes and topics supplied by participants within their individual interviews were identified and consolidated by the research team. The trustworthiness of this study was supported by strategies to maximise its credibility, dependability and confirmability. Four main themes were elicited from the data - (i) Readiness for progression, (ii) Tools and processes, (iii) Expectations and (iv) What I wish I had known first. Within these themes, related findings were also identified by both Grade 2 and Grade 3 staff. This study indicates that the readiness of occupational therapists to climb the career ladder is influenced by the tools and processes they can utilise, and the expectations they have around the realities of their new position. With hindsight, participants highlighted some things they wish they had known at the time of transition, which appeared to have been implicit. This study is the first to address the common issues for occupational therapy staff around progression between grade levels. It therefore provides a basis for further research in other practice settings and for the development of supports for therapists climbing the career ladder. © 2015 Occupational Therapy Australia.

  14. ARSENIC REMOVAL

    EPA Science Inventory

    Presentation covered five topics; arsenic chemistry, best available technology (BAT), surface water technology, ground water technology and case studies of arsenic removal. The discussion on arsenic chemistry focused on the need and method of speciation for AsIII and AsV. BAT me...

  15. Hypermutation of DPYD Deregulates Pyrimidine Metabolism and Promotes Malignant Progression

    PubMed Central

    Edwards, Lauren; Gupta, Rohit; Filipp, Fabian V.

    2016-01-01

    New strategies are needed to diagnose and target human melanoma. To this end, genomic analyses was performed to assess somatic mutations and gene expression signatures using a large cohort of human skin cutaneous melanoma (SKCM) patients from The Cancer Genome Atlas (TCGA) project to identify critical differences between primary and metastatic tumors. Interestingly, pyrimidine metabolism is one of the major pathways to be significantly enriched and deregulated at the transcriptional level in melanoma progression. In addition, dihydropyrimidine dehydrogenase (DPYD) and other important pyrimidine-related genes: DPYS, AK9, CAD, CANT1, ENTPD1, NME6, NT5C1A, POLE, POLQ, POLR3B, PRIM2, REV3L, and UPP2 are significantly enriched in somatic mutations relative to the background mutation rate. Structural analysis of the DPYD protein dimer reveals a potential hotspot of recurring somatic mutations in the ligand binding sites as well as the interfaces of protein domains that mediated electron transfer. Somatic mutations of DPYD are associated with upregulation of pyrimidine degradation, nucleotide synthesis, and nucleic acid processing while salvage and nucleotide conversion is downregulated in TCGA SKCM. PMID:26609109

  16. Speciation and detection of arsenic in aqueous samples: a review of recent progress in non-atomic spectrometric methods.

    PubMed

    Ma, Jian; Sengupta, Mrinal K; Yuan, Dongxing; Dasgupta, Purnendu K

    2014-06-11

    Inorganic arsenic (As) displays extreme toxicity and is a class A human carcinogen. It is of interest to both analytical chemists and environmental scientists. Facile and sensitive determination of As and knowledge of the speciation of forms of As in aqueous samples are vitally important. Nearly every nation has relevant official regulations on permissible limits of drinking water As content. The size of the literature on As is therefore formidable. The heart of this review consists of two tables: one is a compilation of principal official documents and major review articles, including the toxicology and chemistry of As. This includes comprehensive official compendia on As speciation, sample treatment, recommended procedures for the determination of As in specific sample matrices with specific analytical instrument(s), procedures for multi-element (including As) speciation and analysis, and prior comprehensive reviews on arsenic analysis. The second table focuses on the recent literature (2005-2013, the coverage for 2013 is incomplete) on As measurement in aqueous matrices. Recent As speciation and analysis methods based on spectrometric and electrochemical methods, inductively coupled plasma-mass spectrometry, neutron activation analysis and biosensors are summarized. We have deliberately excluded atomic optical spectrometric techniques (atomic absorption, atomic fluorescence, inductively coupled plasma-optical emission spectrometry) not because they are not important (in fact the majority of arsenic determinations are possibly carried out by one of these techniques) but because these methods are sufficiently mature and little meaningful innovation has been made beyond what is in the officially prescribed compendia (which are included) and recent reviews are available.

  17. Activation of the Notch1/STAT3/Twist signaling axis promotes gastric cancer progression.

    PubMed

    Hsu, Kai-Wen; Hsieh, Rong-Hong; Huang, Kuo-Hung; Fen-Yau Li, Anna; Chi, Chin-Wen; Wang, Tzu-Yin; Tseng, Min-Jen; Wu, Kou-Juey; Yeh, Tien-Shun

    2012-08-01

    Gastric carcinoma is one of the most common malignancies and a lethal cancer in the world. Notch signaling and transcription factors STAT3 (signal transducer and activator of transcription 3) and Twist regulate tumor development and are critical regulators of gastric cancer progression. Herein, the relationship among Notch, STAT3 and Twist pathways in the control of gastric cancer progression was studied. We found that Twist and phosphorylated STAT3 levels were promoted by the activated Notch1 receptor in human stomach adenocarcinoma SC-M1, embryonic kidney HEK293 and erythroleukemia K562 cells. Notch1 signaling dramatically induced Twist promoter activity through a C promoter binding factor-1-independent manner and STAT3 phosphorylation. Overexpression of Notch1 receptor intracellular domain (N1IC) enhanced the interaction between nuclear STAT3 and Twist promoter in cells. Gastric cancer progression of SC-M1 cells was promoted by N1IC through STAT3 phosphorylation and Twist expression including colony formation, migration and invasion. STAT3 regulated gastric cancer progression of SC-M1 cells via Twist. N1IC also elevated the progression of other gastric cancer cells such as AGS and KATO III cells through STAT3 and Twist. The N1IC-promoted tumor growth and lung metastasis of SC-M1 cells in mice were suppressed by the STAT3 inhibitor JSI-124 and Twist knockdown. Furthermore, Notch1 and Notch ligand Jagged1 expressions were significantly associated with phosphorylated STAT3 and Twist levels in gastric cancer tissues of patients. Taken together, these results suggest that Notch1/STAT3/Twist signaling axis is involved in progression of human gastric cancer and modulation of this cascade has potential for the targeted combination therapy.

  18. Folic Acid Supplementation Promotes Mammary Tumor Progression in a Rat Model

    PubMed Central

    Deghan Manshadi, Shaidah; Ishiguro, Lisa; Sohn, Kyoung-Jin; Medline, Alan; Renlund, Richard; Croxford, Ruth; Kim, Young-In

    2014-01-01

    Folic acid supplementation may prevent the development of cancer in normal tissues but may promote the progression of established (pre)neoplastic lesions. However, whether or not folic acid supplementation can promote the progression of established (pre)neoplastic mammary lesions is unknown. This is a critically important issue because breast cancer patients and survivors in North America are likely exposed to high levels of folic acid owing to folic acid fortification and widespread supplemental use after cancer diagnosis. We investigated whether folic acid supplementation can promote the progression of established mammary tumors. Female Sprague-Dawley rats were placed on a control diet and mammary tumors were initiated with 7,12-dimethylbenza[a]anthracene at puberty. When the sentinel tumor reached a predefined size, rats were randomized to receive a diet containing the control, 2.5x, 4x, or 5x supplemental levels of folic acid for up to 12 weeks. The sentinel mammary tumor growth was monitored weekly. At necropsy, the sentinel and all other mammary tumors were analyzed histologically. The effect of folic acid supplementation on the expression of proteins involved in proliferation, apoptosis, and mammary tumorigenesis was determined in representative sentinel adenocarcinomas. Although no clear dose-response relationship was observed, folic acid supplementation significantly promoted the progression of the sentinel mammary tumors and was associated with significantly higher sentinel mammary tumor weight and volume compared with the control diet. Furthermore, folic acid supplementation was associated with significantly higher weight and volume of all mammary tumors. The most significant and consistent mammary tumor-promoting effect was observed with the 2.5x supplemental level of folic acid. Folic acid supplementation was also associated with an increased expression of BAX, PARP, and HER2. Our data suggest that folic acid supplementation may promote the progression

  19. Linking Microbial Activity with Arsenic Fate during Cow Dung Disposal of Arsenic-Bearing Wastes

    NASA Astrophysics Data System (ADS)

    Clancy, T. M.; Reddy, R.; Tan, J.; Hayes, K. F.; Raskin, L.

    2014-12-01

    To address widespread arsenic contamination of drinking water sources numerous technologies have been developed to remove arsenic. All technologies result in the production of an arsenic-bearing waste that must be evaluated and disposed in a manner to limit the potential for environmental release and human exposure. One disposal option that is commonly recommended for areas without access to landfills is the mixing of arsenic-bearing wastes with cow dung. These recommendations are made based on the ability of microorganisms to create volatile arsenic species (including mono-, di-, and tri-methylarsine gases) to be diluted in the atmosphere. However, most studies of environmental microbial communities have found only a small fraction (<0.1 %) of the total arsenic present in soils or rice paddies is released via volatilization. Additionally, past studies often have not monitored arsenic release in the aqueous phase. Two main pathways for microbial arsenic volatilization are known and include methylation of arsenic during methanogenesis and methylation by arsenite S-adenosylmethionine methyltransferase. In this study, we compare the roles of these two pathways in arsenic volatilization and aqueous mobilization through mesocosm experiments with cow dung and arsenic-bearing wastes produced during drinking water treatment in West Bengal, India. Arsenic in gaseous, aqueous, and solid phases was measured. Consistent with previous reports, less than 0.02% of the total arsenic present was volatilized. A much higher amount (~5%) of the total arsenic was mobilized into the liquid phase. Through the application of molecular tools, including 16S rRNA sequencing and quantification of gene transcripts involved in methanogenesis, this study links microbial community activity with arsenic fate in potential disposal environments. These results illustrate that disposal of arsenic-bearing wastes by mixing with cow dung does not achieve its end goal of promoting arsenic volatilization

  20. Arsenic poisoning.

    PubMed

    Schoolmeester, W L; White, D R

    1980-02-01

    Arsenic poisoning continues to require awareness of its diverse clinical manifestations. Industry is the major source of arsenic exposure. Although epidemiologic studies strongly contend that arsenic is carcinogenic, there are little supportive research data. Arsenic poisoning, both acute and chronic, is often overlooked initially in the evaluation of the patient with multisystem disease, but once it is suspected, many accurate methods are available to quantitate the amount and duration of exposure. Treatment with dimercaprol remains the mainstay of therapy, and early treatment is necessary to prevent irreversible complications.

  1. Hippo transducer TAZ promotes epithelial mesenchymal transition and supports pancreatic cancer progression

    PubMed Central

    Xie, Dacheng; Cui, Jiujie; Xia, Tian; Jia, Zhiliang; Wang, Liang; Wei, Wenfei; Zhu, Anna; Gao, Yong; Xie, Keping; Quan, Ming

    2015-01-01

    Transcriptional co-activator with PDZ binding motif (TAZ) is a transducer of the Hippo pathway and promotes cancer development and progression. In the present study, we sought to determine the roles and underlying mechanisms of elevated expression and activation of TAZ in pancreatic cancer development and progression. The mechanistic role of TAZ and Hippo signaling in promotion of pancreatic cancer development and progression was examined using cell culture, molecular biology, and mouse models. The relevance of our experimental and mechanistic findings was validated using human pancreatic tumor specimens. We found that TAZ expression was markedly higher in pancreatic tumors than in normal pancreatic tissue. Further analysis of the correlation of TAZ expression with tissue microarray clinicopathologic parameters revealed that this expression was positively associated with tumor differentiation. Also, TAZ expression was higher in pancreatic cancer cell lines than in pancreatic ductal epithelial cells. TAZ activation in pancreatic cancer cells promoted their proliferation, migration, invasion, and epithelial-mesenchymal transition. Further mechanistic studies demonstrated that aberrant expression and activation of TAZ in pancreatic cancer cells resulted from suppression of the expression of Merlin, a positive regulator upstream of the Hippo pathway, and that the oncogenic function of TAZ in pancreatic cancer cells was mediated by TEA/ATTS domain transcription factors. Therefore, TAZ functioned as an oncogene and promoted pancreatic cancer epithelial-mesenchymal transition and progression. TAZ thus may be a target for effective therapeutic strategies for pancreatic cancer. PMID:26416426

  2. Macrophages promote the progression of premalignant mammary lesions to invasive cancer.

    PubMed

    Carron, Emily C; Homra, Samuel; Rosenberg, Jillian; Coffelt, Seth B; Kittrell, Frances; Zhang, Yiqun; Creighton, Chad J; Fuqua, Suzanne A; Medina, Daniel; Machado, Heather L

    2017-01-31

    Breast cancer initiation, progression and metastasis rely on a complex interplay between tumor cells and their surrounding microenvironment. Infiltrating immune cells, including macrophages, promote mammary tumor progression and metastasis; however, less is known about the role of macrophages in early stage lesions. In this study, we utilized a transplantable p53-null model of early progression to characterize the immune cell components of early stage lesions. We show that macrophages are recruited to ductal hyperplasias with a high tumor-forming potential where they are differentiated and polarized toward a tumor-promoting phenotype. These macrophages are a unique subset of macrophages, characterized by pro-inflammatory, anti-inflammatory and immunosuppressive factors. Macrophage ablation studies showed that macrophages are required for both early stage progression and primary tumor formation. These studies suggest that therapeutic targeting of tumor-promoting macrophages may not only be an effective strategy to block tumor progression and metastasis, but may also have critical implications for breast cancer prevention.

  3. The Shh receptor Boc promotes progression of early medulloblastoma to advanced tumors.

    PubMed

    Mille, Frédéric; Tamayo-Orrego, Lukas; Lévesque, Martin; Remke, Marc; Korshunov, Andrey; Cardin, Julie; Bouchard, Nicolas; Izzi, Luisa; Kool, Marcel; Northcott, Paul A; Taylor, Michael D; Pfister, Stefan M; Charron, Frédéric

    2014-10-13

    During cerebellar development, Sonic hedgehog (Shh) signaling drives the proliferation of granule cell precursors (GCPs). Aberrant activation of Shh signaling causes overproliferation of GCPs, leading to medulloblastoma. Although the Shh-binding protein Boc associates with the Shh receptor Ptch1 to mediate Shh signaling, whether Boc plays a role in medulloblastoma is unknown. Here, we show that BOC is upregulated in medulloblastomas and induces GCP proliferation. Conversely, Boc inactivation reduces proliferation and progression of early medulloblastomas to advanced tumors. Mechanistically, we find that Boc, through elevated Shh signaling, promotes high levels of DNA damage, an effect mediated by CyclinD1. High DNA damage in the presence of Boc increases the incidence of Ptch1 loss of heterozygosity, an important event in the progression from early to advanced medulloblastoma. Together, our results indicate that DNA damage promoted by Boc leads to the demise of its own coreceptor, Ptch1, and consequently medulloblastoma progression. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Hmga2 functions as a competing endogenous RNA to promote lung cancer progression

    PubMed Central

    Kumar, Madhu S.; Armenteros-Monterroso, Elena; East, Philip; Chakravorty, Probir; Matthews, Nik; Winslow, Monte M.; Downward, Julian

    2013-01-01

    Non-small cell lung cancer (NSCLC) is the most prevalent histological cancer subtype worldwide1. As the majority of patients present with invasive, metastatic disease2, it is vital to understand the basis for lung cancer progression. Hmga2 is highly expressed in metastatic lung adenocarcinoma where it contributes to cancer progression and metastasis3-6. Here we show that Hmga2 promotes lung cancer progression by operating as a competing endogenous RNA (ceRNA)7-11 for the let-7 microRNA (miRNA) family. Hmga2 can promote the transformation of lung cancer cells independent of protein-coding function but dependent upon the presence of let-7 sites; this occurs without changes in the levels of let-7 isoforms, suggesting that Hmga2 affects let-7 activity by altering miRNA targeting. These effects are further observed in vivo, where Hmga2 ceRNA activity drives lung cancer growth, invasion and dissemination. Integrated analysis of miRNA target prediction algorithms and metastatic lung cancer gene expression data reveals the TGF-β co-receptor Tgfbr312 as a putative target of Hmga2 ceRNA function. Tgfbr3 expression is regulated by the Hmga2 ceRNA via differential recruitment to Argonaute-2 (Ago2), and TGF-β signalling driven by Tgfbr3 is largely necessary for Hmga2 to promote lung cancer progression. Finally, analysis of NSCLC patient gene expression data reveals that HMGA2 and TGFBR3 are co-ordinately regulated in NSCLC patient material, a vital corollary to ceRNA function. Taken together, these results suggest that Hmga2 promotes lung carcinogenesis as both a protein-coding gene and a non-coding RNA; such dual-function regulation of gene expression networks reflects a novel means by which oncogenes promote disease progression. PMID:24305048

  5. Arsenic sulfide promotes apoptosis in retinoid acid resistant human acute promyelocytic leukemic NB4-R1 cells through downregulation of SET protein.

    PubMed

    Tian, Yuwang; Liu, Yanfeng; He, Pengcheng; Liu, Feng; Zhou, Naicen; Cheng, Xiaoyan; Shi, Lili; Zhu, Huachao; Zhao, Jing; Wang, Yuan; Zhang, Mei

    2014-01-01

    Tetra-arsenic tetra-sulfide (As4S4) is an arsenic compound with anti-tumor activity, especially in acute promyelocytic leukemia (APL) that are resistant to retinoic acid (RA). Although recent studies revealed that the therapeutic action of As4S4 is closely associated with the induction of cellular apoptosis, the exact molecular mechanism of action of As4S4 in RA-resistant APL remains to be clarified. In this study, we found that As4S4-induced apoptosis was accompanied by reduced mRNA and protein expression of SET gene in RA-resistant NB4-R1 cells. Moreover, RNAi knockdown of SET gene further promoted As4S4-induced apoptosis, while SET over-expression inhibited it, suggesting that As4S4 induces apoptosis through the reduction of SET protein in NB4-R1 cells. We also demonstrated that the knockdown of SET gene resulted in the upregulation of protein phosphatase 2 (PP2A) expression and the downregulation of promyelocytic leukemia and retinoic acid receptor α fusion gene (PML-RARα) expression, which were enhanced by As4S4 treatments. By contrast, over-expression of SET gene resulted in PP2A downregulation and PML-RARα upregulation, which were abolished by As4S4 pretreatment. Since PP2A is a pro-apoptotic factor and PMLRARα is an anti-apoptotic factor, our results suggest that As4S4-induced apoptosis in NB4-R1 cells is through the downregulation of SET protein expression, which in turn increases PP2A and reduces PML-RARα expressions to lead to cell apoptosis.

  6. In pursuit of progress: promotion motivation and risk preference in the domain of gains.

    PubMed

    Zou, Xi; Scholer, Abigail A; Higgins, E Tory

    2014-02-01

    This article examines the role of promotion motivation in decision making in the domain of gains. Using a stock investment paradigm in which individuals believed that they were making decisions that were real and consequential, we found that promotion motivation, and not prevention motivation, predicted the likelihood of switching between risky and conservative choices in the domain of gains. Promotion-focused participants chose a relatively risky option when their stock portfolio remained unchanged (stuck at 0, the status quo) but switched to a relatively conservative option when they had just experienced a large gain (Studies 1-4), both when regulatory focus was measured (Study 1) and manipulated (Studies 2-4). Studies in which progress was manipulated (Study 3) and measured (Study 4) provided evidence that it is perceptions of progress that underlie this tactical switch in risk preferences within the promotion system. We discuss the implications of these findings for decision making and the role of progress in self-regulation.

  7. Liver is a target of arsenic carcinogenesis.

    PubMed

    Liu, Jie; Waalkes, Michael P

    2008-09-01

    Inorganic arsenic is clearly a human carcinogen causing tumors of the skin, lung, urinary bladder, and possibly liver (IARC, 2004). At the time of construction of this monograph, the evidence for arsenic as a hepatocarcinogen in humans was considered controversial and in rodents considered insufficient. However, recent data has accumulated indicating hepatocarcinogenicity of arsenic. This forum reevaluates epidemiology studies, rodent studies together with in vitro models, and focuses on the liver as a target organ of arsenic toxicity and carcinogenesis. Hepatocellular carcinoma and hepatic angiosarcoma, have been frequently associated with environmental or medicinal exposure to arsenicals. Preneoplastic lesions, including hepatomegaly, hepatoportal sclerosis, fibrosis, and cirrhosis often occur after chronic arsenic exposure. Recent work in mice clearly shows that exposure to inorganic arsenic during gestation induces tumors, including hepatocellular adenoma and carcinoma, in offspring when they reach adulthood. In rats, the methylated arsenicals, dimethylarsinic acid promotes diethylnitrosamine-initiated liver tumors, whereas trimethylarsine oxide induces liver adenomas. Chronic exposure of rat liver epithelial cells to low concentrations of inorganic arsenic induces malignant transformation, producing aggressive, undifferentiated epithelial tumors when inoculated into the Nude mice. There are a variety of potential mechanisms for arsenical-induced hepatocarcinogenesis, such as oxidative DNA damage, impaired DNA damage repair, acquired apoptotic tolerance, hyperproliferation, altered DNA methylation, and aberrant estrogen signaling. Some of these mechanisms may be liver specific/selective. Overall, accumulating evidence clearly indicates that the liver could be an important target of arsenic carcinogenesis.

  8. Sustained TNF production by central nervous system infiltrating macrophages promotes progressive autoimmune encephalomyelitis.

    PubMed

    Valentin-Torres, Alice; Savarin, Carine; Hinton, David R; Phares, Timothy W; Bergmann, Cornelia C; Stohlman, Stephen A

    2016-02-22

    Tumor necrosis factor (TNF) has pleiotropic functions during both the demyelinating autoimmune disease multiple sclerosis (MS) and its murine model experimental autoimmune encephalomyelitis (EAE). How TNF regulates disability during progressive disease remains unresolved. Using a progressive EAE model characterized by sustained TNF and increasing morbidity, this study evaluates the role of unregulated TNF in exacerbating central nervous system (CNS) pathology and inflammation. Progressive MS was mimicked by myelin oligodendrocyte glycoprotein (MOG) peptide immunization of mice expressing a dominant negative IFN-γ receptor alpha chain under the human glial fibrillary acidic protein promoter (GFAPγR1∆). Diseased GFAPγR1∆ mice were treated with anti-TNF or control monoclonal antibody during acute disease to monitor therapeutic effects on sustained disability, demyelination, CNS inflammation, and blood brain barrier (BBB) permeability. TNF was specifically sustained in infiltrating macrophages. Anti-TNF treatment decreased established clinical disability and mortality rate within 7 days. Control of disease progression was associated with a decline in myelin loss and leukocyte infiltration, as well as macrophage activation. In addition to mitigating CNS inflammation, TNF neutralization restored BBB integrity and enhanced CNS anti-inflammatory responses. Sustained TNF production by infiltrating macrophages associated with progressive EAE exacerbates disease severity by promoting inflammation and disruption of BBB integrity, thereby counteracting establishment of an anti-inflammatory environment required for disease remission.

  9. Enhanced carcinogenicity by coexposure to arsenic and iron and a novel remediation system for the elements in well drinking water.

    PubMed

    Kumasaka, Mayuko Y; Yamanoshita, Osamu; Shimizu, Shingo; Ohnuma, Shoko; Furuta, Akio; Yajima, Ichiro; Nizam, Saika; Khalequzzaman, Md; Shekhar, Hossain U; Nakajima, Tamie; Kato, Masashi

    2013-03-01

    Various carcinomas including skin cancer are explosively increasing in arsenicosis patients who drink arsenic-polluted well water, especially in Bangladesh. Although well drinking water in the cancer-prone areas contains various elements, very little is known about the effects of elements except arsenic on carcinogenicity. In order to clarify the carcinogenic effects of coexposure to arsenic and iron, anchorage-independent growth and invasion in human untransformed HaCaT and transformed A431 keratinocytes were examined. Since the mean ratio of arsenic and iron in well water was 1:10 in cancer-prone areas of Bangladesh, effects of 1 μM arsenic and 10 μM iron were investigated. Iron synergistically promoted arsenic-mediated anchorage-independent growth in untransformed and transformed keratinocytes. Iron additionally increased invasion in both types of keratinocytes. Activities of c-SRC and ERK that regulate anchorage-independent growth and invasion were synergistically enhanced in both types of keratinocytes. Our results suggest that iron promotes arsenic-mediated transformation of untransformed keratinocytes and progression of transformed keratinocytes. We then developed a low-cost and high-performance adsorbent composed of a hydrotalcite-like compound for arsenic and iron. The adsorbent rapidly reduced concentrations of both elements from well drinking water in cancer-prone areas of Bangladesh to levels less than those in WHO health-based guidelines for drinking water. Thus, we not only demonstrated for the first time increased carcinogenicity by coexposure to arsenic and iron but also proposed a novel remediation system for well drinking water.

  10. KITENIN promotes glioma invasiveness and progression, associated with the induction of EMT and stemness markers

    PubMed Central

    Oh, Se-Jeong; Kim, Ok; Joo, Young-Eun; Bae, Jeong-A; Yoon, Somy; Ryu, Hyang-Hwa; Jung, Shin; Kim, Kyung-Keun; Lee, Jae-Hyuk; Moon, Kyung-Sub

    2015-01-01

    KITENIN (KAI1 COOH-terminal interacting tetraspanin) promotes tumor invasion and metastasis in various cancers. This study assessed the association between KITENIN expression and advanced glioma grade in patients. In vitro assays revealed that KITENIN knockdown inhibited the invasion and migration of glioma cells, whereas KITENIN overexpression promoted their invasion and migration. In orthotopic mouse tumor models, mice transplanted with KITENIN-transfected glioma cells had significantly shorter survival than mice transplanted with mock-transfected cells. Patients with low KITENIN expression showed a significantly longer progression-free survival than patients with high KITENIN expression. KITENIN induced the expression of the epithelial-mesenchymal transition (EMT) markers (N-cadherin, ZEB1, ZEB2, SNAIL and SLUG) as well as the glioma stemness markers (CD133, ALDH1 and EPH-B1). Taken together, these findings showed that high levels of KITENIN increased glioma invasiveness and progression, associated with the up-regulation of EMT and stemness markers. PMID:25605251

  11. Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5

    PubMed Central

    Vogiatzi, Fotini; Brandt, Dominique T.; Schneikert, Jean; Fuchs, Jeannette; Grikscheit, Katharina; Wanzel, Michael; Pavlakis, Evangelos; Charles, Joël P.; Timofeev, Oleg; Nist, Andrea; Mernberger, Marco; Kantelhardt, Eva J.; Siebolts, Udo; Bartel, Frank; Jacob, Ralf; Rath, Ariane; Moll, Roland; Grosse, Robert; Stiewe, Thorsten

    2016-01-01

    Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in cancer and are often associated with progression from benign to invasive stages with metastatic potential. Mutations inactivate tumor suppression by p53, and some endow the protein with novel gain of function (GOF) properties that actively promote tumor progression and metastasis. By comparative gene expression profiling of p53-mutated and p53-depleted cancer cells, we identified ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a mutant p53 target gene, which functions as a uridine 5′-diphosphatase (UDPase) in the endoplasmic reticulum (ER) to promote the folding of N-glycosylated membrane proteins. A comprehensive pan-cancer analysis revealed a highly significant correlation between p53 GOF mutations and ENTPD5 expression. Mechanistically, mutp53 is recruited by Sp1 to the ENTPD5 core promoter to induce its expression. We show ENTPD5 to be a mediator of mutant p53 GOF activity in clonogenic growth, architectural tissue remodeling, migration, invasion, and lung colonization in an experimental metastasis mouse model. Our study reveals folding of N-glycosylated membrane proteins in the ER as a mechanism underlying the metastatic progression of tumors with mutp53 that could provide new possibilities for cancer treatment. PMID:27956623

  12. Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5.

    PubMed

    Vogiatzi, Fotini; Brandt, Dominique T; Schneikert, Jean; Fuchs, Jeannette; Grikscheit, Katharina; Wanzel, Michael; Pavlakis, Evangelos; Charles, Joël P; Timofeev, Oleg; Nist, Andrea; Mernberger, Marco; Kantelhardt, Eva J; Siebolts, Udo; Bartel, Frank; Jacob, Ralf; Rath, Ariane; Moll, Roland; Grosse, Robert; Stiewe, Thorsten

    2016-12-27

    Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in cancer and are often associated with progression from benign to invasive stages with metastatic potential. Mutations inactivate tumor suppression by p53, and some endow the protein with novel gain of function (GOF) properties that actively promote tumor progression and metastasis. By comparative gene expression profiling of p53-mutated and p53-depleted cancer cells, we identified ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a mutant p53 target gene, which functions as a uridine 5'-diphosphatase (UDPase) in the endoplasmic reticulum (ER) to promote the folding of N-glycosylated membrane proteins. A comprehensive pan-cancer analysis revealed a highly significant correlation between p53 GOF mutations and ENTPD5 expression. Mechanistically, mutp53 is recruited by Sp1 to the ENTPD5 core promoter to induce its expression. We show ENTPD5 to be a mediator of mutant p53 GOF activity in clonogenic growth, architectural tissue remodeling, migration, invasion, and lung colonization in an experimental metastasis mouse model. Our study reveals folding of N-glycosylated membrane proteins in the ER as a mechanism underlying the metastatic progression of tumors with mutp53 that could provide new possibilities for cancer treatment.

  13. Arsenic trioxide promotes mitochondrial DNA mutation and cell apoptosis in primary APL cells and NB4 cell line.

    PubMed

    Meng, Ran; Zhou, Jin; Sui, Meng; Li, ZhiYong; Feng, GuoSheng; Yang, BaoFeng

    2010-01-01

    This study aimed to investigate the effects of arsenic trioxide (As(2)O(3)) on the mitochondrial DNA (mtDNA) of acute promyelocytic leukemia (APL) cells. The NB4 cell line was treated with 2.0 micromol/L As(2)O(3) in vitro, and the primary APL cells were treated with 2.0 micromol/L As(2)O(3) in vitro and 0.16 mg kg(-1) d(-1) As(2)O(3) in vivo. The mitochondrial DNA of all the cells above was amplified by PCR, directly sequenced and analyzed by Sequence Navigatore and Factura software. The apoptosis rates were assayed by flow cytometry. Mitochondrial DNA mutation in the D-loop region was found in NB4 and APL cells before As(2)O(3) use, but the mutation spots were remarkably increased after As(2)O(3) treatment, which was positively correlated to the rates of cellular apoptosis, the correlation coefficient: r (NB4-As2O3)=0.973818, and r (APL-As2O3)=0.934703. The mutation types include transition, transversion, codon insertion or deletion, and the mutation spots in all samples were not constant and regular. It is revealed that As(2)O(3) aggravates mtDNA mutation in the D-loop region of acute promyelocytic leukemia cells both in vitro and in vivo. Mitochondrial DNA might be one of the targets of As(2)O(3) in APL treatment.

  14. Arsenic Trioxide Activate Transcription of Heme Oxygenase-1 by Promoting Nuclear Translocation of NFE2L2.

    PubMed

    Yue, Zhen; Zhong, Lingzhi; Mou, Yan; Wang, Xiaotong; Zhang, Haiying; Wang, Yang; Xia, Jianxin; Li, Ronggui; Wang, Zonggui

    2015-01-01

    In a previous study, we found that induced expression of Heme Oxygenase-1 (HO-1) is responsible for the resistance of human osteosarcoma MG63 cells to the chemotherapeutic agent arsenic trioxide (ATO). The present study was aimed at investigating the molecular mechanisms underlying the induction of HO-1 that occurs after exposure of MG63 cells to ATO. First, using RT-QPCT and Western-blot, we found that ATO strongly induced the expression of heme oxygenase-1 (HO-1) in these human osteosarcoma cells. Then by analyzing HO-1 mRNA of MG63 cells exposed to ATO in the presence and absence of a transcription inhibitor Actinomycin-D (Act-D), we demonstrated that ATO activates HO-1 expression in MG63 cells by regulating the transcription of the gene. Finally, through the analysis of the NFE2L2 protein levels among the total cellular and nuclear proteins by Western-blot and Immunocytochemical staning, we determined that ATO enhanced the nuclear translocation of nuclear factor erythroid 2-like 2 (NFE2L2), also known as Nrf2. From these results we have concluded that transcription activation of HO-1 resulting from the nuclear translocation of NFE2L2 is the underlying molecular mechanism for its high induction, which, in turn, is responsible for the resistance of human osteosarcoma cells to ATO treatment.

  15. Leptin-STAT3-G9a Signaling Promotes Obesity-Mediated Breast Cancer Progression.

    PubMed

    Chang, Chao-Ching; Wu, Meng-Ju; Yang, Jer-Yen; Camarillo, Ignacio G; Chang, Chun-Ju

    2015-06-01

    Obesity has been linked to breast cancer progression but the underlying mechanisms remain obscure. Here we report how leptin, an obesity-associated adipokine, regulates a transcriptional pathway to silence a genetic program of epithelial homeostasis in breast cancer stem-like cells (CSC) that promotes malignant progression. Using genome-wide ChIP-seq and RNA expression profiling, we defined a role for activated STAT3 and G9a histone methyltransferase in epigenetic silencing of miR-200c, which promotes the formation of breast CSCs defined by elevated cell surface levels of the leptin receptor (OBR(hi)). Inhibiting the STAT3/G9a pathway restored expression of miR-200c, which in turn reversed the CSC phenotype to a more differentiated epithelial phenotype. In a rat model of breast cancer driven by diet-induced obesity, STAT3 blockade suppressed the CSC-like OBR(hi) population and abrogated tumor progression. Together, our results show how targeting STAT3-G9a signaling regulates CSC plasticity during obesity-related breast cancer progression, suggesting a novel therapeutic paradigm to suppress CSC pools and limit breast malignancy. ©2015 American Association for Cancer Research.

  16. Myeloma cell–derived Runx2 promotes myeloma progression in bone

    PubMed Central

    Trotter, Timothy N.; Li, Mei; Pan, Qianying; Peker, Deniz; Rowan, Patrick D.; Li, Juan; Zhan, Fenghuang; Suva, Larry J.; Javed, Amjad

    2015-01-01

    The progression of multiple myeloma (MM) is governed by a network of molecular signals, the majority of which remain to be identified. Recent studies suggest that Runt-related transcription factor 2 (Runx2), a well-known bone-specific transcription factor, is also expressed in solid tumors, where expression promotes both bone metastasis and osteolysis. However, the function of Runx2 in MM remains unknown. The current study demonstrated that (1) Runx2 expression in primary human MM cells is significantly greater than in plasma cells from healthy donors and patients with monoclonal gammopathy of undetermined significance; (2) high levels of Runx2 expression in MM cells are associated with a high-risk population of MM patients; and (3) overexpression of Runx2 in MM cells enhanced tumor growth and disease progression in vivo. Additional studies demonstrated that MM cell–derived Runx2 promotes tumor progression through a mechanism involving the upregulation of Akt/β-catenin/Survivin signaling and enhanced expression of multiple metastatic genes/proteins, as well as the induction of a bone-resident cell-like phenotype in MM cells. Thus, Runx2 expression supports the aggressive phenotype of MM and is correlated with poor prognosis. These data implicate Runx2 expression as a major regulator of MM progression in bone and myeloma bone disease. PMID:25862559

  17. Smoc2 potentiates proliferation of hepatocellular carcinoma cells via promotion of cell cycle progression

    PubMed Central

    Su, Jing-Ran; Kuai, Jing-Hua; Li, Yan-Qing

    2016-01-01

    AIM To determine the influence of Smoc2 on hepatocellular carcinoma (HCC) cell proliferation and to find a possible new therapeutic target for preventing HCC progression. METHODS We detected expression of Smoc2 in HCC tissues and corresponding non-tumor liver (CNL) tissues using PCR, western blot, and immunohistochemistry methods. Subsequently, we down-regulated and up-regulated Smoc2 expression using siRNA and lentivirus transfection assay, respectively. Then, we identified the effect of Smoc2 on cell proliferation and cell cycle using CCK-8 and flow cytometry, respectively. The common cell growth signaling influenced by Smoc2 was detected by western blot assay. RESULTS The expression of Smoc2 was significantly higher in HCC tissues compared with CNL tissues. Overexpression of Smoc2 promoted HCC cell proliferation and cell cycle progression. Down-regulation of Smoc2 led to inhibition of cell proliferation and cell cycle progression. Smoc2 had positive effect on ERK and AKT signaling. CONCLUSION Smoc2 promotes the proliferation of HCC cells through accelerating cell cycle progression and might act as an anti-cancer therapeutic target in the future. PMID:28018113

  18. TNF-α augments CXCR2 and CXCR3 to promote progression of renal cell carcinoma.

    PubMed

    Sun, Kuang-Hui; Sun, Guang-Huan; Wu, Yi-Ching; Ko, Bai-Jiun; Hsu, Hui-Tzu; Wu, Sheng-Tang

    2016-11-01

    Within the tumour microenvironment, a complex network of chemokines and their receptors affects the initiation and progression of tumours. The higher levels of tumour necrosis factor-alpha (TNF-α) are associated with tumour progression and an anti-TNF-α monoclonal antibody has been used successfully to treat patients with renal cell carcinoma (RCC). However, the role of chemokines and their receptors in the TNF-α-promoted progression of RCC remains unclear. In this study, TNF-α was found to enhance the migration, invasion and epithelial-mesenchymal transition (EMT) of RCC cells. To further investigate the molecular mechanism of TNF-α on the progression of RCC, reverse transcription and quantitative PCR was used to screen chemokines and chemokine receptors that were associated with tumorigenesis. The results showed that TNF-α significantly increased the expressions of CXCR2 and CXCR3 and their related ligands in RCC cells. Subsequently, we used a lentiviral shRNA system to knockdown the expression of CXCR2 and/or CXCR3 in RCC cells. CXCR2 and CXCR3 silencing inhibited the induction of Slug and ZEB-1 with TNF-α treatment of RCC cells. In addition, the knockdown of both CXCR2 and CXCR3 resulted in a greater decrease in cell migration, invasion and clonogenic ability compared with either CXCR2 or CXCR3 knockdown alone. Moreover, CXCR2 and CXCR3 silencing significantly reduced the sphere-forming ability of RCC cells. High expression levels of CXCR2 and CXCR3 in cancer tissues correlated with tumour progression of renal cell carcinoma. These findings suggest that TNF-α augments CXCR2 and CXCR3 to promote the progression of renal cell carcinoma leading to a poor prognosis.

  19. TMED3 promotes hepatocellular carcinoma progression via IL-11/STAT3 signaling

    PubMed Central

    Zheng, Hao; Yang, Yuan; Han, Jun; Jiang, Wei-hua; Chen, Cheng; Wang, Meng-chao; Gao, Rong; Li, Shuai; Tian, Tao; Wang, Jian; Ma, Li-jun; Ren, Hao; Zhou, Wei-ping

    2016-01-01

    Transmembrane p24 trafficking protein 3(TMED3) is a metastatic suppressor in colon cancer, but its function in the progression of hepatocellular carcinoma (HCC) is unknown. Here, we report that TMED3 was up-regulated in HCC and portal vein tumor thrombus. TMED3 up-regulation in HCC was significantly correlated with aggressive characteristics and predicted poor prognosis in HCC patients. TMED3 overexpression in HCC cell lines promoted cell migration and invasion. In contrast, TMED3 knockdown suppressed HCC metastasis both in vitro and in vivo. Gene microarray analysis revealed decreased IL-11 expression in TMED3-knockdown cells. We propose that TMED3 promotes HCC metastasis through IL-11/STAT3 signaling. Taken together, these findings demonstrate that TMED3 promotes HCC metastasis and is a potential prognostic biomarker in HCC. PMID:27901021

  20. Polymorphisms in the TNF-α and IL10 Gene Promoters and Risk of Arsenic-Induced Skin Lesions and Other Nondermatological Health Effects

    PubMed Central

    Banerjee, Nilanjana; Nandy, Sujay; Kearns, James K.; Bandyopadhyay, Apurba K.; Das, Jayanta K.; Majumder, Papiya; Basu, Santanu; Banerjee, Saptarshi; Sau, Tanmoy Jyoti; States, J. Christopher; Giri, Ashok K.

    2011-01-01

    In West Bengal, India, at present, more than 26 million people are exposed to arsenic through drinking water. Among them, only 15–20% manifest arsenic-induced noncancerous, precancerous, and cancerous skin lesions, indicating that genetic variants play important role in arsenic susceptibility. Chronic arsenic exposure has been associated with impairment of immune systems in the exposed individuals. Because cytokines are important immune mediators, alteration in expression of these gene products may lead to arsenic-specific disease manifestations. The aim of the present work was to investigate the association between the TNF-α−308G>A (rs1800629) and IL10 −3575T>A (rs1800890) polymorphisms and arsenic-induced dermatological and nondermatological health outcomes. A case-control study was conducted in West Bengal, India, involving 207 cases with arsenic-induced skin lesions and 190 controls without skin lesions having similar arsenic exposure. The polymorphisms were determined using conventional PCR-sequencing method. ELISA was done to determine the serum levels of the two cytokines tumor necrosis factor α (TNF-α) and interleukin 10 (IL10). Associations between the polymorphisms studied and nondermatological health effects in the study subjects were determined from our epidemiological survey data. Individuals with GA/AA (−308 TNF-α) and TA/AA (−3575 IL10) genotypes were at higher risk of developing arsenic-induced skin lesions, ocular, and respiratory diseases. Also the −308 TNF A allele corresponded to a higher production of TNF-α, and −3575 IL10 A allele corresponded to a lower production of IL10. Thus, the polymorphisms studied impart significant risk toward development of arsenic-induced dermatological and nondermatological health effects in the chronically exposed population of West Bengal, India. PMID:21357384

  1. Biochar in Co-Contaminated Soil Manipulates Arsenic Solubility and Microbiological Community Structure, and Promotes Organochlorine Degradation

    PubMed Central

    Gregory, Samuel J.; Anderson, Christopher W. N.; Camps-Arbestain, Marta; Biggs, Patrick J.; Ganley, Austen R. D.; O’Sullivan, Justin M.; McManus, Michael T.

    2015-01-01

    We examined the effect of biochar on the water-soluble arsenic (As) concentration and the extent of organochlorine degradation in a co-contaminated historic sheep-dip soil during a 180-d glasshouse incubation experiment. Soil microbial activity, bacterial community and structure diversity were also investigated. Biochar made from willow feedstock (Salix sp) was pyrolysed at 350 or 550°C and added to soil at rates of 10 g kg-1 and 20 g kg-1 (representing 30 t ha-1 and 60 t ha-1). The isomers of hexachlorocyclohexane (HCH) alpha-HCH and gamma-HCH (lindane), underwent 10-fold and 4-fold reductions in concentration as a function of biochar treatment. Biochar also resulted in a significant reduction in soil DDT levels (P < 0.01), and increased the DDE:DDT ratio. Soil microbial activity was significantly increased (P < 0.01) under all biochar treatments after 60 days of treatment compared to the control. 16S amplicon sequencing revealed that biochar-amended soil contained more members of the Chryseobacterium, Flavobacterium, Dyadobacter and Pseudomonadaceae which are known bioremediators of hydrocarbons. We hypothesise that a recorded short-term reduction in the soluble As concentration due to biochar amendment allowed native soil microbial communities to overcome As-related stress. We propose that increased microbiological activity (dehydrogenase activity) due to biochar amendment was responsible for enhanced degradation of organochlorines in the soil. Biochar therefore partially overcame the co-contaminant effect of As, allowing for enhanced natural attenuation of organochlorines in soil. PMID:25923541

  2. Obesity-Induced Inflammation and Desmoplasia Promote Pancreatic Cancer Progression and Resistance to Chemotherapy.

    PubMed

    Incio, Joao; Liu, Hao; Suboj, Priya; Chin, Shan M; Chen, Ivy X; Pinter, Matthias; Ng, Mei R; Nia, Hadi T; Grahovac, Jelena; Kao, Shannon; Babykutty, Suboj; Huang, Yuhui; Jung, Keehoon; Rahbari, Nuh N; Han, Xiaoxing; Chauhan, Vikash P; Martin, John D; Kahn, Julia; Huang, Peigen; Desphande, Vikram; Michaelson, James; Michelakos, Theodoros P; Ferrone, Cristina R; Soares, Raquel; Boucher, Yves; Fukumura, Dai; Jain, Rakesh K

    2016-08-01

    It remains unclear how obesity worsens treatment outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). In normal pancreas, obesity promotes inflammation and fibrosis. We found in mouse models of PDAC that obesity also promotes desmoplasia associated with accelerated tumor growth and impaired delivery/efficacy of chemotherapeutics through reduced perfusion. Genetic and pharmacologic inhibition of angiotensin-II type-1 receptor reverses obesity-augmented desmoplasia and tumor growth and improves response to chemotherapy. Augmented activation of pancreatic stellate cells (PSC) in obesity is induced by tumor-associated neutrophils (TAN) recruited by adipocyte-secreted IL1β. PSCs further secrete IL1β, and inactivation of PSCs reduces IL1β expression and TAN recruitment. Furthermore, depletion of TANs, IL1β inhibition, or inactivation of PSCs prevents obesity-accelerated tumor growth. In patients with pancreatic cancer, we confirmed that obesity is associated with increased desmoplasia and reduced response to chemotherapy. We conclude that cross-talk between adipocytes, TANs, and PSCs exacerbates desmoplasia and promotes tumor progression in obesity. Considering the current obesity pandemic, unraveling the mechanisms underlying obesity-induced cancer progression is an urgent need. We found that the aggravation of desmoplasia is a key mechanism of obesity-promoted PDAC progression. Importantly, we discovered that clinically available antifibrotic/inflammatory agents can improve the treatment response of PDAC in obese hosts. Cancer Discov; 6(8); 852-69. ©2016 AACR.See related commentary by Bronte and Tortora, p. 821This article is highlighted in the In This Issue feature, p. 803. ©2016 American Association for Cancer Research.

  3. Genotoxic and epigenetic mechanisms in arsenic carcinogenicity.

    PubMed

    Bustaffa, Elisa; Stoccoro, Andrea; Bianchi, Fabrizio; Migliore, Lucia

    2014-05-01

    Arsenic is a human carcinogen with weak mutagenic properties that induces tumors through mechanisms not yet completely understood. People worldwide are exposed to arsenic-contaminated drinking water, and epidemiological studies showed a high percentage of lung, bladder, liver, and kidney cancer in these populations. Several mechanisms by which arsenical compounds induce tumorigenesis were proposed including genotoxic damage and chromosomal abnormalities. Over the past decade, a growing body of evidence indicated that epigenetic modifications have a role in arsenic-inducing adverse effects on human health. The main epigenetic mechanisms are DNA methylation in gene promoter regions that regulate gene expression, histone tail modifications that regulate the accessibility of transcriptional machinery to genes, and microRNA activity (noncoding RNA able to modulate mRNA translation). The "double capacity" of arsenic to induce mutations and epimutations could be the main cause of arsenic-induced carcinogenesis. The aim of this review is to better clarify the mechanisms of the initiation and/or the promotion of arsenic-induced carcinogenesis in order to understand the best way to perform an early diagnosis and a prompt prevention that is the key point for protecting arsenic-exposed population. Studies on arsenic-exposed population should be designed in order to examine more comprehensively the presence and consequences of these genetic/epigenetic alterations.

  4. Patched1 functions as a gatekeeper by promoting cell cycle progression.

    PubMed

    Adolphe, Christelle; Hetherington, Rehan; Ellis, Tammy; Wainwright, Brandon

    2006-02-15

    Mutations in the Hedgehog receptor, Patched 1 (Ptch1), have been linked to both familial and sporadic forms of basal cell carcinoma (BCC), leading to the hypothesis that loss of Ptch1 function is sufficient for tumor progression. By combining conditional knockout technology with the inducible activity of the Keratin6 promoter, we provide in vivo evidence that loss of Ptch1 function from the basal cell population of mouse skin is sufficient to induce rapid skin tumor formation, reminiscent of human BCC. Elimination of Ptch1 does not promote the nuclear translocation of beta-catenin and does not induce ectopic activation or expression of Notch pathway constituents. In the absence of Ptch1, however, a large proportion of basal cells exhibit nuclear accumulation of the cell cycle regulators cyclin D1 and B1. Collectively, our data suggest that Ptch1 likely functions as a tumor suppressor by inhibiting G1-S phase and G2-M phase cell cycle progression, and the rapid onset of tumor progression clearly indicates Ptch1 functions as a "gatekeeper." In addition, we note the high frequency and rapid onset of tumors in this mouse model makes it an ideal system for testing therapeutic strategies, such as Patched pathway inhibitors.

  5. Inflammatory risk factors and pathologies promoting Alzheimer's disease progression: is RAGE the key?

    PubMed

    Matrone, Carmela; Djelloul, Mehdi; Taglialatela, Giulio; Perrone, Lorena

    2015-02-01

    Epidemiological studies reveal growing evidence that most cases of Alzheimer`s Disease (AD) likely involve a combination of genetic and environmental risk factors. Identifying and validating these risk factors remains one of the most critical scientific challenges. Several diseases appear to have strong implications for neurodegeneration leading to dementia. This risk encompasses different forms of cardiovascular disease, carotid atherosclerosis, history of hypertension or high cholesterol, Type II diabetes, stroke or transient ischemic attack and brain trauma. However, the molecular pathways that are common and central in the progression of these diseases and AD are not yet elucidated. Unveiling these critical mechanisms at the molecular level is necessary for the development of therapeutic strategies aimed at preventing AD progression. The Receptor for Advanced Glycation Endproducts (RAGE) plays a key role in all the diseases that represent a risk for AD. RAGE-mediated signaling also contributes to neurodegeneration in AD, suggesting that it may mediate the effect of risk factors in promoting AD. We will summarize the current knowledge on the role of RAGE in pathologies promoting AD and in AD progression. We will also provide evidence showing the relevance of RAGE-induced inflammation as a risk pathway that is implicated in AD pathophysiology.

  6. TOO MANY MOUTHS promotes cell fate progression in stomatal development of Arabidopsis stems.

    PubMed

    Bhave, Neela S; Veley, Kira M; Nadeau, Jeanette A; Lucas, Jessica R; Bhave, Sanjay L; Sack, Fred D

    2009-01-01

    Mutations in TOO MANY MOUTHS (TMM), which encodes a receptor-like protein, cause stomatal patterning defects in Arabidopsis leaves but eliminate stomatal formation in stems. Stomatal development in wild-type and tmm stems was analyzed to define TMM function. Epidermal cells in young tmm stems underwent many asymmetric divisions characteristic of entry into the stomatal pathway. The resulting precursor cells, meristemoids, appropriately expressed cell fate markers such as pTMM:GFP. However, instead of progressing developmentally by forming a guard mother cell, the meristemoids arrested, dedifferentiated, and enlarged. Thus asymmetric divisions are necessary but not sufficient for stomatal formation in stems, and TMM promotes the fate and developmental progression of early precursor cells. Comparable developmental and mature stomatal phenotypes were also found in tmm hypocotyls and in the proximal flower stalk. TMM is also a positive regulator of meristemoid division in leaves suggesting that TMM generally promotes meristemoid activity. Our results are consistent with a model in which TMM interacts with other proteins to modulate precursor cell fate and progression in an organ and domain-specific manner. Finally, the consistent presence of a small number of dedifferentiated meristemoids in mature wild-type stems suggests that precursor cell arrest is a normal feature of Arabidopsis stem development.

  7. PIAS1-FAK Interaction Promotes the Survival and Progression of Non-Small Cell Lung Cancer.

    PubMed

    Constanzo, Jerfiz D; Tang, Ke-Jing; Rindhe, Smita; Melegari, Margherita; Liu, Hui; Tang, Ximing; Rodriguez-Canales, Jaime; Wistuba, Ignacio; Scaglioni, Pier Paolo

    2016-05-01

    The sequence of genomic alterations acquired by cancer cells during tumor progression and metastasis is poorly understood. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that integrates cytoskeleton remodeling, mitogenic signaling and cell survival. FAK has previously been reported to undergo nuclear localization during cell migration, cell differentiation and apoptosis. However, the mechanism behind FAK nuclear accumulation and its contribution to tumor progression has remained elusive. We report that amplification of FAK and the SUMO E3 ligase PIAS1 gene loci frequently co-occur in non-small cell lung cancer (NSCLC) cells, and that both gene products are enriched in a subset of primary NSCLCs. We demonstrate that endogenous FAK and PIAS1 proteins interact in the cytoplasm and the cell nucleus of NSCLC cells. Ectopic expression of PIAS1 promotes proteolytic cleavage of the FAK C-terminus, focal adhesion maturation and FAK nuclear localization. Silencing of PIAS1 deregulates focal adhesion turnover, increases susceptibility to apoptosis in vitro and impairs tumor xenograft formation in vivo. Nuclear FAK in turn stimulates gene transcription favoring DNA repair, cell metabolism and cytoskeleton regulation. Consistently, ablation of FAK by CRISPR/Cas9 editing, results in basal DNA damage, susceptibility to ionizing radiation and impaired oxidative phosphorylation. Our findings provide insight into a mechanism regulating FAK cytoplasm-nuclear distribution and demonstrate that FAK activity in the nucleus promotes NSCLC survival and progression by increasing cell-ECM interaction and DNA repair regulation.

  8. Association Study between Promoter Polymorphism of TPH1 and Progression of Idiopathic Scoliosis

    PubMed Central

    Yablanski, Vasil; Nikolova, Svetla; Vlaev, Evgeni; Savov, Alexey; Kremensky, Ivo

    2016-01-01

    The concept of disease-modifier genes as an element of genetic heterogeneity has been widely accepted and reported. The aim of the current study is to investigate the association between the promoter polymorphism TPH1 (rs10488682) and progression of idiopathic scoliosis (IS) in Eastern European population sample. A total of 105 patients and 210 healthy gender-matched controls were enrolled in this study. The TPH1 promoter polymorphism was genotyped by amplification followed by restriction. The statistical analysis was performed by Fisher's Exact Test. The results indicated that the genotypes and alleles of TPH1 (rs10488682) are not correlated with curve severity, curve pattern, or bracing. Therefore, the examined polymorphic variant could not be considered as a genetic factor with modifying effect of IS. In conclusion, this case-control study revealed no statistically significant association between TPH1 (rs10488682) and progression of IS in Eastern European population sample. These preliminary results should be replicated in extended population studies including larger sample sizes. The identification of molecular markers for IS could be useful for a more accurate prognosis of the risk for a rapid progression of the curve. That would permit early stage treatment of the patient with the least invasive procedures. PMID:27293961

  9. Long noncoding RNA BCAR4 promotes osteosarcoma progression through activating GLI2-dependent gene transcription.

    PubMed

    Chen, Fenyong; Mo, Jiadong; Zhang, Li

    2016-10-01

    Despite great advances have been made in the understanding of biology of osteosarcoma, the molecular mechanisms involved in osteosarcoma tumorigenesis and progression are still largely unknown. Long noncoding RNA (lncRNA) is a new type of RNA molecule, which plays pivotal roles in many tumors. lncRNA BCAR4 has been identified as an oncogenetic lncRNA involved in the progression of breast cancer. However, the functions and clinical significances of BCAR4 in osteosarcoma are unknown now. In this study, we found that BCAR4 was significantly upregulated in osteosarcoma tissues. Increased expression of BCAR4 was significantly correlated with large tumor size, advanced Enneking stage, lung metastasis, and poor prognosis. Functional experiments demonstrated that knockdown of BCAR4 inhibits the proliferation and migration of osteosarcoma cell in vitro. Consistently, knockdown of BCAR4 inhibits osteosarcoma tumorigenesis and lung metastasis in vivo. Chromatin isolation by RNA purification assay showed that BCAR4 physically associates with the promoters of GLI2 target genes. The depletion of BCAR4 inhibits the expression of GLI2 target genes and GLI2 reporter luciferase activity in a dose-dependent manner. The expression of BCAR4 and GLI2 target genes is significantly correlated in osteosarcoma tissues. Depletion of DLI2 abolished the effects of BCAR4 on osteosarcoma. Taken together, these findings demonstrated that BCAR4 promotes osteosarcoma progression via activating GLI2-dependent gene transcription and serves as a potential prognostic biomarker and a therapeutic target of osteosarcoma.

  10. Cell cycle-coupled expansion of AR activity promotes cancer progression.

    PubMed

    McNair, C; Urbanucci, A; Comstock, C E S; Augello, M A; Goodwin, J F; Launchbury, R; Zhao, S G; Schiewer, M J; Ertel, A; Karnes, J; Davicioni, E; Wang, L; Wang, Q; Mills, I G; Feng, F Y; Li, W; Carroll, J S; Knudsen, K E

    2017-03-23

    The androgen receptor (AR) is required for prostate cancer (PCa) survival and progression, and ablation of AR activity is the first line of therapeutic intervention for disseminated disease. While initially effective, recurrent tumors ultimately arise for which there is no durable cure. Despite the dependence of PCa on AR activity throughout the course of disease, delineation of the AR-dependent transcriptional network that governs disease progression remains elusive, and the function of AR in mitotically active cells is not well understood. Analyzing AR activity as a function of cell cycle revealed an unexpected and highly expanded repertoire of AR-regulated gene networks in actively cycling cells. New AR functions segregated into two major clusters: those that are specific to cycling cells and retained throughout the mitotic cell cycle ('Cell Cycle Common'), versus those that were specifically enriched in a subset of cell cycle phases ('Phase Restricted'). Further analyses identified previously unrecognized AR functions in major pathways associated with clinical PCa progression. Illustrating the impact of these unmasked AR-driven pathways, dihydroceramide desaturase 1 was identified as an AR-regulated gene in mitotically active cells that promoted pro-metastatic phenotypes, and in advanced PCa proved to be highly associated with development of metastases, recurrence after therapeutic intervention and reduced overall survival. Taken together, these findings delineate AR function in mitotically active tumor cells, thus providing critical insight into the molecular basis by which AR promotes development of lethal PCa and nominate new avenues for therapeutic intervention.

  11. Role of CDH13 promoter methylation in the carcinogenesis, progression, and prognosis of colorectal cancer

    PubMed Central

    Ye, Meng; Huang, Tao; Li, Jinyun; Zhou, Chongchang; Yang, Ping; Ni, Chao; Chen, Si

    2017-01-01

    Abstract Background: H-cadherin (CDH13) is commonly downregulated through promoter methylation in various cancers. However, the role of CDH13 promoter methylation status in patients with colorectal cancer (CRC) remains to be clarified. Methods: Eligible articles were identified from online electronic database based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement criteria. The pooled odds ratio (OR) and the corresponding 95% confidence interval (95% CI) were calculated and analyzed. Results: Eventually, a total of nine studies were included in this meta-analysis, including 488 CRC, 298 adjacent, 144 normal, 68 premalignant tissues. The results demonstrated that CDH13 promoter methylation was notably higher in CRC than in normal, adjacent, and premalignant tissues (cancer tissues vs normal tissues: OR = 16.94, P < 0.001; cancer tissues vs adjacent tissues: OR = 20.06, P < 0.001; cancer tissues vs premalignant tissues: OR = 2.23, P = 0.038). CDH13 promoter methylation had a significantly increased risk for poorly differentiated CRC (OR = 4.07, P = 0.001). CDH13 promoter methylation was not associated with sex status, tumor stage, and lymph node status (all P > 0.05). One study with 85 CRC patients reported that CDH13 promoter methylation was correlated with poor prognosis in overall survival (OS). Conclusions: CDH13 promoter methylation may play an important role in the initiation and progression of CRC, and may be correlated with OS of patients with CRC. Additional studies with large sample sizes are needed to further confirm our findings in the future. PMID:28121942

  12. RMI1 Promotes DNA Replication Fork Progression and Recovery from Replication Fork Stress

    PubMed Central

    Yang, Jay; O'Donnell, Lara; Durocher, Daniel

    2012-01-01

    RMI1 is a member of an evolutionarily conserved complex composed of BLM and topoisomerase IIIα (TopoIIIα). This complex exhibits strand passage activity in vitro, which is likely important for DNA repair and DNA replication in vivo. The inactivation of RMI1 causes genome instability, including elevated levels of sister chromatid exchange and accelerated tumorigenesis. Using molecular combing to analyze DNA replication at the single-molecule level, we show that RMI1 is required to promote normal replication fork progression. The fork progression defect in RMI1-depleted cells is alleviated in cells lacking BLM, indicating that RMI1 functions downstream of BLM in promoting replication elongation. RMI1 localizes to subnuclear foci with BLM and TopoIIIα in response to replication stress. The proper localization of the complex requires a BLM-TopoIIIα-RMI1 interaction and is essential for RMI1 to promote recovery from replication stress. These findings reveal direct roles of RMI1 in DNA replication and the replication stress response, which could explain the molecular basis for its involvement in suppressing sister chromatid exchange and tumorigenesis. PMID:22645306

  13. Epithelial derived CTGF promotes breast tumor progression via inducing EMT and collagen I fibers deposition

    PubMed Central

    Zhao, Zhen; Sheng, Jianting; Wang, Jiang; Liu, Jiyong; Cui, Kemi; Chang, Jenny; Zhao, Hong; Wong, Stephen

    2015-01-01

    Interactions among tumor cells, stromal cells, and extracellular matrix compositions are mediated through cytokines during tumor progression. Our analysis of 132 known cytokines and growth factors in published clinical breast cohorts and our 84 patient-derived xenograft models revealed that the elevated connective tissue growth factor (CTGF) in tumor epithelial cells significantly correlated with poor clinical prognosis and outcomes. CTGF was able to induce tumor cell epithelial-mesenchymal transition (EMT), and promote stroma deposition of collagen I fibers to stimulate tumor growth and metastasis. This process was mediated through CTGF-tumor necrosis factor receptor I (TNFR1)-IκB autocrine signaling. Drug treatments targeting CTGF, TNFR1, and IκB signaling each prohibited the EMT and tumor progression. PMID:26318291

  14. A high-selenium lentil dietary intervention in Bangladesh to counteract arsenic toxicity: study protocol for a randomized controlled trial.

    PubMed

    Krohn, Regina M; Raqib, Rubhana; Akhtar, Evana; Vandenberg, Albert; Smits, Judit E G

    2016-04-27

    Millions of people worldwide are exposed to dangerous levels of arsenic (above the WHO water standard of 10 ppb) in drinking water and food. Lack of nutritious foods exacerbates the adverse health effects of arsenic poisoning. The micronutrient selenium is a known antagonist to arsenic, promoting the excretion of arsenic from the body. Studies are in progress examining the potential of using selenium supplement pills to counteract arsenic toxicity. We are planning a clinical trial to test whether high-selenium lentils, as a whole food solution, can improve the health of arsenic-exposed Bangladeshi villagers. A total of 400 participants (about 80 families) will be divided into two groups via computer-generated block randomization. Eligibility criteria are age (≥14) years) and arsenic concentration in the household tube well (≥100 ppb). In this double-blind study, one group will eat high-selenium lentils grown in western Canada; the other will consume low-selenium lentils grown in Idaho, USA. Each participant will consume 65 g of lentils each day for 6 months. At the onset, midterm, and end of the trial, blood, urine and stool, plus hair (day 1 and at 6 months only) samples will be collected and a health examination conducted including assessment of acute lung inflammation, body mass and height, and blood pressure. The major outcome will be arsenic excretion in urine and feces, as well as arsenic deposition in hair and morbidity outcomes as assessed by a biweekly questionnaire. Secondary outcomes include antioxidant status, lipid profile, lung inflammation status, and blood pressure. Selenium pills as a treatment for arsenic exposure are costly and inconvenient, whereas a whole food approach to lower the toxic burden of arsenic may be a practical remedy for Bangladeshi people while efforts to provide safe drinking water are continuing. If high-selenium lentils prove to be effective in counteracting arsenic toxicity, agronomic partnerships between Canada and

  15. Smad3 promotes cancer progression by inhibiting E4BP4-mediated NK cell development.

    PubMed

    Tang, Patrick Ming-Kuen; Zhou, Shuang; Meng, Xiao-Ming; Wang, Qing-Ming; Li, Chun-Jie; Lian, Guang-Yu; Huang, Xiao-Ru; Tang, Yong-Jiang; Guan, Xin-Yuan; Yan, Bryan Ping-Yen; To, Ka-Fai; Lan, Hui-Yao

    2017-03-06

    TGF-β is known to influence tumour progression. Here we report an additional role of Smad3 in the tumour microenvironment regulating cancer progression. Deletion or inhibition of Smad3 in the tumour microenvironment suppresses tumour growth, invasion and metastasis in two syngeneic mouse tumour models. Smad3(-/-) bone marrow gives rise to an expanded NK cell population with enhanced tumour-suppressive activities in vivo, and promotes differentiation of NK cells ex vivo. We identify E4BP4/NFIL3 as a direct Smad3 target gene critical for NK cell differentiation. Smad3 suppresses transcription of IFN-γ via E4BP4 in a T-bet independent manner. Therefore disruption of Smad3 enhances both the E4BP4-mediated NK cell differentiation and anti-cancer effector functions in vivo and in vitro. Furthermore, systemic treatment with a Smad3 inhibitor SIS3 effectively suppresses cancer progression. In summary, suppression of NK cell-mediated immunosurveillance via the Smad3-E4BP4 axis contributes to cancer progression. We propose targeting Smad3-dependent tumour microenvironment may represent an effective anti-cancer strategy.

  16. Phosphate May Promote CKD Progression and Attenuate Renoprotective Effect of ACE Inhibition

    PubMed Central

    Ruggenenti, Piero; Perna, Annalisa; Leonardis, Daniela; Tripepi, Rocco; Tripepi, Giovanni; Mallamaci, Francesca; Remuzzi, Giuseppe

    2011-01-01

    Phosphate may promote the onset and progression of chronic nephropathies. Here we evaluated the relationships between baseline serum phosphate levels, disease progression, and response to ACE inhibition in 331 patients with proteinuric nephropathies in the prospective Ramipril Efficacy In Nephropathy (REIN) trial. Independent of treatment, patients with phosphate levels in the highest two quartiles progressed significantly faster either to ESRD or to a composite endpoint of doubling of serum creatinine or ESRD compared with patients with phosphate levels below the median (P < 0.001). Results were similar when we analyzed phosphate as a continuous variable (P ≤ 0.004). The renoprotective effect of ramipril decreased as serum phosphate increased (P ≤ 0.008 for interaction); this modification of the treatment effect by phosphate persisted despite adjusting for potential confounders such as GFR and urinary protein. In summary, these data suggest that phosphate is an independent risk factor for progression of renal disease among patients with proteinuric CKD, and high levels of phosphate may even attenuate the renoprotective effect of ACE inhibitors. Future trials should test whether reducing serum phosphate improves renal outcomes and optimizes the renoprotective effect of ACE inhibition. PMID:21852581

  17. Smad3 promotes cancer progression by inhibiting E4BP4-mediated NK cell development

    PubMed Central

    Tang, Patrick Ming-Kuen; Zhou, Shuang; Meng, Xiao-Ming; Wang, Qing-Ming; Li, Chun-Jie; Lian, Guang-Yu; Huang, Xiao-Ru; Tang, Yong-Jiang; Guan, Xin-Yuan; Yan, Bryan Ping-Yen; To, Ka-Fai; Lan, Hui-Yao

    2017-01-01

    TGF-β is known to influence tumour progression. Here we report an additional role of Smad3 in the tumour microenvironment regulating cancer progression. Deletion or inhibition of Smad3 in the tumour microenvironment suppresses tumour growth, invasion and metastasis in two syngeneic mouse tumour models. Smad3−/− bone marrow gives rise to an expanded NK cell population with enhanced tumour-suppressive activities in vivo, and promotes differentiation of NK cells ex vivo. We identify E4BP4/NFIL3 as a direct Smad3 target gene critical for NK cell differentiation. Smad3 suppresses transcription of IFN-γ via E4BP4 in a T-bet independent manner. Therefore disruption of Smad3 enhances both the E4BP4-mediated NK cell differentiation and anti-cancer effector functions in vivo and in vitro. Furthermore, systemic treatment with a Smad3 inhibitor SIS3 effectively suppresses cancer progression. In summary, suppression of NK cell-mediated immunosurveillance via the Smad3-E4BP4 axis contributes to cancer progression. We propose targeting Smad3-dependent tumour microenvironment may represent an effective anti-cancer strategy. PMID:28262747

  18. Interleukin-6 promotes tumor progression in colitis-associated colorectal cancer through HIF-1α regulation

    PubMed Central

    Han, Jun; Xi, Qiulei; Meng, Qingyang; Liu, Jingzheng; Zhang, Yongxian; Han, Yusong; Zhuang, Qiulin; Jiang, Yi; Ding, Qiurong; Wu, Guohao

    2016-01-01

    Interleukin-6 (IL-6) is a well-known etiological factor of colitis-associated colorectal cancer (CAC) and has a significant role in CAC progression. In addition, hypoxia-inducible factor 1α (HIF-1α) serves a primary role in the progression of CAC. However, the association between IL-6 and HIF-1α during the progression of CAC remains unclear. To investigate this association, the present study induced CAC in a mouse model using azoxymethane and dextran sulfate sodium. In addition, an anti-IL-6 receptor antibody was used to inhibit IL-6. In this model, anti-IL-6 receptor antibody treatment significantly inhibited the development of CAC and the expression of HIF-1α, in colorectal adenomas and adenocarcinomas. In patients with CAC, the HIF-1α gene was demonstrated to be overexpressed in tumor tissue compared with adjacent non-malignant tissue. Furthermore, HIF-1α mRNA expression was positively correlated with serum IL-6 concentration. The results of the present study suggest that IL-6 promotes CAC progression, in the early stage of the disease, through HIF-1α regulation. PMID:28105173

  19. Signal transducer and activator of transcription 3 promotes angiogenesis and drives malignant progression in glioma.

    PubMed

    Doucette, Tiffany A; Kong, Ling-Yuan; Yang, Yuhui; Ferguson, Sherise D; Yang, Jinbo; Wei, Jun; Qiao, Wei; Fuller, Gregory N; Bhat, Krishna P; Aldape, Kenneth; Priebe, Waldemar; Bögler, Oliver; Heimberger, Amy B; Rao, Ganesh

    2012-09-01

    Signal transducer and activator of transcription (STAT) 3 has been described as a "master regulator" of signaling pathways involved in the transition from low-grade glioma (LGG) to high-grade glioma (HGG). Although STAT3 is overexpressed in HGGs, it remains unclear whether its overexpression is sufficient to induce or promote the malignant progression of glioma. To characterize the effect of STAT3 expression on tumor progression in vivo, we expressed the STAT3 gene in glioneuronal progenitor cells in mice. STAT3 was expressed alone or concurrently with platelet-derived growth factor B (PDGFB), a well-described initiator of LGG. STAT3 alone was insufficient to induce tumor formation; however, coexpression of STAT3 with PDGFB in mice resulted in a significantly higher incidence of HGGs than PDGFB alone. The median symptomatic tumor latency in mice coexpressing STAT3 and PDGFB was significantly shorter, and mice that developed symptomatic tumors demonstrated significantly higher expression of phosphorylated STAT3 intratumorally. In HGGs, expression of STAT3 was associated with suppression of apoptosis and an increase in tumor cell proliferation. HGGs induced by STAT3 and PDGFB also displayed frequent foci of necrosis and microvascular proliferation. The expression of CD31 (a marker of endothelial proliferation) was significantly higher in tumors induced by coexpression of STAT3 and PDGFB. When mice injected with PDGFB and STAT3 were treated with a STAT3 inhibitor, median survival increased and the incidence of HGG and CD31 expression decreased significantly. These results demonstrate that STAT3 promotes the malignant progression of glioma. Inhibiting STAT3 expression mitigates tumor progression and improves survival, validating it as a therapeutic target.

  20. Bcl-2 promotes malignant progression in a PDGF-B-dependent murine model of oligodendroglioma

    PubMed Central

    Doucette, Tiffany; Fuller, Gregory N.; Yang, Yuhui; Suki, Dima; Zhang, Wei; Fults, Daniel W.

    2011-01-01

    A significant subset of gliomas arises after activation of the pro-proliferative platelet-derived growth factor (PDGF) pathway. The progression of low-grade gliomas to more malignant tumors may be due to oncogenic cellular programs combining with those suppressing apoptosis. Anti-apoptotic genes are overexpressed in a variety of cancers and the anti-apoptotic gene, BCL2, is associated with treatment resistance and tumor recurrence in gliomas. However, the impact of anti-apoptotic gene expression to tumor formation and progression is unclear. We overexpressed Bcl-2 in a PDGFB-dependent mouse model of oligodendroglioma, a common glioma subtype, to assess its effect in vivo. We hypothesized that the anti-apoptotic effect would complement the pro-proliferative effect of PDGFB to promote tumor formation and progression to anaplastic oligodendroglioma (AO). Here, we show that co-expression of PDGFB and Bcl-2 results in a higher overall tumor formation rate compared to PDGFB alone. Co-expression of PDGFB and Bcl-2 promotes progression to AO with prominent foci of necrosis, a feature of high-grade gliomas. Median tumor latency was shorter in mice injected with PDGFB and Bcl-2 compared to those injected with PDGFB alone. Although independent expression of Bcl-2 was insufficient to induce tumors, suppression of apoptosis (detected by cleaved caspase-3 expression) was more pronounced in AOs induced by PDGFB and Bcl-2 compared to those induced by PDGFB alone. Tumor cell proliferation (detected by phosphohistone H3 activity) was also more robust in high-grade tumors induced by PDGFB and Bcl-2. Our results indicate that suppressed apoptosis enhances oligodendroglioma formation and engenders a more malignant phenotype. PMID:21171016

  1. ZEB1 promotes the progression and metastasis of cervical squamous cell carcinoma via the promotion of epithelial-mesenchymal transition

    PubMed Central

    Ma, Yihui; Zheng, Xiangyu; Zhou, Jun; Zhang, Ying; Chen, Kuisheng

    2015-01-01

    Objective: The process of epithelial-mesenchymal transition (EMT) clearly contributes to cancer metastasis. The aim of this study was to investigate the expression of the EMT-related transcription repressor ZEB1 and the expression of EMT-associated markers (E-cadherin, β-catenin and N-cadherin) in cervical squamous cell carcinoma. In addition, the role of ZEB1 and these EMT-associated markers in the progression and metastasis of cervical squamous cell carcinoma was explored. Methods: The expression of ZEB1, E-cadherin, β-catenin and N-cadherin was evaluated in 81 specimens of cervical squamous cell carcinoma by immunohistochemistry; the clinicopathological significance of these markers was then analyzed. Results: 1) Of the 81 samples, 37 cases (45.7%) were positive for ZEB1, and nuclear expression of ZEB1 in tumor cells was positively associated with the differentiation status of the tumor tissue (P < 0.05), vascular invasion (P < 0.05) and lymph node metastasis (P < 0.05). 2) The loss of E-cadherin and β-catenin expression in tumor cells and the acquisition of N-cadherin expression were positively associated with the differentiation status of the tumor tissue (P < 0.05) and with the occurrence of vascular invasion (P < 0.05). 3) A significant negative correlation was observed between ZEB1 and E-cadherin expression (Spearman = -0.636, P < 0.05) and between ZEB1 and β-catenin expression (Spearman = -0.417, P < 0.05). Moreover, a significant positive correlation was observed between ZEB1 and N-cadherin expression (Spearman = 0.557, P < 0.05). Conclusions: These results emphasize the role of EMT in cervical squamous cell carcinoma. The upregulation of ZEB1 is associated with the abnormal expression of E-cadherin, β-catenin and N-cadherin, which might promote the progression and metastasis of cervical squamous cell carcinoma. PMID:26617850

  2. Cannabinoid receptor 1 promotes hepatocellular carcinoma initiation and progression through multiple mechanisms.

    PubMed

    Mukhopadhyay, Bani; Schuebel, Kornel; Mukhopadhyay, Partha; Cinar, Resat; Godlewski, Grzegorz; Xiong, Keming; Mackie, Ken; Lizak, Martin; Yuan, Qiaoping; Goldman, David; Kunos, George

    2015-05-01

    Hepatocellular carcinoma (HCC) has high mortality and no adequate treatment. Endocannabinoids interact with hepatic cannabinoid 1 receptors (CB1Rs) to promote hepatocyte proliferation in liver regeneration by inducing cell cycle proteins involved in mitotic progression, including Forkhead Box M1. Because this protein is highly expressed in HCC and contributes to its genesis and progression, we analyzed the involvement of the endocannabinoid/CB1R system in murine and human HCC. Postnatal diethylnitrosamine treatment induced HCC within 8 months in wild-type mice but fewer and smaller tumors in CB1R(-/-) mice or in wild-type mice treated with the peripheral CB1R antagonist JD5037, as monitored in vivo by serial magnetic resonance imaging. Genome-wide transcriptome analysis revealed CB1R-dependent, tumor-induced up-regulation of the hepatic expression of CB1R, its endogenous ligand anandamide, and a number of tumor-promoting genes, including the GRB2 interactome as well as Forkhead Box M1 and its downstream target, the tryptophan-catalyzing enzyme indoleamine 2,3-dioxygenase. Increased indoleamine 2,3-dioxygenase activity and consequent induction of immunosuppressive T-regulatory cells in tumor tissue promote immune tolerance. The endocannabinoid/CB1R system is up-regulated in chemically induced HCC, resulting in the induction of various tumor-promoting genes, including indoleamine 2,3-dioxygenase; and attenuation of these changes by blockade or genetic ablation of CB1R suppresses the growth of HCC and highlights the therapeutic potential of peripheral CB1R blockade. © 2015 by the American Association for the Study of Liver Diseases. This article has been contributed to by U.S. Government employees, and their work is in the public domain in the U.S.A.

  3. Cannabinoid Receptor 1 Promotes Hepatocellular Carcinoma Initiation and Progression via Multiple Mechanisms

    PubMed Central

    Mukhopadhyay, Bani; Schuebel, Kornel; Mukhopadhyay, Partha; Cinar, Resat; Godlewski, Grzegorz; Xiong, Keming; Mackie, Ken; Lizak, Martin; Yuan, Qiaoping; Goldman, David; Kunos, George

    2015-01-01

    Hepatocellular carcinoma (HCC) has high mortality and no adequate treatment. Endocannabinoids interact with hepatic CB1 receptors (CB1R) to promote hepatocyte proliferation in liver regeneration via inducing cell-cycle proteins involved in mitotic progression, including Forkhead Box M1 (FOXM1). Because FOXM1 is highly expressed in HCC and contributes to its genesis and progression, we analyzed the involvement of the endocannabinoid/CB1R system in murine and human HCC. Postnatal diethylnitrosamine (DEN) treatment induced HCC within 8 months in wild-type mice, but fewer and smaller tumors in CB1R−/− mice or in wild-type mice treated with the peripheral CB1R antagonist JD5037, as monitored in vivo by serial magnetic resonance imaging. Genome-wide transcriptome analysis revealed CB1R-dependent, tumor-induced upregulation of the hepatic expression of CB1R, its endogenous ligand anandamide, and a number of tumor promoting genes, including the GRB2 interactome as well as FOXM1 and its downstream target the tryptophan-catalyzing enzyme indoleamine 2,3-dioxygenase (IDO2). Increased IDO2 activity and consequent induction of immunosuppressive Treg cells in tumor tissue promote immune tolerance. Conclusion The endocannabinoid/CB1R system is upregulated in chemically induced HCC resulting in the induction of various tumor promoting genes, including IDO2, and attenuation of these changes by blockade or genetic ablation of CB1R suppresses the growth of HCC and highlights the therapeutic potential of peripheral CB1R blockade. PMID:25580584

  4. CD147 reinforces [Ca2+]i oscillations and promotes oncogenic progression in hepatocellular carcinoma.

    PubMed

    Tang, Juan; Guo, Yun-Shan; Yu, Xiao-Ling; Huang, Wan; Zheng, Ming; Zhou, Ying-Hui; Nan, Gang; Wang, Jian-Chao; Yang, Hai-Jiao; Yu, Jing-Min; Jiang, Jian-Li; Chen, Zhi-Nan

    2015-10-27

    Oscillations in intracellular Ca2+ concentrations ([Ca2+]i) mediate various cellular function. Although it is known that [Ca2+]i oscillations are susceptible to dysregulation in tumors, the tumor-specific regulators of [Ca2+]i oscillations are poorly characterized. We discovered that CD147 promotes hepatocellular carcinoma (HCC) metastasis and proliferation by enhancing the amplitude and frequency of [Ca2+]i oscillations in HCC cells. CD147 activates two distinct signaling pathways to regulate [Ca2+]i oscillations. By activating FAK-Src-IP3R1 signaling pathway, CD147 promotes Ca2+ release from endoplasmic reticulum (ER) and enhances the amplitude of [Ca2+]i oscillations. Furthermore, CD147 accelerates ER Ca2+refilling and enhances the frequency of [Ca2+]i oscillations through activating CaMKP-PAK1-PP2A-PLB-SERCA signaling pathway. Besides, CD147-promoted ER Ca2+ release and refilling are tightly regulated by changing [Ca2+]i. CD147 may activate IP3R1 channel under low [Ca2+]i conditions and CD147 may activate SERCA pump under high [Ca2+]i conditions. CD147 deletion suppresses HCC tumorigenesis and increases the survival rate of liver-specific CD147 knockout mice by regulating [Ca2+]i oscillations in vivo. Together, these results reveal that CD147 functions as a critical regulator of ER-dependent [Ca2+]i oscillations to promote oncogenic progression in HCC.

  5. Arsenic transformation and plant growth promotion characteristics of As-resistant endophytic bacteria from As-hyperaccumulator Pteris vittata.

    PubMed

    Xu, Jia-Yi; Han, Yong-He; Chen, Yanshan; Zhu, Ling-Jia; Ma, Lena Q

    2016-02-01

    The ability of As-resistant endophytic bacteria in As transformation and plant growth promotion was determined. The endophytes were isolated from As-hyperaccumulator Pteris vittata (PV) after growing for 60 d in a soil containing 200 mg kg(-1) arsenate (AsV). They were isolated in presence of 10 mM AsV from PV roots, stems, and leaflets, representing 4 phyla and 17 genera. All endophytes showed at least one plant growth promoting characteristics including IAA synthesis, siderophore production and P solubilization. The root endophytes had higher P solubilization ability than the leaflet (60.0 vs. 18.3 mg L(-1)). In presence of 10 mM AsV, 6 endophytes had greater growth than the control, suggesting As-stimulated growth. Furthermore, root endophytes were more resistant to AsV while the leaflet endophytes were more tolerant to arsenite (AsIII), which corresponded to the dominant As species in PV tissues. Bacterial As resistance was positively correlated to their ability in AsV reduction but not AsIII oxidation. The roles of those endophytes in promoting plant growth and As resistance in P. vittata warrant further investigation.

  6. [Initiation, promotion, initiation experiments with radon and cigarette smoke: Lung tumors in rats]. Progress report

    SciTech Connect

    Moolgavkar, S.H.

    1994-10-01

    During the past several years, the authors have made considerable progress in modeling carcinogenesis in general, and in modeling radiation carcinogenesis, in particular. They present an overview of their progress in developing stochastic carcinogenesis models and applying them to experimental and epidemiologic data sets. Traditionally, cancer models have been used for the analysis of incidence (or prevalence) data in epidemiology and time to tumor data in experimental studies. The relevant quantities for the analysis of these data are the hazard function and the probability of tumor. The derivation of these quantities is briefly described here. More recently, the authors began to use these models for the analysis of data on intermediate lesions on the pathway to cancer. Such data are available in experimental carcinogenesis studies, in particular in initiation and promotion studies on the mouse skin and the rat liver. If however, quantitative information on intermediate lesions on the pathway to lung cancer were to be come available at some future date, the methods that they have developed for the analysis of initiation-promotion experiments could easily be applied to the analysis of these lesions. The mathematical derivations here are couched in terms of a particular two-mutation model of carcinogenesis. Extension to models postulating more than two mutations is not always straightforward.

  7. Nuclear localization of TEF3-1 promotes cell cycle progression and angiogenesis in cancer.

    PubMed

    Teng, Kaixuan; Deng, Cuilan; Xu, Jie; Men, Qiuxu; Lei, Tao; Di, Da; Liu, Ting; Li, Wenhua; Liu, Xin

    2016-03-22

    TEF3-1 (transcriptional enhancer factor 3 isoform 1), also known as TEAD4 (TEA domain family member 4), was recently revealed as an oncogenic character in cancer development. However, the underlying molecular pathogenic mechanisms remain undefined. In this paper, we investigated nuclear TEF3-1 could promote G1/S transition in HUVECs, and the expression levels of cyclins and CDKs were upregulated. Additionally, if TEF3-1 was knocked down, the expression of cyclins and CDKs was downregulated while the expression of P21, a negative regulator of the cell cycle, was upregulated. A microarray analysis also confirmed that TEF3-1 overexpression upregulates genes that are related to cell cycle progression and the promotion of angiogenesis. Moreover, we observed that nuclear TEF3-1 was highly expressed during the formation of vascular structures in gastric cancer (GC). Finally, tumor xenograft experiments indicated that, when TEF3-1 was knocked down, tumor growth and angiogenesis were also suppressed. Taken together, these results demonstrate for the first time that TEF3-1 localization to the nucleus stimulates the cell cycle progression in HUVECs and specifically contributes to tumor angiogenesis. Nuclear TEF3-1 in HUVECs may serve as an oncogenic biomarker, and the suppression of TEF3-1 may be a potential target in anti-tumor therapy.

  8. Histone demethylase PHF8 promotes progression and metastasis of gastric cancer

    PubMed Central

    Li, Shuyan; Sun, Ao; Liang, Xiuming; Ma, Lin; Shen, Li; Li, Tongyu; Zheng, Lixin; Shang, Wenjing; Zhao, Wei; Jia, Jihui

    2017-01-01

    Histone demethylase plant homeodomain (PHD) finger protein 8 (PHF8) has been implicated in tumor development and malignant progression in various types of cancers. However, its potential roles in gastric cancer (GC) have not been explored. In this report, we show that PHF8 expression is upregulated in GC tissues, and the enhanced PHF8 level indicates a poor prognosis of GC patients. PHF8 knockdown reduces proliferation and metastasis of GC cells, while PHF8 overexpression has the opposite effects. Mechanistically, PHF8 interacts with β-catenin, and binds to the promoter region of vimentin, leading to the promotion of vimentin transcription. In addition, we show that H. pylori, the single most important risk factor for GC, markedly induce PHF8 expression. Our results suggest that H. pylori-induced PHF8-β-catenin-vimentin axis activation is a novel mechanism for GC malignant progression. Thus, we identify PHF8 as an oncogenic factor of GC, and suggest PHF8 might be a potential molecular target for therapeutic approaches for GC. PMID:28401003

  9. SALL4 promotes gastric cancer progression through activating CD44 expression.

    PubMed

    Yuan, X; Zhang, X; Zhang, W; Liang, W; Zhang, P; Shi, H; Zhang, B; Shao, M; Yan, Y; Qian, H; Xu, W

    2016-11-07

    The stem cell factor SALL4 (Sal-like protein 4) plays important roles in the development and progression of cancer. SALL4 is critically involved in tumour growth, metastasis and therapy resistance. However, the underlying mechanisms responsible for the oncogenic roles of SALL4 have not been well characterized. In this study, we demonstrated that SALL4 knockdown by short hairpin RNA greatly inhibited the proliferation, migration and invasion of gastric cancer cells. We further confirmed the inhibitory effects of SALL4 knockdown on gastric cancer cells by using a tetracycline-inducible system. Mechanistically, SALL4 knockdown downregulated the expression of CD44. The results of luciferase assay and chromatin immunoprecipitation study showed that SALL4 bound to CD44 promoter region and transcriptionally activated CD44. The results of rescue study revealed that CD44 overexpression antagonized SALL4 knockdown-mediated inhibition of gastric cancer cell proliferation, migration, and invasion in vitro and gastric cancer growth in vivo. Collectively, our findings indicate that SALL4 promotes gastric cancer progression through directly activating CD44 expression, which suggests a novel mechanism for the oncogenic roles of SALL4 in gastric cancer and represents a new target for gastric cancer therapy.

  10. SALL4 promotes gastric cancer progression through activating CD44 expression

    PubMed Central

    Yuan, X; Zhang, X; Zhang, W; Liang, W; Zhang, P; Shi, H; Zhang, B; Shao, M; Yan, Y; Qian, H; Xu, W

    2016-01-01

    The stem cell factor SALL4 (Sal-like protein 4) plays important roles in the development and progression of cancer. SALL4 is critically involved in tumour growth, metastasis and therapy resistance. However, the underlying mechanisms responsible for the oncogenic roles of SALL4 have not been well characterized. In this study, we demonstrated that SALL4 knockdown by short hairpin RNA greatly inhibited the proliferation, migration and invasion of gastric cancer cells. We further confirmed the inhibitory effects of SALL4 knockdown on gastric cancer cells by using a tetracycline-inducible system. Mechanistically, SALL4 knockdown downregulated the expression of CD44. The results of luciferase assay and chromatin immunoprecipitation study showed that SALL4 bound to CD44 promoter region and transcriptionally activated CD44. The results of rescue study revealed that CD44 overexpression antagonized SALL4 knockdown-mediated inhibition of gastric cancer cell proliferation, migration, and invasion in vitro and gastric cancer growth in vivo. Collectively, our findings indicate that SALL4 promotes gastric cancer progression through directly activating CD44 expression, which suggests a novel mechanism for the oncogenic roles of SALL4 in gastric cancer and represents a new target for gastric cancer therapy. PMID:27819668

  11. Inorganic Arsenic and Human Prostate Cancer

    PubMed Central

    Benbrahim-Tallaa, Lamia; Waalkes, Michael P.

    2008-01-01

    Objective We critically evaluated the etiologic role of inorganic arsenic in human prostate cancer. Data sources We assessed data from relevant epidemiologic studies concerning environmental inorganic arsenic exposure. Whole animal studies were evaluated as were in vitro model systems of inorganic arsenic carcinogenesis in the prostate. Data synthesis Multiple studies in humans reveal an association between environmental inorganic arsenic exposure and prostate cancer mortality or incidence. Many of these human studies provide clear evidence of a dose–response relationship. Relevant whole animal models showing a relationship between inorganic arsenic and prostate cancer are not available. However, cellular model systems indicate arsenic can induce malignant transformation of human prostate epithelial cells in vitro. Arsenic also appears to impact prostate cancer cell progression by precipitating events leading to androgen independence in vitro. Conclusion Available evidence in human populations and human cells in vitro indicates that the prostate is a target for inorganic arsenic carcinogenesis. A role for this common environmental contaminant in human prostate cancer initiation and/or progression would be very important. PMID:18288312

  12. Metabolic interrelationships between arsenic and selenium

    PubMed Central

    Levander, Orville A.

    1977-01-01

    In 1938, Moxon discovered that arsenic protected against selenium toxicity. Since that time it has been shown that this protective effect of arsenic against selenium poisoning can be demonstrated in many different animal species under a wide variety of conditions. Antagonistic effects between arsenic and selenium have also been noted in teratologic experiments. Early metabolic studies showed that arsenic inhibited the expiration of volatile selenium compounds by rats injected with acutely toxic doses of both elements. This was puzzling since pulmonary excretion had long been regarded as a means by which animals could rid themselves of excess selenium. However, later work demonstrated that arsenic increased the biliary excretion of selenium. Not only did arsenic stimulate the excretion of selenium in the bile, but selenium also stimulated the excretion of arsenic in the bile. This increased biliary excretion of selenium caused by arsenic provides a reasonable rationale for the ability of arsenic to counteract the toxicity of selenium, although the chemical mechanism by which arsenic does this is not certain. The most satisfactory explanation is that these two elements react in the liver to form a detoxication conjugate which is then excreted into the bile. This is consistent with the fact that both arsenic and selenium each increase the biliary excretion of the other. Several other metabolic interactions between arsenic and selenium have been demonstrated in vitro, but their physiological significance is not clear. Although arsenic decreased selenium toxicity under most conditions, there is a pronounced synergistic toxicity between arsenic and two methylated selenium metabolites, trimethylselenonium ion or dimethyl selenide. The ecological consequences of these synergisms are largely unexplored, although it is likely that selenium methylation occurs in the environment. All attempts to promote or prevent selenium deficiency diseases in animals by feeding arsenic have

  13. Arsenic-Redox Transformation and Plant Growth Promotion by Purple Nonsulfur Bacteria Rhodopseudomonas palustris CS2 and Rhodopseudomonas faecalis SS5.

    PubMed

    Batool, Kanza; Tuz Zahra, Fatima; Rehman, Yasir

    2017-01-01

    Arsenic (As) is a well-known toxic metalloid found naturally and released by different industries, especially in developing countries. Purple nonsulfur bacteria (PNSB) are known for wastewater treatment and plant growth promoting abilities. As-resistant PNSB were isolated from a fish pond. Based on As-resistance and plant growth promoting attributes, 2 isolates CS2 and SS5 were selected and identified as Rhodopseudomonas palustris and Rhodopseudomonas faecalis, respectively, through 16S rRNA gene sequencing. Maximum As(V) resistance shown by R. faecalis SS5 and R. palustris CS2 was up to 150 and 100 mM, respectively. R. palustris CS2 showed highest As(V) reduction up to 62.9% (6.29 ± 0.24 mM), while R. faecalis SS5 showed maximum As(III) oxidation up to 96% (4.8 ± 0.32 mM), respectively. Highest auxin production was observed by R. palustris CS2 and R. faecalis SS, up to 77.18 ± 3.7 and 76.67 ± 2.8 μg mL(-1), respectively. Effects of these PNSB were tested on the growth of Vigna mungo plants. A statistically significant increase in growth was observed in plants inoculated with isolates compared to uninoculated plants, both in presence and in absence of As. R. palustris CS2 treated plants showed 17% (28.1 ± 0.87 cm) increase in shoot length and 21.7% (7.07 ± 0.42 cm) increase in root length, whereas R. faecalis SS5 treated plants showed 12.8% (27.09 ± 0.81 cm) increase in shoot length and 18.8% (6.9 ± 0.34 cm) increase in root length as compared to the control plants. In presence of As, R. palustris CS2 increased shoot length up to 26.3% (21.0 ± 1.1 cm), while root length increased up to 31.3% (5.3 ± 0.4 cm), whereas R. faecalis SS5 inoculated plants showed 25% (20.7 ± 1.4 cm) increase in shoot length and 33.3% (5.4 ± 0.65 cm) increase in root length as compared to the control plants. Bacteria with such diverse abilities could be ideal for plant growth promotion in As-contaminated sites.

  14. Arsenic-Redox Transformation and Plant Growth Promotion by Purple Nonsulfur Bacteria Rhodopseudomonas palustris CS2 and Rhodopseudomonas faecalis SS5

    PubMed Central

    Batool, Kanza; tuz Zahra, Fatima

    2017-01-01

    Arsenic (As) is a well-known toxic metalloid found naturally and released by different industries, especially in developing countries. Purple nonsulfur bacteria (PNSB) are known for wastewater treatment and plant growth promoting abilities. As-resistant PNSB were isolated from a fish pond. Based on As-resistance and plant growth promoting attributes, 2 isolates CS2 and SS5 were selected and identified as Rhodopseudomonas palustris and Rhodopseudomonas faecalis, respectively, through 16S rRNA gene sequencing. Maximum As(V) resistance shown by R. faecalis SS5 and R. palustris CS2 was up to 150 and 100 mM, respectively. R. palustris CS2 showed highest As(V) reduction up to 62.9% (6.29 ± 0.24 mM), while R. faecalis SS5 showed maximum As(III) oxidation up to 96% (4.8 ± 0.32 mM), respectively. Highest auxin production was observed by R. palustris CS2 and R. faecalis SS, up to 77.18 ± 3.7 and 76.67 ± 2.8 μg mL−1, respectively. Effects of these PNSB were tested on the growth of Vigna mungo plants. A statistically significant increase in growth was observed in plants inoculated with isolates compared to uninoculated plants, both in presence and in absence of As. R. palustris CS2 treated plants showed 17% (28.1 ± 0.87 cm) increase in shoot length and 21.7% (7.07 ± 0.42 cm) increase in root length, whereas R. faecalis SS5 treated plants showed 12.8% (27.09 ± 0.81 cm) increase in shoot length and 18.8% (6.9 ± 0.34 cm) increase in root length as compared to the control plants. In presence of As, R. palustris CS2 increased shoot length up to 26.3% (21.0 ± 1.1 cm), while root length increased up to 31.3% (5.3 ± 0.4 cm), whereas R. faecalis SS5 inoculated plants showed 25% (20.7 ± 1.4 cm) increase in shoot length and 33.3% (5.4 ± 0.65 cm) increase in root length as compared to the control plants. Bacteria with such diverse abilities could be ideal for plant growth promotion in As-contaminated sites. PMID:28386559

  15. Replication licensing promotes cyclin D1 expression and G1 progression in untransformed human cells

    PubMed Central

    Liu, Peijun; Slater, Damien M.; Lenburg, Marc; Nevis, Kathleen; Cook, Jeanette Gowen; Vaziri, Cyrus

    2011-01-01

    Defects in DNA replication are implicated as early and causal events in malignancy. However, the immediate effects of impaired DNA replication licensing on cell cycle progression of non-malignant human cells are unknown. Therefore, we have investigated the acute effects of Mcm7 ablation using synchronized cultures of untransformed Human Dermal Fibroblasts (HDF). Mcm7 ablation elicited a G1 delay associated with impaired activation of CDK4 and CDK2 and reduced Rb phosphorylation. The cell cycle delay of Mcm7-ablated cells was not associated with a DNA damage response. However, levels of cyclin D1 mRNA were specifically reduced and binding of RNA Polymerase II to the CYCD1 promoter was decreased in Mcm7-depleted cells. Similar to Mcm7-deficiency, Mcm2- or Cdc6-depletion led to impaired cyclin D expression. Ectopic overexpression of Cdc6 in quiescent cells promoted cyclin D1 expression, CDK4 activation and G1 progression. Therefore timely and efficient expression of cyclin D1 during G1 phase requires replication licensing. Reconstitution of cyclin D1 expression was insufficient to correct the G1 delay of Mcm7-depleted cells, indicating that additional cell cycle events during G1 are dependent on replication licensing. However, ectopic expression of the HPV-E7 oncoprotein, and the resulting bypass of the requirement for cyclin D1-Rb signaling enabled Mcm7-depleted cells to enter S-phase. HPV-E7-induced S-phase entry of Mcm7-depleted cells led to a DNA damage response, a hallmark of pre-malignancy. Taken together, our results suggest the existence of a ‘replication licensing restriction point’ that couples pre-RC assembly with G1 progression in normal cells to minimize replication stress, DNA damage and tumorigenesis. PMID:19106611

  16. Cell-cycle coupled expansion of AR activity promotes cancer progression

    PubMed Central

    McNair, Christopher; Urbanucci, Alfonso; Comstock, Clay E.S.; Augello, Michael A.; Goodwin, Jonathan F.; Launchbury, Rosalind; Zhao, Shuang; Schiewer, Mathew J.; Ertel, Adam; Karnes, Jeffrey; Davicioni, Elai; Wang, Liguo; Wang, Qianben; Mills, Ian G.; Feng, Felix Y.; Li, Wei; Carroll, Jason S.; Knudsen, Karen E.

    2016-01-01

    The androgen receptor (AR) is required for prostate cancer (PCa) survival and progression, and ablation of AR activity is the first line of therapeutic intervention for disseminated disease. While initially effective, recurrent tumors ultimately arise for which there is no durable cure. Despite the dependence of PCa on AR activity throughout the course of disease, delineation of the AR-dependent transcriptional network that governs disease progression remains elusive, and the function of AR in mitotically active cells is not well understood. Analyzing AR activity as a function of cell cycle revealed an unexpected and highly expanded repertoire of AR-regulated gene networks in actively cycling cells. New AR functions segregated into two major clusters: those that are specific to cycling cells and retained throughout the mitotic cell cycle (“Cell Cycle Common”), versus those that were specifically enriched in a subset of cell cycle phases (“Phase Restricted”). Further analyses identified previously unrecognized AR functions in major pathways associated with clinical PCa progression. Illustrating the impact of these unmasked AR-driven pathways, dihydroceramide-desaturase 1 (DEGS1) was identified as an AR regulated gene in mitotically active cells that promoted pro-metastatic phenotypes, and in advanced PCa proved to be highly associated with development of metastases, recurrence after therapeutic intervention, and reduced overall survival. Taken together, these findings delineate AR function in mitotically active tumor cells, thus providing critical insight into the molecular basis by which AR promotes development of lethal PCa and nominate new avenues for therapeutic intervention. PMID:27669432

  17. DNAJC6 promotes hepatocellular carcinoma progression through induction of epithelial–mesenchymal transition

    SciTech Connect

    Yang, Tao; Li, Xiao-Na; Li, Xing-Guang; Li, Ming; Gao, Peng-Zhi

    2014-12-12

    Highlights: • DNAJC6 is up-regulated in hepatocellular carcinoma tissues. • DNAJC6 promotes hepatocellular carcinoma cell proliferation and invasion. • DNAJC6 induces epithelial–mesenchymal transition by activating transforming growth factor β signaling. - Abstract: Epithelial–mesenchymal transition (EMT) is a developmental program, which is associated with hepatocellular carcinoma (HCC) development and progression. DNAJC6 (DNA/HSP40 homolog subfamily C member 6) encodes auxilin, which is responsible for juvenile Parkinsonism with phenotypic variability. However, the role of DNAJC6 in HCC development and progression is limited. Here, we report that DNAJC6 is up-regulated in HCC tissues and up-regulation of DNAJC6 expression predicts poor outcome in patients with HCC. Furthermore, overexpression of DNAJC6 enhances the ability for acquisition of mesenchymal traits, enhanced cell proliferation and invasion. DNAJC6 positively regulated expression of EMT-related transcription factor, also activating transforming growth factor β (TGF-β) pathway to contribute to EMT. Our findings demonstrated an important function of DNAJC6 in the progression of HCC by induction of EMT, and they implicate DNAJC6 as a marker of poor outcome in HCC.

  18. Interferon Regulatory Factor 7 Promoted Glioblastoma Progression and Stemness by Modulating IL-6 Expression in Microglia

    PubMed Central

    Li, Zongze; Huang, Qiming; Chen, Heping; Lin, Zhiqin; Zhao, Meng; Jiang, Zhongli

    2017-01-01

    Background: Interferon Regulatory Factor 7 (IRF7) is associated with chronic inflammation initiated by the activation of microglia. However it remains poorly defined how IRF7 activates microglia to initiate inflammatory microenvironment, and thus promotes the growth and malignancy of glioblastoma multiforme (GBM). This study investigated the role of IRF7 expression in microglia which increases GBM progression. Methods: We established stable human microglia (HMs) over-expressing IRF-7 or empty vector by lentiviral transduction and stable selection. These HM-IRF-7 cells were co-cultured with U87-MG to examine their influence on GBM, in terms of cell proliferation, apoptosis and stemness of U87-MG. By qRT-PCR and ELISA assays, the expression of key genes and secretion of inflammatory factors were identified in inflammatory signal pathway respectively. We also analyzed whether the expression of IRF7 and its target gene IL-6 correlated with PFS (progression-free survival) and OS (overall survival) in clinical samples by Kaplan-Meier survival curves. Results: HMs can be engineered to stably express high level of IFR7 with IRF7 lentivirus, and was found to promote U87-MG growth and inhibit its apoptosis in co-culture. Meanwhile, U87-MG seemed to show stem cell character with ALDH1 expression. These results may be related to IRF7 initiating IL-6 expression and secretion in both HM and U87-MG cells. The IRF7 and IL-6 were highly expressed in GBM tissues, and IL-6 secretion was high in GBM serums, both of which were significantly correlated with PFS and OS. Conclusions: The immune function of HMs was changed while it expressed IRF7 genes. The results demonstrated for the first time that IRF7 of microglia promoted GBM growth and stemness by mediating IL-6 expression, and revealed that IRF-7 and IL-6 were independent factors affecting the overall survival probability. PMID:28243325

  19. Cadherin-12 enhances proliferation in colorectal cancer cells and increases progression by promoting EMT.

    PubMed

    Ma, Junjun; Zhao, Jingkun; Lu, Jun; Wang, Puxiongzhi; Feng, Hao; Zong, Yaping; Ou, Baochi; Zheng, Minhua; Lu, Aiguo

    2016-07-01

    Cadherin-12 (CDH12) is a subtype of N-cadherin family. In this study, we investigated the expression of CDH12 and the role of CDH12 in prognosis of colorectal cancer (CRC) patients. In addition, we observed the influence of CDH12 on proliferation and progression of CRC cell lines. By using immunohistochemical staining, we analyzed CRC samples and adjacent non-tumor tissues collected from 78 patients who underwent laparoscopic surgery in Shanghai Minimally Invasive Center, China. Statistical analyses were used to analyze relationship between CDH12 and tumor features. Kaplan-Meier method was used to analyze patients' survival. Proliferation ability of CRC cells was tested by CCK-8 assay, and transwell assays were performed to detect migration and invasion ability. Western blot assay was performed to investigate epithelial-mesenchymal transition (EMT) variants. We found that expression of CDH12 in tumor tissue was higher than in adjacent normal tissue. High expression of CDH12 was associated with tumor invasion depth and predicts poor prognosis of CRC patients. Ectopic/repressing expression of CDH12 increased/decreased the proliferation and migration ability of CRC cells. CDH12 is able to increase cancer cell migration and invasion via promoting EMT by targeting transcriptional factor Snail. These findings may conclude that CDH12 may act as a predictor in CRC patients' prognosis and an oncogene in CRC cell proliferation and migration. CDH12 may influence CRC cell progression through promoting EMT by targeting Snail. In addition, CDH12 is promoted by MCP1 through induction of MCPIP.

  20. Arsenic in Food

    MedlinePlus

    ... Vaccines, Blood & Biologics Animal & Veterinary Cosmetics Tobacco Products Food Home Food Foodborne Illness & Contaminants Metals Arsenic Share ... of the Method used to Measure Arsenic in Foods Inductively Coupled Plasma-Mass Spectrometric Determination of Arsenic, ...

  1. Toxic Substances Portal- Arsenic

    MedlinePlus

    ... plants combines with carbon and hydrogen to form organic arsenic compounds. Inorganic arsenic compounds are mainly used ... uses; it is still used in industrial applications. Organic arsenic compounds are used as pesticides, primarily on ...

  2. Arsenic, inorganic

    Integrated Risk Information System (IRIS)

    Arsenic , inorganic ; CASRN 7440 - 38 - 2 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcinoge

  3. Obstructive sleep apnea promotes cancer development and progression: a concise review.

    PubMed

    Cao, Jie; Feng, Jing; Li, Lian; Chen, Baoyuan

    2015-05-01

    Obstructive sleep apnoea-hypopnoea (OSA) is an increasingly common sleep disorder which is widely accepted to be associated with high rates of morbidity and mortality. OSA is an independent risk factor for cardiovascular diseases, cerebrovascular disease, and metabolic disease. Recently, several studies have demonstrated that patients with OSA have a higher prevalence of cancer and cancer-related mortality. The epidemiological surveys suggest that patients with OSA had a higher incidence of cancer and cancer-related mortality than patients without OSA. Animal studies indicate that the activation of HIF-1 and VEGF pathways in response to intermittent hypoxia may promote the blood supply which supports tumor growth. In addition, tumor-associated macrophages may be altered by intermittent hypoxia (or sleep fragmentation) to a tumor-promoting phenotype yielding more aggressive cancer behavior. The relationship between OSA and cancer has been confirmed, in which patients with OSA have a relative high prevalence of cancer and cancer-related mortality. The mechanism of OSA promoting cancer development and progression may be related with intermittent hypoxia and possibly sleep fragmentation. The activation of several cancer-related pathways may play an important role in tumor growth and metastasis. More clinical data and basic studies are needed to explain and confirm the relationship between OSA and cancer.

  4. CD147 promotes melanoma progression through hypoxia-induced MMP2 activation.

    PubMed

    Zeng, W; Su, J; Wu, L; Yang, D; Long, T; Li, D; Kuang, Y; Li, J; Qi, M; Zhang, J; Chen, X

    2014-01-01

    Hypoxia enhances MMP2 expression and the invasion and metastatic potential of melanoma cells. CD147 has been shown to induce MMP2 in multiple cancers. To investigate the role of CD147 in hypoxiainduced MMP2 activation, we performed immunohistochemistry (IHC) staining in 206 normal and melanoma tissue samples, and analyzed the correlation between HIF1α and CD147. ChIP (chromosome Immunoprecipitation) in melanoma cell lines supports that HIF1α directly binds to CD147 promoter. Moreover, we made a series of deletion mutants of CD147 promoter, and identified a conserved HIF1α binding site. Point mutation in this site significantly decreased CD147 response to hypoxia. Importantly, knocking down CD147 attenuates MMP2 response to hypoxia in melanoma cell lines. MMP2 could not be efficiently activated by hypoxia in CD147 depletion cells. ELISA data showed that MMP2 secretion was reduced in CD147 depletion cells than control under hypoxia condition. To verify the data from cell culture model, we performed in vivo mouse xenograft experiment. IHC staining showed reduced MMP2 level in CD147 depleted xenografts compared to the control group, with the HIF1α level being comparable. Our study demonstrates a novel pathway mediated by CD147 to promote the MMP2 activation induced by hypoxia, and helps to understand the interplay between hypoxia and melanoma progression.

  5. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis.

    PubMed

    Ehling, Josef; Bartneck, Matthias; Wei, Xiao; Gremse, Felix; Fech, Viktor; Möckel, Diana; Baeck, Christer; Hittatiya, Kanishka; Eulberg, Dirk; Luedde, Tom; Kiessling, Fabian; Trautwein, Christian; Lammers, Twan; Tacke, Frank

    2014-12-01

    In chronic liver injury, angiogenesis, the formation of new blood vessels from pre-existing ones, may contribute to progressive hepatic fibrosis and to development of hepatocellular carcinoma. Although hypoxia-induced expression of vascular endothelial growth factor (VEGF) occurs in advanced fibrosis, we hypothesised that inflammation may endorse hepatic angiogenesis already at early stages of fibrosis. Angiogenesis in livers of c57BL/6 mice upon carbon tetrachloride- or bile duct ligation-induced chronic hepatic injury was non-invasively monitored using in vivo contrast-enhanced micro computed tomography (µCT) and ex vivo anatomical µCT after hepatic Microfil perfusion. Functional contributions of monocyte-derived macrophage subsets for angiogenesis were explored by pharmacological inhibition of CCL2 using the Spiegelmer mNOX-E36. Contrast-enhanced in vivo µCT imaging allowed non-invasive monitoring of the close correlation of angiogenesis, reflected by functional hepatic blood vessel expansion, with experimental fibrosis progression. On a cellular level, inflammatory monocyte-derived macrophages massively accumulated in injured livers, colocalised with newly formed vessels in portal tracts and exhibited pro-angiogenic gene profiles including upregulated VEGF and MMP9. Functional in vivo and anatomical ex vivo µCT analyses demonstrated that inhibition of monocyte infiltration by targeting the chemokine CCL2 prevented fibrosis-associated angiogenesis, but not fibrosis progression. Monocyte-derived macrophages primarily fostered sprouting angiogenesis within the portal vein tract. Portal vein diameter as a measure of portal hypertension depended on fibrosis, but not on angiogenesis. Inflammation-associated angiogenesis is promoted by CCL2-dependent monocytes during fibrosis progression. Innovative in vivo µCT methodology can accurately monitor angiogenesis and antiangiogenic therapy effects in experimental liver fibrosis. Published by the BMJ Publishing Group

  6. CD97 amplifies LPA receptor signaling and promotes thyroid cancer progression in a mouse model.

    PubMed

    Ward, Y; Lake, R; Martin, P L; Killian, K; Salerno, P; Wang, T; Meltzer, P; Merino, M; Cheng, S-y; Santoro, M; Garcia-Rostan, G; Kelly, K

    2013-05-30

    CD97, a member of the adhesion family of G-protein-coupled receptors (GPCRs), complexes with and potentiates lysophosphatidic acid (LPA) receptor signaling to the downstream effector RHOA. We show here that CD97 was expressed in a majority of thyroid cancers but not normal thyroid epithelium and that the level of CD97 expression was further elevated with progression to poorly differentiated and undifferentiated carcinoma. Intratumoral progression also showed that CD97 expression correlates with invasiveness and dedifferentiation. To determine the functional role of CD97, we produced a transgenic model of thyroglobulin promoter-driven CD97 expression. Transgenic CD97 in combination with Thrb(PV), an established mouse model of thyroid follicular cell carcinogenesis, significantly increased the occurrence of vascular invasion and lung metastasis. Expression of transgenic CD97 in thyroid epithelium led to elevated ERK phosphorylation and increased numbers of Ki67+ cells in developing tumors. In addition, tumor cell cultures derived from CD97 transgenic as compared with non-transgenic mice demonstrated enhanced, constitutive and LPA-stimulated ERK activation. In human thyroid cancer cell lines, CD97 depletion reduced RHO-GTP and decreased LPA-stimulated invasion but not EGF-stimulated invasion, further suggesting that CD97 influences an LPA-associated mechanism of progression. Consistent with the above, CD97 expression in human thyroid cancers correlated with LPA receptor and markers of aggressiveness including Ki67 and pAKT. This study shows an autonomous effect of CD97 on thyroid cancer progression and supports the investigation of this GPCR as a therapeutic target for these cancers.

  7. Arsenic-mediated activation of the Nrf2-Keap1 antioxidant pathway.

    PubMed

    Lau, Alexandria; Whitman, Samantha A; Jaramillo, Melba C; Zhang, Donna D

    2013-02-01

    Arsenic is present in the environment and has become a worldwide health concern due to its toxicity and carcinogenicity. However, the specific mechanism(s) by which arsenic elicits its toxic effects has yet to be fully elucidated. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) has been recognized as the master regulator of a cellular defense mechanism against toxic insults. This review highlights studies demonstrating that arsenic activates the Nrf2-Keap1 antioxidant pathway by a distinct mechanism from that of natural compounds such as sulforaphane (SF) found in broccoli sprouts or tert-butylhyrdoquinone (tBHQ), a natural antioxidant commonly used as a food preservative. Evidence also suggests that arsenic prolongs Nrf2 activation and may mimic constitutive activation of Nrf2, which has been found in several human cancers due to disruption of the Nrf2-Keap1 axis. The current literature strongly suggests that activation of Nrf2 by arsenic potentially contributes to, rather than protects against, arsenic toxicity and carcinogenicity. The mechanism(s) by which known Nrf2 activators, such as the natural chemopreventive compounds SF and lipoic acid, protect against the deleterious effects caused by arsenic will also be discussed. These findings will provide insight to further understand how arsenic promotes a prolonged Nrf2 response, which will lead to the identification of novel molecular markers and development of rational therapies for the prevention or intervention of arsenic-induced diseases. The National Institute of Environmental Health Science (NIEHS) Outstanding New Environmental Scientist (ONES) award has provided the opportunity to review the progress both in the fields of arsenic toxicology and Nrf2 biology. Much of the funding has led to (1) the novel discovery that arsenic activates the Nrf2 pathway by a mechanism different to that of other Nrf2 activators, such as sulforaphane and tert-butylhydroquinone, (2) activation of Nrf

  8. Arsenic-Mediated Activation of the Nrf2-Keap1 Antioxidant Pathway

    PubMed Central

    Lau, Alexandria; Whitman, Samantha A.; Jaramillo, Melba C.; Zhang, Donna D.

    2013-01-01

    Arsenic is present in the environment and has become a worldwide health concern due to its toxicity and carcinogenicity. However, the specific mechanism(s) by which arsenic elicits its toxic effects has yet to be fully elucidated. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) has been recognized as the master regulator of a cellular defense mechanism against toxic insults. This review highlights studies demonstrating that arsenic activates the Nrf2-Keap1 antioxidant pathway by a distinct mechanism from that of natural compounds such as sulforaphane (SF) found in broccoli sprouts or tert-butylhyrdoquinone (tBHQ), a natural antioxidant commonly used as a food preservative. Evidence also suggests that arsenic prolongs Nrf2 activation and may mimic constitutive activation of Nrf2, which has been found in several human cancers due to disruption of the Nrf2-Keap1 axis. The current literature strongly suggests that activation of Nrf2 by arsenic potentially contributes to, rather than protects against, arsenic toxicity and carcinogenicity. The mechanism(s) by which known Nrf2 activators, such as the natural chemopreventive compounds SF and lipoic acid, protect against the deleterious effects caused by arsenic will also be discussed. These findings will provide insight to further understand how arsenic promotes a prolonged Nrf2 response, which will lead to the identification of novel molecular markers and development of rational therapies for the prevention or intervention of arsenic-induced diseases. The National Institute of Environmental Health Science (NIEHS) Outstanding New Environmental Scientist (ONES) award has provided the opportunity to review the progress both in the fields of arsenic toxicology and Nrf2 biology. Much of the funding has led to (1) the novel discovery that arsenic activates the Nrf2 pathway by a mechanism different to that of other Nrf2 activators, such as sulforaphane and tert-butylhydroquinone, (2) activation of Nrf

  9. FGF19 Contributes to Tumor Progression in Gastric Cancer by Promoting Migration and Invasion.

    PubMed

    Wang, Shuang; Zhao, Daqi; Tian, Ruihua; Shi, Hailong; Chen, Xiangming; Liu, Wenzhi; Wei, Lin

    2016-01-01

    Gastric cancer is the fourth most common type of cancer and second leading cause of cancer-related death in the world. Since patients are often diagnosed at a late stage, very few effective therapies are left in the arsenal. FGF19, as a hormone, has been reported to promote tumor growth in various types of cancer; however, its function in gastric cancer remains unknown. In the current study, we showed that FGF19 is overexpressed in gastric cancer and is associated with depth of invasion, lymph node metastasis, and TNM stage. In addition, in vitro experiments demonstrated that FGF19 is able to enhance migration and invasion abilities of gastric cancer cells. Given its great potency in gastric cancer progression, FGF19 may be an effective target of treatment for advanced gastric cancer patients.

  10. Volcano collapse promoted by progressive strength reduction: New data from Mount St. Helens

    USGS Publications Warehouse

    Reid, Mark E.; Keith, Terry E.C.; Kayen, Robert; Iverson, Neal R.; Iverson, Richard M.; Brien, Dianne

    2010-01-01

    Rock shear strength plays a fundamental role in volcano flank collapse, yet pertinent data from modern collapse surfaces are rare. Using samples collected from the inferred failure surface of the massive 1980 collapse of Mount St. Helens (MSH), we determined rock shear strength via laboratory tests designed to mimic conditions in the pre-collapse edifice. We observed that the 1980 failure shear surfaces formed primarily in pervasively shattered older dome rocks; failure was not localized in sloping volcanic strata or in weak, hydrothermally altered rocks. Our test results show that rock shear strength under large confining stresses is reduced ∼20% as a result of large quasi-static shear strain, as preceded the 1980 collapse of MSH. Using quasi-3D slope-stability modeling, we demonstrate that this mechanical weakening could have provoked edifice collapse, even in the absence of transiently elevated pore-fluid pressures or earthquake ground shaking. Progressive strength reduction could promote collapses at other volcanic edifices.

  11. Worldwide occurrences of arsenic in ground water

    USGS Publications Warehouse

    Nordstrom, D. Kirk

    2002-01-01

    Numerous aquifers worldwide carry soluble arsenic at concentrations greater than the World Health Organization--and U.S. Environmental Protection Agency--recommended drinking water standard of 10 mg per liter. Sources include both natural (black shales, young sediments with low flushing rates, gold mineralization, and geothermal environments) and anthropogenic (mining activities, livestock feed additives, pesticides, and arsenic trioxide wastes and stockpiles). Increased solubility and mobility of arsenic is promoted by high pH (>8.5), competing oxyanions, and reducing conditions. In this Policy Forum, Nordstrom argues that human health risks from arsenic in ground water can be minimized by incorporating hydrogeochemical knowledge into water management decisions and by more careful monitoring for arsenic in geologically high-risk areas.

  12. Nocturnal hypoxia-induced oxidative stress promotes progression of pediatric non-alcoholic fatty liver disease.

    PubMed

    Sundaram, Shikha S; Halbower, Ann; Pan, Zhaoxing; Robbins, Kristen; Capocelli, Kelley E; Klawitter, Jelena; Shearn, Colin T; Sokol, Ronald J

    2016-09-01

    Oxidative stress is proposed as a central mediator in NAFLD pathogenesis, but the specific trigger for reactive oxygen species generation has not been clearly delineated. In addition, emerging evidence shows that obesity related obstructive sleep apnea (OSA) and nocturnal hypoxia are associated with NAFLD progression in adults. The aim of this study was to determine if OSA/nocturnal hypoxia-induced oxidative stress promotes the progression of pediatric NAFLD. Subjects with biopsy proven NAFLD and lean controls were studied. Subjects underwent polysomnograms, liver histology scoring, laboratory testing, urine F(2)-isoprostanes (measure of lipid peroxidation) and 4-hydroxynonenal liver immunohistochemistry (in situ hepatic lipid peroxidation). We studied 36 adolescents with NAFLD and 14 lean controls. The OSA/hypoxia group (69% of NAFLD subjects) had more severe fibrosis (64% stage 0-2; 36% stage 3) than those without OSA/hypoxia (100% stage 0-2), p=0.03. Higher F(2)-isoprostanes correlated with apnea/hypoxia index (r=0.39, p=0.03), % time SaO2 <90% (r=0.56, p=0.0008) and inversely with SaO2 nadir (r=-0.46, p=0.008). OSA/hypoxia was most severe in subjects with the greatest 4HNE staining (p=0.03). Increasing F(2)-isoprostanes(r=0.32, p=0.04) and 4HNE hepatic staining (r=0.47, p=0.007) were associated with worsening steatosis. Greater oxidative stress occurred in subjects with definite NASH as measured by F(2)-isoprostanes (p=0.06) and hepatic 4HNE (p=0.03) compared to those with borderline/not NASH. These data support the role of nocturnal hypoxia as a trigger for localized hepatic oxidative stress, an important factor associated with the progression of NASH and hepatic fibrosis in obese pediatric patients. Obstructive sleep apnea and low nighttime oxygen are associated with NAFLD progression in adults. In this study, we show that adolescents with NAFLD who have OSA and low oxygen have significant scar tissue in their livers. NAFLD subjects affected by OSA and low

  13. E3 ubiquitin ligases promote progression of differentiation during C. elegans embryogenesis

    PubMed Central

    Du, Zhuo; He, Fei; Yu, Zidong; Bowerman, Bruce; Bao, Zhirong

    2014-01-01

    Regulated choice between cell fate maintenance and differentiation provides decision points in development to progress toward more restricted cell fates or to maintain the current one. C. elegans embryogenesis follows an invariant cell lineage where cell fate is generally more restricted upon each cell division. EMS is a progenitor cell in the four-cell embryo that gives rise to the endomesoderm. We recently found that when ubiquitin-mediated protein degradation is compromised, the anterior daughter of EMS, namely MS, reiterates the EMS fate. This observation demonstrates an essential function of ubiquitin-mediated protein degradation in driving the progression of EMS-to-MS differentiation. Here we report a genome-wide screen of the ubiquitin pathway and extensive lineage analyses. The results suggest a broad role of E3 ligases in driving differentiation progression. First, we identified three substrate-binding proteins for two CRL (Cullin-RING ubiquitin Ligase) E3 complexes that promote the progression from the EMS fate to MS, namely LIN-23/β-TrCP and FBXB-3 for the CRL1/SCF complex and ZYG-11/ZYG-11B for the CRL2 complex. Genetic analyses suggest these E3 ligases function through a multifunctional protein OMA-1 and the endomesoderm lineage specifier SKN-1 to drive differentiation. Second, we found that depletion of components of the CRL1/SCF complex induces fate reiteration in all major founder cell lineages. These data suggest that regulated choice between self-renewal and differentiation is widespread during C. elegans embryogenesis as in organisms with regulative development, and ubiquitin-mediated protein degradation drives the choice towards differentiation. Finally, bioinformatic analysis of time series gene expression data showed that expression of E3 genes is transiently enriched during time windows of developmental stage transitions. Transcription factors show similar enrichment, but not other classes of regulatory genes. Based on these findings we

  14. Impact of early developmental arsenic exposure on promotor CpG-island methylation of genes involved in neuronal plasticity.

    PubMed

    Martínez, Liborio; Jiménez, Verónica; García-Sepúlveda, Christian; Ceballos, Fátima; Delgado, Juan Manuel; Niño-Moreno, Perla; Doniz, Lesly; Saavedra-Alanís, Víctor; Castillo, Claudia G; Santoyo, Martha E; González-Amaro, Roberto; Jiménez-Capdeville, María E

    2011-04-01

    Epigenetic mechanisms are crucial to regulate the expression of different genes required for neuronal plasticity. Neurotoxic substances such as arsenic, which induces cognitive deficits in exposed children before any other manifestation of toxicity, could interfere with the epigenetic modulation of neuronal gene expression required for learning and memory. This study assessed in Wistar rats the effects that developmental arsenic exposure had on DNA methylation patterns in hippocampus and frontal cortex. Animals were exposed to arsenic in drinking water (3 and 36ppm) from gestation until 4 months of age, and DNA methylation in brain cells was determined by flow cytometry, immunohistochemistry and methylation-specific polymerase chain reaction (PCR) of the promoter regions of reelin (RELN) and protein phosphatase 1 (PP1) at 1, 2, 3 and 4 months of age. Immunoreactivity to 5 methyl-cytosine was significantly higher in the cortex and hippocampus of exposed animals compared to controls at 1 month, and DNA hypomethylation was observed the following months in the cortex at high arsenic exposure. Furthermore, we observed a significant increase in the non-methylated form of PP1 gene promoter at 2 and 3 months of age, either in cortex or hippocampus. In order to determine whether this exposure level is associated with memory deficits, a behavioral test was performed at the same age points, revealing progressive and dose-dependent deficits of fear memory. Our results demonstrate alterations of the methylation pattern of genes involved in neuronal plasticity in an animal model of memory deficit associated with arsenic exposure.

  15. Promoter methylation of PCDH10 by HOTAIR regulates the progression of gastrointestinal stromal tumors

    PubMed Central

    Lee, Na Keum; Lee, Jung Hwa; Kim, Won Kyu; Yun, Seongju; Youn, Young Hoon; Park, Chan Hyuk; Choi, Yun Young; Kim, Hogeun; Lee, Sang Kil

    2016-01-01

    HOTAIR, a long non-coding RNA (lncRNA), plays a crucial role in tumor initiation and metastasis by interacting with the PRC2 complex and the modulation of its target genes. The role of HOTAIR in gastrointestinal stromal tumors (GISTs) is remains unclear. Herein we investigate the mechanism of HOTAIR in the genesis and promotion of GISTs. The expression of HOTAIR was found to be higher in surgically resected high-risk GISTs than that in low- and intermediate-risk GISTs. Using GIST-T1 and GIST882 cells, we demonstrated that HOTAIR repressed apoptosis, was associated with cell cycle progression, and controlled the invasion and migration of GIST cells. Using a gene expression microarray and lists of HOTAIR-associated candidate genes, we suggested that protocadherin 10 (PCDH10) is a key molecule. PCDH10 expression was significantly decreased in GIST-T1 and GIST882 cells, possibly as a consequence of hypermethylation. We observed that HOTAIR induced PCDH10 methylation in a SUZ12-dependent manner. In this study, we found that the malignant character of GISTs was initiated and amplified by PCDH10 in a process regulated by HOTAIR. In summary, our findings imply that PCDH10 and HOTAIR may be useful markers of disease progression and therapeutic targets. PMID:27659532

  16. MVP-mediated exosomal sorting of miR-193a promotes colon cancer progression

    PubMed Central

    Teng, Yun; Ren, Yi; Hu, Xin; Mu, Jingyao; Samykutty, Abhilash; Zhuang, Xiaoying; Deng, Zhongbin; Kumar, Anil; Zhang, Lifeng; Merchant, Michael L.; Yan, Jun; Miller, Donald M.; Zhang, Huang-Ge

    2017-01-01

    Exosomes are emerging mediators of intercellular communication; whether the release of exosomes has an effect on the exosome donor cells in addition to the recipient cells has not been investigated to any extent. Here, we examine different exosomal miRNA expression profiles in primary mouse colon tumour, liver metastasis of colon cancer and naive colon tissues. In more advanced disease, higher levels of tumour suppressor miRNAs are encapsulated in the exosomes. miR-193a interacts with major vault protein (MVP). Knockout of MVP leads to miR-193a accumulation in the exosomal donor cells instead of exosomes, inhibiting tumour progression. Furthermore, miR-193a causes cell cycle G1 arrest and cell proliferation repression through targeting of Caprin1, which upregulates Ccnd2 and c-Myc. Human colon cancer patients with more advanced disease show higher levels of circulating exosomal miR-193a. In summary, our data demonstrate that MVP-mediated selective sorting of tumour suppressor miRNA into exosomes promotes tumour progression. PMID:28211508

  17. Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

    PubMed Central

    Ferrarese, Roberto; Harsh, Griffith R.; Yadav, Ajay K.; Bug, Eva; Maticzka, Daniel; Reichardt, Wilfried; Dombrowski, Stephen M.; Miller, Tyler E.; Masilamani, Anie P.; Dai, Fangping; Kim, Hyunsoo; Hadler, Michael; Scholtens, Denise M.; Yu, Irene L.Y.; Beck, Jürgen; Srinivasasainagendra, Vinodh; Costa, Fabrizio; Baxan, Nicoleta; Pfeifer, Dietmar; von Elverfeldt, Dominik; Backofen, Rolf; Weyerbrock, Astrid; Duarte, Christine W.; He, Xiaolin; Prinz, Marco; Chandler, James P.; Vogel, Hannes; Chakravarti, Arnab; Rich, Jeremy N.; Carro, Maria S.; Bredel, Markus

    2014-01-01

    Tissue-specific alternative splicing is critical for the emergence of tissue identity during development, yet the role of this process in malignant transformation is undefined. Tissue-specific splicing involves evolutionarily conserved, alternative exons that represent only a minority of the total alternative exons identified. Many of these conserved exons have functional features that influence signaling pathways to profound biological effect. Here, we determined that lineage-specific splicing of a brain-enriched cassette exon in the membrane-binding tumor suppressor annexin A7 (ANXA7) diminishes endosomal targeting of the EGFR oncoprotein, consequently enhancing EGFR signaling during brain tumor progression. ANXA7 exon splicing was mediated by the ribonucleoprotein PTBP1, which is normally repressed during neuronal development. PTBP1 was highly expressed in glioblastomas due to loss of a brain-enriched microRNA (miR-124) and to PTBP1 amplification. The alternative ANXA7 splicing trait was present in precursor cells, suggesting that glioblastoma cells inherit the trait from a potential tumor-initiating ancestor and that these cells exploit this trait through accumulation of mutations that enhance EGFR signaling. Our data illustrate that lineage-specific splicing of a tissue-regulated alternative exon in a constituent of an oncogenic pathway eliminates tumor suppressor functions and promotes glioblastoma progression. This paradigm may offer a general model as to how tissue-specific regulatory mechanisms can reprogram normal developmental processes into oncogenic ones. PMID:24865424

  18. Challenges and opportunities for promoting booster seat use: progressive dissemination of a high-threat message.

    PubMed

    Will, Kelli England; Dunaway, Krystall E; Kokorelis, Diane A; Sabo, Cynthia Shier; Lorek, Edward J

    2012-11-01

    Motivating parents to take certain safety precautions when traveling with their children remains challenging for advocates. Caregivers of booster-aged children are particularly difficult to reach because they do not consider their children to be of "safety-seat" age and have inherently low perceptions of vulnerability to crash injury. Unfortunately, most booster seat programs fail to adequately motivate their intended population because they are primarily informational in nature and rely on caregivers to seek out and attend to the information. In this article, interventions using threat appeal tactics and progressive dissemination methods are recommended to effectively target participation and perceptions of vulnerability among this population. Recent research on risk communication indicates that threat appeals are supported when they contain high threat and high efficacy components. Threat appeal tactics are particularly desirable when perception of vulnerability is low, as is the case with parents of booster-aged children. In addition to theoretical arguments for more aggressive intervention approaches, a case example is presented wherein such techniques were used to promote booster seat use. The intervention resulted in significant increases in knowledge, risk-reduction attitudes, sense of efficacy, and observed booster seat use. Through use of progressive dissemination methods, the intervention has reached an audience of 431,600 people and counting.

  19. MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice.

    PubMed

    Williams, Andrew H; Valdez, Gregorio; Moresi, Viviana; Qi, Xiaoxia; McAnally, John; Elliott, Jeffrey L; Bassel-Duby, Rhonda; Sanes, Joshua R; Olson, Eric N

    2009-12-11

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of motor neurons, denervation of target muscles, muscle atrophy, and paralysis. Understanding ALS pathogenesis may require a fuller understanding of the bidirectional signaling between motor neurons and skeletal muscle fibers at neuromuscular synapses. Here, we show that a key regulator of this signaling is miR-206, a skeletal muscle-specific microRNA that is dramatically induced in a mouse model of ALS. Mice that are genetically deficient in miR-206 form normal neuromuscular synapses during development, but deficiency of miR-206 in the ALS mouse model accelerates disease progression. miR-206 is required for efficient regeneration of neuromuscular synapses after acute nerve injury, which probably accounts for its salutary effects in ALS. miR-206 mediates these effects at least in part through histone deacetylase 4 and fibroblast growth factor signaling pathways. Thus, miR-206 slows ALS progression by sensing motor neuron injury and promoting the compensatory regeneration of neuromuscular synapses.

  20. Inflammatory peroxidases promote breast cancer progression in mice via regulation of the tumour microenvironment.

    PubMed

    Panagopoulos, Vasilios; Leach, Damien A; Zinonos, Irene; Ponomarev, Vladimir; Licari, Giovanni; Liapis, Vasilios; Ingman, Wendy V; Anderson, Peter; DeNichilo, Mark O; Evdokiou, Andreas

    2017-04-01

    Myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are heme-containing enzymes, well known for their antimicrobial activity, are released in high quantities by infiltrating immune cells in breast cancer. However, the functional importance of their presence within the tumour microenvironment is unclear. We have recently described a new role for peroxidases as key regulators of fibroblast and endothelial cell functionality. In the present study, we investigate for the first time, the ability of peroxidases to promote breast cancer development and progression. Using the 4T1 syngeneic murine orthotopic breast cancer model, we examined whether increased levels of peroxidases in developing mammary tumours influences primary tumour growth and metastasis. We showed that MPO and EPO stimulation increased mammary tumour growth and enhanced lung metastases, effects that were associated with reduced tumour necrosis, increased collagen deposition and neo-vascularisation within the primary tumour. In vitro, peroxidase treatment, robustly stimulated human mammary fibroblast migration and collagen type I and type VI secretion. Mechanistically, peroxidases induced the transcription of pro-tumorigenic and metastatic MMP1, MMP3 and COX-2 genes. Taken together, these findings identify peroxidases as key contributors to cancer progression by augmenting pro-tumorigenic collagen production and angiogenesis. Importantly, this identifies inflammatory peroxidases as therapeutic targets in breast cancer therapy.

  1. miR-146a promotes the initiation and progression of melanoma by activating Notch signaling

    PubMed Central

    Forloni, Matteo; Dogra, Shaillay Kumar; Dong, Yuying; Conte, Darryl; Ou, Jianhong; Zhu, Lihua Julie; Deng, April; Mahalingam, Meera; Green, Michael R; Wajapeyee, Narendra

    2014-01-01

    Oncogenic mutations in BRAF and NRAS occur in 70% of melanomas. In this study, we identify a microRNA, miR-146a, that is highly upregulated by oncogenic BRAF and NRAS. Expression of miR-146a increases the ability of human melanoma cells to proliferate in culture and form tumors in mice, whereas knockdown of miR-146a has the opposite effects. We show these oncogenic activities are due to miR-146a targeting the NUMB mRNA, a repressor of Notch signaling. Previous studies have shown that pre-miR-146a contains a single nucleotide polymorphism (C>G rs2910164). We find that the ability of pre-miR-146a/G to activate Notch signaling and promote oncogenesis is substantially higher than that of pre-miR-146a/C. Analysis of melanoma cell lines and matched patient samples indicates that during melanoma progression pre-miR-146a/G is enriched relative to pre-miR-146a/C, resulting from a C-to-G somatic mutation in pre-miR-146a/C. Collectively, our results reveal a central role for miR-146a in the initiation and progression of melanoma. DOI: http://dx.doi.org/10.7554/eLife.01460.001 PMID:24550252

  2. PPARδ promotes tumor progression via activation of Glut1 and SLC1-A5 transcription.

    PubMed

    Zhang, Wenbo; Xu, Ying; Xu, Qinggang; Shi, Haifeng; Shi, Juanjuan; Hou, Yongzhong

    2017-07-01

    Malignant cancer cell uncontrolled growth depends on the persistent nutrient availability such as glucose and amino acids, which is required for cancer cell energetic and biosynthetic pathways. As a nuclear hormone receptor, peroxisome-proliferator-activated receptor δ (PPARδ) plays a critical role in inflammation and cancer, however, it is still unclear the regulatory mechanism of PPARδ on cancer cell metabolism. Here, we found that PPARδ directly regulated neutral amino acid transporter SLC1-A5 (solute carrier family 1 member 5) and glucose transporter-1 (Glut1) gene transcription, leading to uptake of glucose and amino acid, activation of mTOR signaling, and tumor progression. In contrast, silence of PPARδ or its antagonist inhibited this event. More importantly, PPARδ promoted cancer cell metabolic reprogramming resulting in chemoresistance, which was alleviated by PPARδ antagonist. These findings revealed a novel mechanism of PPARδ-mediated tumor progression, which provided a potential strategy for cancer treatment. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. AMOTL1 Promotes Breast Cancer Progression and Is Antagonized by Merlin1

    PubMed Central

    Couderc, Christophe; Boin, Alizée; Fuhrmann, Laetitia; Vincent-Salomon, Anne; Mandati, Vinay; Kieffer, Yann; Mechta-Grigoriou, Fatima; Del Maestro, Laurence; Chavrier, Philippe; Vallerand, David; Brito, Isabelle; Dubois, Thierry; De Koning, Leanne; Bouvard, Daniel; Louvard, Daniel; Gautreau, Alexis; Lallemand, Dominique

    2016-01-01

    The Hippo signaling network is a key regulator of cell fate. In the recent years, it was shown that its implication in cancer goes well beyond the sole role of YAP transcriptional activity and its regulation by the canonical MST/LATS kinase cascade. Here we show that the motin family member AMOTL1 is an important effector of Hippo signaling in breast cancer. AMOTL1 connects Hippo signaling to tumor cell aggressiveness. We show that both canonical and noncanonical Hippo signaling modulates AMOTL1 levels. The tumor suppressor Merlin triggers AMOTL1 proteasomal degradation mediated by the NEDD family of ubiquitin ligases through direct interaction. In parallel, YAP stimulates AMOTL1 expression. The loss of Merlin expression and the induction of Yap activity that are frequently observed in breast cancers thus result in elevated AMOTL1 levels. AMOTL1 expression is sufficient to trigger tumor cell migration and stimulates proliferation by activating c-Src. In a large cohort of human breast tumors, we show that AMOTL1 protein levels are upregulated during cancer progression and that, importantly, the expression of AMOTL1 in lymph node metastasis appears predictive of the risk of relapse. Hence we uncover an important mechanism by which Hippo signaling promotes breast cancer progression by modulating the expression of AMOTL1. PMID:26806348

  4. Neural protein gamma-synuclein interacting with androgen receptor promotes human prostate cancer progression

    PubMed Central

    2012-01-01

    Background Gamma-synuclein (SNCG) has previously been demonstrated to be significantly correlated with metastatic malignancies; however, in-depth investigation of SNCG in prostate cancer is still lacking. In the present study, we evaluated the role of SNCG in prostate cancer progression and explored the underlying mechanisms. Methods First, alteration of SNCG expression in LNCaP cell line to test the ability of SNCG on cellular properties in vitro and vivo whenever exposing with androgen or not. Subsequently, the Dual-luciferase reporter assays were performed to evaluate whether the role of SNCG in LNCaP is through AR signaling. Last, the association between SNCG and prostate cancer progression was assessed immunohistochemically using a series of human prostate tissues. Results Silencing SNCG by siRNA in LNCaP cells contributes to the inhibition of cellular proliferation, the induction of cell-cycle arrest at the G1 phase, the suppression of cellular migration and invasion in vitro, as well as the decrease of tumor growth in vivo with the notable exception of castrated mice. Subsequently, mechanistic studies indicated that SNCG is a novel androgen receptor (AR) coactivator. It interacts with AR and promotes prostate cancer cellular growth and proliferation by activating AR transcription in an androgen-dependent manner. Finally, immunohistochemical analysis revealed that SNCG was almost undetectable in benign or androgen-independent tissues prostate lesions. The high expression of SNCG is correlated with peripheral and lymph node invasion. Conclusions Our data suggest that SNCG may serve as a biomarker for predicting human prostate cancer progression and metastasis. It also may become as a novel target for biomedical therapy in advanced prostate cancer. PMID:23231703

  5. Overexpression of Tiam1 promotes the progression of laryngeal squamous cell carcinoma.

    PubMed

    Wang, Shuang; Li, Shisheng; Tang, Qinglai; Yang, Shu; Wang, Shuhui; Liu, Jiajia; Yang, Mi; Yang, Xinming

    2015-04-01

    T-lymphoma invasion and metastasis‑inducing factor 1 (Tiam1) has been reported in various types of human cancer, which play important roles in facilitating the meta-stasis of malignant tumor. However, the investigation of Tiam1 in laryngeal squamous-cell carcinoma is extremely rare. The aim of the present study was to assess Tiam1 expression and examine its function in tumorigenesis and the metastasis of laryngeal squamous cell carcinoma (LSCC) in vitro. Tiam1 expression in 98 primary LSCC tissue specimens was analyzed by immunohistochemistry and correlated with clinicopathological parameters and patients' survival. To investigate the effects of Tiam1 on the progression of LSCC, Tiam1/C1199 plasmid was transfected into LSCC, and proliferation, apoptosis, migration and invasion of transfected cells were examined using MTT, flow cytometry, wound-healing and Transwell assay, respectively. The results showed that, Tiam1 was detected in all primary LSCC samples. Additionally, Tiam1 overexpression was closely correlated with tumor progression and patient survival. Tiam1 overexpression was statistically significant, and served as an independent predictor of prognosis for patients with LSCC. The upregulation of Tiam1 by Tiam1/C1199 plasmid had no effect on the prolife-ration of transfected cells, but decreased the apoptotic rate of transfected cells, while the ability of migration and invasion was increased. These results suggested that Tiam1 overexpression in LSCC is possibly involved in the promotion of migration and invasion, and is a promising therapeutic target in the prevention of the progression of LSCC.

  6. Spontaneous initiation, promotion and progression of colorectal cancer in the novel A/J Min/+ mouse.

    PubMed

    Sødring, Marianne; Gunnes, Gjermund; Paulsen, Jan Erik

    2016-04-15

    The C57BL/6J multiple intestinal neoplasia (Min/+) mouse is a widely used murine model for familial adenomatous polyposis, a hereditary form of human colorectal cancer. However, it is a questionable model partly because the vast majority of tumors arise in the small intestine, and partly because the fraction of tumors that progress to invasive carcinomas is minuscule. A/J mice are typically more susceptible to carcinogen-induced colorectal cancer than C57BL/6J mice. To investigate whether the novel Min/+ mouse on the A/J genetic background could be a better model for colorectal cancer, we examined the spontaneous intestinal tumorigenesis in 81 A/J Min/+ mice ranging in age from 4 to 60 weeks. The A/J Min/+ mouse exhibited a dramatic increase in number of colonic lesions when compared to what has been reported for the conventional Min/+ mouse; however, an increase in small intestinal lesions did not occur. In addition, this novel mouse model displayed a continual development of colonic lesions highlighted by the transition from early lesions (flat ACF) to tumors over time. In mice older than 40 weeks, 13 colonic (95% CI: 8.7-16.3) and 21 small intestinal (95% CI: 18.6-24.3) tumors were recorded. Notably, a considerable proportion of those lesions progressed to carcinomas in both the colon (21%) and small intestine (51%). These findings more closely reflect aspects of human colorectal carcinogenesis. In conclusion, the novel A/J Min/+ mouse may be a relevant model for initiation, promotion and progression of colorectal cancer.

  7. O-GlcNAcylation of histone deacetylases 1 in hepatocellular carcinoma promotes cancer progression.

    PubMed

    Zhu, Guizhou; Tao, Tao; Zhang, Dongmei; Liu, Xiaojuan; Qiu, Huiyuan; Han, LiJian; Xu, Zhiwei; Xiao, Ying; Cheng, Chun; Shen, Aiguo

    2016-08-01

    Hepatocellular carcinoma (HCC) is a malignant tumor originating in the liver. Previous studies have indicated that O-GlcNAc transferase (OGT) and histone deacetylase-1 (HDAC1) play important roles in the pathogenesis of HCC. In the present study, we investigated the physical link between OGT and HDAC1. The O-GlcNAcylation of HDAC1 is overexpressed in HCC. We found that HDAC1 has two major sites of O-GlcNAcylation in its histone deacetylase domain. HDAC1 O-GlcNAcylation increases the activated phosphorylation of HDAC1, which enhances its enzyme activity. HDAC1 O-GlcNAc mutants promote the p21 transcription regulation through affecting the acetylation levels of histones from chromosome, and then influence the proliferation of HCC cells. We also found that mutants of O-GlcNAcylation site of HDAC1 affect invasion and migration of HepG2 cells. E-cadherin level is highly up-regulated in HDAC1 O-GlcNAc mutant-treated liver cancer cells, which inhibit the occurrence and development of HCC. Our findings suggest that OGT promotes the O-GlcNAc modification of HDAC1in the development of HCC. Therefore, inhibiting O-GlcNAcylation of HDAC1 may repress the progression of HCC.

  8. Oral health information systems--towards measuring progress in oral health promotion and disease prevention.

    PubMed Central

    Petersen, Poul Erik; Bourgeois, Denis; Bratthall, Douglas; Ogawa, Hiroshi

    2005-01-01

    This article describes the essential components of oral health information systems for the analysis of trends in oral disease and the evaluation of oral health programmes at the country, regional and global levels. Standard methodology for the collection of epidemiological data on oral health has been designed by WHO and used by countries worldwide for the surveillance of oral disease and health. Global, regional and national oral health databanks have highlighted the changing patterns of oral disease which primarily reflect changing risk profiles and the implementation of oral health programmes oriented towards disease prevention and health promotion. The WHO Oral Health Country/Area Profile Programme (CAPP) provides data on oral health from countries, as well as programme experiences and ideas targeted to oral health professionals, policy-makers, health planners, researchers and the general public. WHO has developed global and regional oral health databanks for surveillance, and international projects have designed oral health indicators for use in oral health information systems for assessing the quality of oral health care and surveillance systems. Modern oral health information systems are being developed within the framework of the WHO STEPwise approach to surveillance of noncommunicable, chronic disease, and data stored in the WHO Global InfoBase may allow advanced health systems research. Sound knowledge about progress made in prevention of oral and chronic disease and in health promotion may assist countries to implement effective public health programmes to the benefit of the poor and disadvantaged population groups worldwide. PMID:16211160

  9. MicroRNA-224 promotes tumor progression in nonsmall cell lung cancer

    PubMed Central

    Cui, Ri; Meng, Wei; Sun, Hui-Lung; Kim, Taewan; Ye, Zhenqing; Fassan, Matteo; Jeon, Young-Jun; Li, Bin; Vicentini, Caterina; Peng, Yong; Lee, Tae Jin; Luo, Zhenghua; Liu, Lan; Xu, Dongyuan; Tili, Esmerina; Jin, Victor; Middleton, Justin; Chakravarti, Arnab; Lautenschlaeger, Tim; Croce, Carlo M.

    2015-01-01

    Lung cancer is the leading cause of cancer-related deaths worldwide. Despite advancements and improvements in surgical and medical treatments, the survival rate of lung cancer patients remains frustratingly poor. Local control for early-stage nonsmall cell lung cancer (NSCLC) has dramatically improved over the last decades for both operable and inoperable patients. However, the molecular mechanisms of NSCLC invasion leading to regional and distant disease spread remain poorly understood. Here, we identify microRNA-224 (miR-224) to be significantly up-regulated in NSCLC tissues, particularly in resected NSCLC metastasis. Increased miR-224 expression promotes cell migration, invasion, and proliferation by directly targeting the tumor suppressors TNFα-induced protein 1 (TNFAIP1) and SMAD4. In concordance with in vitro studies, mouse xenograft studies validated that miR-224 functions as a potent oncogenic miRNA in NSCLC in vivo. Moreover, we found promoter hypomethylation and activated ERK signaling to be involved in the regulation of miR-224 expression in NSCLC. Up-regulated miR-224, thus, facilitates tumor progression by shifting the equilibrium of the partially antagonist functions of SMAD4 and TNFAIP1 toward enhanced invasion and growth in NSCLC. Our findings indicate that targeting miR-224 could be effective in the treatment of certain lung cancer patients. PMID:26187928

  10. α-Catulin downregulates E-cadherin and promotes melanoma progression and invasion.

    PubMed

    Kreiseder, Birgit; Orel, Lukas; Bujnow, Constantin; Buschek, Stefan; Pflueger, Maren; Schuett, Wolfgang; Hundsberger, Harald; de Martin, Rainer; Wiesner, Christoph

    2013-02-01

    Metastasis is associated with poor prognosis for melanoma responsible for about 90% of skin cancer-related mortality. To metastasize, melanoma cells must escape keratinocyte control, invade across the basement membrane and survive in the dermis by resisting apoptosis before they can intravasate into the circulation. α-Catulin (CTNNAL1) is a cytoplasmic molecule that integrates the crosstalk between nuclear factor-kappa B and Rho signaling pathways, binds to β-catenin and increases the level of both α-catenin and β-catenin and therefore has potential effects on inflammation, apoptosis and cytoskeletal reorganization. Here, we show that α-catulin is highly expressed in melanoma cells. Expression of α-catulin promoted melanoma progression and occurred concomitantly with the downregulation of E-cadherin and the upregulation of expression of mesenchymal genes such as N-cadherin, Snail/Slug and the matrix metalloproteinases 2 and 9. Knockdown of α-catulin promoted adhesion to and inhibited migration away from keratinocytes in an E-cadherin-dependent manner and decreased the transmigration through a keratinocyte monolayer, as well as in Transwell assays using collagens, laminin and fibronectin coating. Moreover, knockdown promoted homotypic spheroid formation and concomitantly increased E-cadherin expression along with downregulation of transcription factors implicated in its repression (Snail/Slug, Twist and ZEB). Consistent with the molecular changes, α-catulin provoked invasion of melanoma cells in a three-dimensional culture assay by the upregulation of matrix metalloproteinases 2 and 9 and the activation of ROCK/Rho. As such, α-catulin may represent a key driver of the metastatic process, implicating potential for therapeutic interference.

  11. Arsenic surveillance program

    NASA Technical Reports Server (NTRS)

    1993-01-01

    Background information about arsenic is presented including forms, common sources, and clinical symptoms of arsenic exposure. The purpose of the Arsenic Surveillance Program and LeRC is outlined, and the specifics of the Medical Surveillance Program for Arsenic Exposure at LeRC are discussed.

  12. Earth Abides Arsenic Biotransformations.

    PubMed

    Zhu, Yong-Guan; Yoshinaga, Masafumi; Zhao, Fang-Jie; Rosen, Barry P

    2014-05-01

    Arsenic is the most prevalent environmental toxic element and causes health problems throughout the world. The toxicity, mobility, and fate of arsenic in the environment are largely determined by its speciation, and arsenic speciation changes are driven, at least to some extent, by biological processes. In this article, biotransformation of arsenic is reviewed from the perspective of the formation of Earth and the evolution of life, and the connection between arsenic geochemistry and biology is described. The article provides a comprehensive overview of molecular mechanisms of arsenic redox and methylation cycles as well as other arsenic biotransformations. It also discusses the implications of arsenic biotransformation in environmental remediation and food safety, with particular emphasis on groundwater arsenic contamination and arsenic accumulation in rice.

  13. Earth Abides Arsenic Biotransformations

    PubMed Central

    Zhu, Yong-Guan; Yoshinaga, Masafumi; Zhao, Fang-Jie; Rosen, Barry P.

    2015-01-01

    Arsenic is the most prevalent environmental toxic element and causes health problems throughout the world. The toxicity, mobility, and fate of arsenic in the environment are largely determined by its speciation, and arsenic speciation changes are driven, at least to some extent, by biological processes. In this article, biotransformation of arsenic is reviewed from the perspective of the formation of Earth and the evolution of life, and the connection between arsenic geochemistry and biology is described. The article provides a comprehensive overview of molecular mechanisms of arsenic redox and methylation cycles as well as other arsenic biotransformations. It also discusses the implications of arsenic biotransformation in environmental remediation and food safety, with particular emphasis on groundwater arsenic contamination and arsenic accumulation in rice. PMID:26778863

  14. Earth Abides Arsenic Biotransformations

    NASA Astrophysics Data System (ADS)

    Zhu, Yong-Guan; Yoshinaga, Masafumi; Zhao, Fang-Jie; Rosen, Barry P.

    2014-05-01

    Arsenic is the most prevalent environmental toxic element and causes health problems throughout the world. The toxicity, mobility, and fate of arsenic in the environment are largely determined by its speciation, and arsenic speciation changes are driven, at least to some extent, by biological processes. In this article, biotransformation of arsenic is reviewed from the perspective of the formation of Earth and the evolution of life, and the connection between arsenic geochemistry and biology is described. The article provides a comprehensive overview of molecular mechanisms of arsenic redox and methylation cycles as well as other arsenic biotransformations. It also discusses the implications of arsenic biotransformation in environmental remediation and food safety, with particular emphasis on groundwater arsenic contamination and arsenic accumulation in rice.

  15. Protection, promotion and support of breast-feeding in Europe: progress from 2002 to 2007.

    PubMed

    Cattaneo, Adriano; Burmaz, Tea; Arendt, Maryse; Nilsson, Ingrid; Mikiel-Kostyra, Krystyna; Kondrate, Irena; Communal, Marie José; Massart, Catherine; Chapin, Elise; Fallon, Maureen

    2010-06-01

    To assess progress in the protection, promotion and support of breast-feeding in Europe. Data for 2002 and 2007 were gathered with the same questionnaire. Of thirty countries, twenty-nine returned data for 2002, twenty-four for 2007. The number of countries with national policies complying with WHO recommendations increased. In 2007, six countries lacked a national policy, three a national plan, four a national breast-feeding coordinator and committee. Little improvement was reported in pre-service training; however, the number of countries with good coverage in the provision of WHO/UNICEF courses for in-service training increased substantially, as reflected in a parallel increase in the number of Baby Friendly Hospitals and the proportion of births taking place in them. Little improvement was reported as far as implementation of the International Code on Marketing of Breastmilk Substitutes is concerned. Except for Ireland and the UK, where some improvement occurred, no changes were reported on maternity protection. Due to lack of standard methods, it was difficult to compare rates of breast-feeding among countries. With this in mind, slight improvements in the rates of initiation, exclusivity and duration were reported by countries where data at two points in time were available. Breast-feeding rates continue to fall short of global recommendations. National policies are improving slowly but are hampered by the lack of action on maternity protection and the International Code. Pre-service training and standard monitoring of breast-feeding rates are the areas where more efforts are needed to accelerate progress.

  16. Enhanced heme function and mitochondrial respiration promote the progression of lung cancer cells.

    PubMed

    Hooda, Jagmohan; Cadinu, Daniela; Alam, Md Maksudul; Shah, Ajit; Cao, Thai M; Sullivan, Laura A; Brekken, Rolf; Zhang, Li

    2013-01-01

    Lung cancer is the leading cause of cancer-related mortality, and about 85% of the cases are non-small-cell lung cancer (NSCLC). Importantly, recent advance in cancer research suggests that altering cancer cell bioenergetics can provide an effective way to target such advanced cancer cells that have acquired mutations in multiple cellular regulators. This study aims to identify bioenergetic alterations in lung cancer cells by directly measuring and comparing key metabolic activities in a pair of cell lines representing normal and NSCLC cells developed from the same patient. We found that the rates of oxygen consumption and heme biosynthesis were intensified in NSCLC cells. Additionally, the NSCLC cells exhibited substantially increased levels in an array of proteins promoting heme synthesis, uptake and function. These proteins include the rate-limiting heme biosynthetic enzyme ALAS, transporter proteins HRG1 and HCP1 that are involved in heme uptake, and various types of oxygen-utilizing hemoproteins such as cytoglobin and cytochromes. Several types of human tumor xenografts also displayed increased levels of such proteins. Furthermore, we found that lowering heme biosynthesis and uptake, like lowering mitochondrial respiration, effectively reduced oxygen consumption, cancer cell proliferation, migration and colony formation. In contrast, lowering heme degradation does not have an effect on lung cancer cells. These results show that increased heme flux and function are a key feature of NSCLC cells. Further, increased generation and supply of heme and oxygen-utilizing hemoproteins in cancer cells will lead to intensified oxygen consumption and cellular energy production by mitochondrial respiration, which would fuel cancer cell proliferation and progression. The results show that inhibiting heme and respiratory function can effectively arrest the progression of lung cancer cells. Hence, understanding heme function can positively impact on research in lung cancer

  17. Heme oxygenase-1 gene promoter microsatellite polymorphism is associated with progressive atherosclerosis and incident cardiovascular disease

    PubMed Central

    Pechlaner, Raimund; Willeit, Peter; Summerer, Monika; Santer, Peter; Egger, Georg; Kronenberg, Florian; Demetz, Egon; Weiss, Günter; Tsimikas, Sotirios; Witztum, Joseph L.; Willeit, Karin; Iglseder, Bernhard; Paulweber, Bernhard; Kedenko, Lyudmyla; Haun, Margot; Meisinger, Christa; Gieger, Christian; Müller-Nurasyid, Martina; Peters, Annette; Willeit, Johann; Kiechl, Stefan

    2015-01-01

    Objective The enzyme heme oxygenase-1 (HO-1) exerts cytoprotective effects in response to various cellular stressors. A variable number tandem repeat (VNTR) polymorphism in the HO-1 gene promoter region has previously been linked to cardiovascular disease (CVD). We examined this association prospectively in the general population. Approach and Results Incidence of stroke, myocardial infarction, or vascular death was registered between 1995 and 2010 in 812 participants of the Bruneck Study aged 45 to 84 years (49.4% males). Carotid atherosclerosis progression was quantified by high-resolution ultrasound. HO-1 VNTR length was determined by polymerase chain reaction. Subjects with ≥32 tandem repeats on both HO-1 alleles compared to the rest of the population (recessive trait) featured substantially increased CVD risk (hazard ratio [95% confidence interval], 5.45 (2.39, 12.42); P<0.0001), enhanced atherosclerosis progression (median difference in atherosclerosis score [interquartile range], 2.1 [0.8, 5.6] vs. 0.0 [0.0, 2.2] mm; P=0.0012), and a trend towards higher levels of oxidised phospholipids on apoB-100 (median OxPL/apoB level [interquartile range], 11364 [4160, 18330] vs. 4844 [3174, 12284] relative light units; P=0.0554). Increased CVD risk in those homozygous for ≥32 repeats was also detected in a pooled analysis of 7848 participants of the Bruneck, SAPHIR, and KORA prospective studies (HR [95% CI], 3.26 [1.50, 7.33]; P=0.0043). Conclusions This study found a strong association between the HO-1 VNTR polymorphism and CVD risk confined to subjects with a high number of repeats on both HO-1 alleles, and provides evidence for accelerated atherogenesis and decreased anti-oxidant defence in this vascular high-risk group. PMID:25359861

  18. Androgen Receptor Promotes Ligand-Independent Prostate Cancer Progression through c-Myc Upregulation

    PubMed Central

    Gao, Lina; Schwartzman, Jacob; Gibbs, Angela; Lisac, Robert; Kleinschmidt, Richard; Wilmot, Beth; Bottomly, Daniel; Coleman, Ilsa; Nelson, Peter; McWeeney, Shannon; Alumkal, Joshi

    2013-01-01

    The androgen receptor (AR) is the principal therapeutic target in prostate cancer. For the past 70 years, androgen deprivation therapy (ADT) has been the major therapeutic focus. However, some patients do not benefit, and those tumors that do initially respond to ADT eventually progress. One recently described mechanism of such an effect is growth and survival-promoting effects of the AR that are exerted independently of the AR ligands, testosterone and dihydrotestosterone. However, specific ligand-independent AR target genes that account for this effect were not well characterized. We show here that c-Myc, which is a key mediator of ligand-independent prostate cancer growth, is a key ligand-independent AR target gene. Using microarray analysis, we found that c-Myc and AR expression levels strongly correlated with each other in tumors from patients with castration-resistant prostate cancer (CRPC) progressing despite ADT. We confirmed that AR directly regulates c-Myc transcription in a ligand-independent manner, that AR and c-Myc suppression reduces ligand-independent prostate cancer cell growth, and that ectopic expression of c-Myc attenuates the anti-growth effects of AR suppression. Importantly, treatment with the bromodomain inhibitor JQ1 suppressed c-Myc function and suppressed ligand-independent prostate cancer cell survival. Our results define a new link between two critical proteins in prostate cancer – AR and c-Myc – and demonstrate the potential of AR and c-Myc-directed therapies to improve prostate cancer control. PMID:23704919

  19. SOX4 Promotes Progression in OLP-Associated Squamous Cell Carcinoma

    PubMed Central

    Liu, Yi; Cui, Li; Huang, Junwei; Ji, Eoon Hye; Chen, Wei; Messadi, Diana; Hu, Shen

    2016-01-01

    Background: The development of oral squamous cell carcinoma (OSCC) is a multistep process that involves in both genetic alterations and epigenetic modifications. Previous studies suggest SOX4 might function as an oncogene or a tumor suppressor in different types of cancers. However, whether SOX4 involves in promoting the progression of oral precancer to cancer is unknown. Methods: Liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used to identify the proteins that may be differentially expressed between oral lichen planus (OLP) and OLP-associated OSCC (OLP-OSCC) formalin-fixed paraffin-embedded (FFPE) tissues. Immunohistochemistry (IHC) and Western blotting were performed to evaluate SOX4 expression between OLP and OLP-OSCC tissues and among oral cancer cell lines and normal human oral keratinocytes (NHOKs). SOX4 siRNA was used to knock down the expression of SOX4 in UM1 oral cancer cells. MTT, cell counting, migration and Matrigel invasion assays were utilized to examine the effect of SOX4 down-regulation on proliferation, migration and invasion capacity of UM1 cells. Results: LC-MS/MS analysis showed that 88 proteins including SOX4 were only identified in OLP-OSCC FFPE tissues when compared to OLP FFPE tissues. IHC confirmed that SOX4 expression was significantly higher in OLP-OSCC than OLP and Western blot analysis indicated that SOX4 was over-expressed in UM1/UM2 cells when compared to NHOKs. Knockdown of SOX4 significantly inhibited the proliferation, migration and invasion of UM1 cells (P<0.01). Conclusions: Our study indicated that SOX4 is significantly upregulated in OLP-OSCC versus OLP tissues. In addition, down-regulation of SOX4 led to significantly reduced proliferation, migration and invasion capability of oral cancer cells. These findings suggest that SOX4 might be actively involved in the progression of OLP to OSCC. PMID:27471569

  20. Enhanced Heme Function and Mitochondrial Respiration Promote the Progression of Lung Cancer Cells

    PubMed Central

    Alam, Md Maksudul; Shah, Ajit; Cao, Thai M.; Sullivan, Laura A.; Brekken, Rolf; Zhang, Li

    2013-01-01

    Lung cancer is the leading cause of cancer-related mortality, and about 85% of the cases are non-small-cell lung cancer (NSCLC). Importantly, recent advance in cancer research suggests that altering cancer cell bioenergetics can provide an effective way to target such advanced cancer cells that have acquired mutations in multiple cellular regulators. This study aims to identify bioenergetic alterations in lung cancer cells by directly measuring and comparing key metabolic activities in a pair of cell lines representing normal and NSCLC cells developed from the same patient. We found that the rates of oxygen consumption and heme biosynthesis were intensified in NSCLC cells. Additionally, the NSCLC cells exhibited substantially increased levels in an array of proteins promoting heme synthesis, uptake and function. These proteins include the rate-limiting heme biosynthetic enzyme ALAS, transporter proteins HRG1 and HCP1 that are involved in heme uptake, and various types of oxygen-utilizing hemoproteins such as cytoglobin and cytochromes. Several types of human tumor xenografts also displayed increased levels of such proteins. Furthermore, we found that lowering heme biosynthesis and uptake, like lowering mitochondrial respiration, effectively reduced oxygen consumption, cancer cell proliferation, migration and colony formation. In contrast, lowering heme degradation does not have an effect on lung cancer cells. These results show that increased heme flux and function are a key feature of NSCLC cells. Further, increased generation and supply of heme and oxygen-utilizing hemoproteins in cancer cells will lead to intensified oxygen consumption and cellular energy production by mitochondrial respiration, which would fuel cancer cell proliferation and progression. The results show that inhibiting heme and respiratory function can effectively arrest the progression of lung cancer cells. Hence, understanding heme function can positively impact on research in lung cancer

  1. Promoter-Targeted Histone Acetylation of Chromatinized Parvoviral Genome Is Essential for the Progress of Infection

    PubMed Central

    Mäntylä, Elina; Salokas, Kari; Oittinen, Mikko; Aho, Vesa; Mäntysaari, Pekka; Palmujoki, Lassi; Kalliolinna, Olli; Ihalainen, Teemu O.; Niskanen, Einari A.; Timonen, Jussi

    2016-01-01

    ABSTRACT The association of host histones with parvoviral DNA is poorly understood. We analyzed the chromatinization and histone acetylation of canine parvovirus DNA during infection by confocal imaging and in situ proximity ligation assay combined with chromatin immunoprecipitation and high-throughput sequencing. We found that during late infection, parvovirus replication bodies were rich in histones bearing modifications characteristic of transcriptionally active chromatin, i.e., histone H3 lysine 27 acetylation (H3K27ac). H3K27ac, in particular, was located in close proximity to the viral DNA-binding protein NS1. Importantly, our results show for the first time that in the chromatinized parvoviral genome, the two viral promoters in particular were rich in H3K27ac. Histone acetyltransferase (HAT) inhibitors efficiently interfered with the expression of viral proteins and infection progress. Altogether, our data suggest that the acetylation of histones on parvoviral DNA is essential for viral gene expression and the completion of the viral life cycle. IMPORTANCE Viral DNA introduced into cell nuclei is exposed to cellular responses to foreign DNA, including chromatinization and epigenetic silencing, both of which determine the outcome of infection. How the incoming parvovirus resists cellular epigenetic downregulation of its genes is not understood. Here, the critical role of epigenetic modifications in the regulation of parvovirus infection was demonstrated. We showed for the first time that a successful parvovirus infection is characterized by the deposition of nucleosomes with active histone acetylation on the viral promoter areas. The results provide new insights into the regulation of parvoviral gene expression, which is an important aspect of the development of parvovirus-based virotherapy. PMID:26842481

  2. G beta gamma signaling reduces intracellular cAMP to promote meiotic progression in mouse oocytes.

    PubMed

    Gill, Arvind; Hammes, Stephen R

    2007-02-01

    In nearly every vertebrate species, elevated intracellular cAMP maintains oocytes in prophase I of meiosis. Prior to ovulation, gonadotropins trigger various intra-ovarian processes, including the breakdown of gap junctions, the activation of EGF receptors, and the secretion of steroids. These events in turn decrease intracellular cAMP levels in select oocytes to allow meiotic progression, or maturation, to resume. Studies suggest that cAMP levels are kept elevated in resting oocytes by constitutive G protein signaling, and that the drop in intracellular cAMP that accompanies maturation may be due in part to attenuation of this inhibitory G protein-mediated signaling. Interestingly, one of these G protein regulators of meiotic arrest is the Galpha(s) protein, which stimulates adenylyl cyclase to raise intracellular cAMP in two important animal models of oocyte development: Xenopus leavis frogs and mice. In addition to G(alpha)(s), constitutive Gbetagamma activity similarly stimulates adenylyl cyclase to raise cAMP and prevent maturation in Xenopus oocytes; however, the role of Gbetagamma in regulating meiosis in mouse oocytes has not been examined. Here we show that Gbetagamma does not contribute to the maintenance of murine oocyte meiotic arrest. In fact, contrary to observations in frog oocytes, Gbetagamma signaling in mouse oocytes reduces cAMP and promotes oocyte maturation, suggesting that Gbetagamma might in fact play a positive role in promoting oocyte maturation. These observations emphasize that, while many general concepts and components of meiotic regulation are conserved from frogs to mice, specific differences exist that may lead to important insights regarding ovarian development in vertebrates.

  3. Transplacental arsenic carcinogenesis in mice

    SciTech Connect

    Waalkes, Michael P. Liu, Jie; Diwan, Bhalchandra A.

    2007-08-01

    Our work has focused on the carcinogenic effects of in utero arsenic exposure in mice. Our data show that a short period of maternal exposure to inorganic arsenic in the drinking water is an effective, multi-tissue carcinogen in the adult offspring. These studies have been reproduced in three temporally separate studies using two different mouse strains. In these studies pregnant mice were treated with drinking water containing sodium arsenite at up to 85 ppm arsenic from days 8 to 18 of gestation, and the offspring were observed for up to 2 years. The doses used in all these studies were well tolerated by both the dam and offspring. In C3H mice, two separate studies show male offspring exposed to arsenic in utero developed liver carcinoma and adrenal cortical adenoma in a dose-related fashion during adulthood. Prenatally exposed female C3H offspring show dose-related increases in ovarian tumors and lung carcinoma and in proliferative lesions (tumors plus preneoplastic hyperplasia) of the uterus and oviduct. In addition, prenatal arsenic plus postnatal exposure to the tumor promoter, 12-O-tetradecanoyl phorbol-13-acetate (TPA) in C3H mice produces excess lung tumors in both sexes and liver tumors in females. Male CD1 mice treated with arsenic in utero develop tumors of the liver and adrenal and renal hyperplasia while females develop tumors of urogenital system, ovary, uterus and adrenal and hyperplasia of the oviduct. Additional postnatal treatment with diethylstilbestrol or tamoxifen after prenatal arsenic in CD1 mice induces urinary bladder transitional cell proliferative lesions, including carcinoma and papilloma, and enhances the carcinogenic response in the liver of both sexes. Overall this model has provided convincing evidence that arsenic is a transplacental carcinogen in mice with the ability to target tissues of potential human relevance, such as the urinary bladder, lung and liver. Transplacental carcinogenesis clearly occurs with other agents in humans

  4. Transplacental Arsenic Carcinogenesis in Mice

    PubMed Central

    Waalkes, Michael P.; Liu, Jie; Diwan, Bhalchandra A.

    2007-01-01

    Our work has focused on the carcinogenic effects of in utero arsenic exposure in mice. Our data show a short period of maternal exposure to inorganic arsenic in the drinking water is an effective, multi-tissue carcinogen in the adult offspring. These studies have been reproduced in three temporally separate studies using two different mouse strains. In these studies pregnant mice were treated with drinking water containing sodium arsenite at up to 85 ppm arsenic from day 8 to 18 of gestation, and the offspring were observed for up to two years. The doses used in all these studies were well tolerated by both the dam and offspring. In C3H mice, two separate studies show male offspring exposed to arsenic in utero developed liver carcinoma and adrenal cortical adenoma in a dose-related fashion during adulthood. Prenatally exposed female C3H offspring show dose-related increases in ovarian tumors and lung carcinoma and in proliferative lesions (tumors plus preneoplastic hyperplasia) of the uterus and oviduct. In addition, prenatal arsenic plus postnatal exposure to the tumor promoter, 12-O-tetradecanoyl phorbol-13-acetate (TPA) in C3H mice produces excess lung tumors in both sexes and liver tumors in females. Male CD1 mice treated with arsenic in utero develop tumors of the liver and adrenal and renal hyperplasia while females develop tumors of urogenital system, ovary, uterus and adrenal and hyperplasia of the oviduct. Additional postnatal treatment with diethylstilbestrol or tamoxifen after prenatal arsenic in CD1 mice induces urinary bladder transitional cell proliferative lesions, including carcinoma and papilloma, and enhances the carcinogenic response in the liver of both sexes. Overall this model has provided convincing evidence that arsenic is a transplacental carcinogen in mice with the ability to target tissues of potential human relevance, such as the urinary bladder, lung and liver. Transplacental carcinogenesis clearly occurs with other agents in humans and

  5. THE CELLUAR METABOLISM OF ARSENIC

    EPA Science Inventory

    Because the methylation of arsenic produces intermediates and terminal products that exceed inorganic arsenic in potency as enzyme inhibitors, cytotoxins, and genotoxins, the methylation of arsenic is properly regarded as an activation process. The methylation of arsenic is an e...

  6. THE CELLUAR METABOLISM OF ARSENIC

    EPA Science Inventory

    Because the methylation of arsenic produces intermediates and terminal products that exceed inorganic arsenic in potency as enzyme inhibitors, cytotoxins, and genotoxins, the methylation of arsenic is properly regarded as an activation process. The methylation of arsenic is an e...

  7. Feasibility of Water Treatment Technologies for Arsenic and Fluoride Removal

    DTIC Science & Technology

    2004-11-17

    1 Feasibility of Water Treatment Technologies for Arsenic and Fluoride Removal AWWA Water Quality Technology Conference 17 November 2004; Arsenic I...Brian C. Pickard, P.E., R.S. U.S. Army Center for Health Promotion and Preventive Medicine Aberdeen Proving Ground, MD Muhammad Bari, P.E. Chief...Technologies for Arsenic and Fluoride Removal 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK

  8. Promoting the Social Inclusion and Academic Progress of Gypsy, Roma and Traveller Children: A Secondary School Case Study

    ERIC Educational Resources Information Center

    Gould, Siobhan

    2017-01-01

    The aim of this study was to identify support strategies used to promote "social inclusion" and "academic progress" of Key Stage 3 and 4 Gypsy, Roma and Traveller (GRT) pupils. The study used an interpretivist approach, incorporating an embedded single case study with several participant groups, namely GRT pupils, GRT parents,…

  9. Chem I Supplement: Arsenic and Old Myths.

    ERIC Educational Resources Information Center

    Sarquis, Mickey

    1979-01-01

    Describes the history of arsenic, the properties of arsenic, production and uses of arsenicals, arsenic in the environment; toxic levels of arsenic, arsenic in the human body, and the Marsh Test. (BT)

  10. Chem I Supplement: Arsenic and Old Myths.

    ERIC Educational Resources Information Center

    Sarquis, Mickey

    1979-01-01

    Describes the history of arsenic, the properties of arsenic, production and uses of arsenicals, arsenic in the environment; toxic levels of arsenic, arsenic in the human body, and the Marsh Test. (BT)

  11. MiR-217 promotes cutaneous squamous cell carcinoma progression by targeting PTRF

    PubMed Central

    Bai, Ming; Zhang, Mingzi; Long, Fei; Yu, Nanze; Zeng, Ang; Wang, Xiaojun

    2017-01-01

    Increasing evidences have suggested that microRNAs (miRNAs) act a critical role in tumor initiation, progression and metastasis. Deregulated expression of miR-217 has been identified in various tumors. However, the expression and role of miR-217 in the development of cutaneous squamous cell carcinoma (cSCC) remain unclear. In our study, we showed that miR-217 expression was upregulated in the cSCC tissues compared to adjacent non-tumor samples. We also demonstrated that miR-217 expression was upregualted in the cSCCcSCC cell lines. Overexpression of miR-217 promoted cSCCcSCC cell growth, cell cycle and invasion. We identified Polymerase I and Transcript Release Factor (PTRF) as a direct target gene of miR-217 in the SCC13 cell. In addition, PTRF expression was downregulated in the cSCCcSCC tissues. Moreover, we demonstrated that there was a significant inverse correlation between miR-217 and PTRF expression in the cSCCcSCC. Furthermore, overexpression of PTRF could rescue miR-217’s oncogenic effect on cSCC. Therefore, these results suggested that upregulation of miR-217 could contribute to development of cSCCcSCC through targeting PTRF. PMID:28337292

  12. FoxD3 deficiency promotes breast cancer progression by induction of epithelial–mesenchymal transition

    SciTech Connect

    Chu, Tian-Li; Zhao, Hong-Meng; Li, Yue; Chen, Ao-Xiang; Sun, Xuan; Ge, Jie

    2014-04-04

    Highlights: • FOXD3 is down-regulated in breast cancer tissues. • FOXD3 inhibits breast cancer cell proliferation and invasion. • FoxD3 deficiency induces epithelial–mesenchymal transition. - Abstract: The transcription factor forkhead box D3 (FOXD3) plays an important role in the development of neural crest and gastric cancer cells. However, the function and mechanisms of FOXD3 in the breast tumorigenesis and progression is still limited. Here, we report that FOXD3 is a tumor suppressor of breast cancer tumorigenicity and aggressiveness. We found that FOXD3 is down-regulated in breast cancer tissues. Patients with low FOXD3 expression have a poor outcome. Depletion of FOXD3 expression promotes breast cancer cell proliferation and invasion in vitro, whereas overexpression of FOXD3 inhibits breast cancer cell proliferation and invasion both in vitro and in vivo. In addition, depletion of FOXD3 is linked to epithelial–mesenchymal transition (EMT)-like phenotype. Our results indicate FOXD3 exhibits tumor suppressive activity and may be useful for breast therapy.

  13. Crosstalk between ATF4 and MTA1/HDAC1 promotes osteosarcoma progression.

    PubMed

    Zeng, Heng; Zhang, Jin-Ming; Du, Yu; Wang, Jiang; Ren, Ye; Li, Mi; Li, Hao; Cai, Zhuo; Chu, Qian; Yang, Caihong

    2016-02-09

    The stress response gene activating transcription factor 4 (ATF4) is involved in metastatic behavior and cellular protection. Here we show that ATF4 is upregulated in osteosarcoma (OS) cell lines and patient clinical samples as compared to matched non-tumor tissue. Overexpression of ATF4 in OS cells promoted cell proliferation, migration and lung metastasis. Furthermore, the expression of ATF4 was markedly reduced in metastasis associated protein (MTA1) or histone deacetylase 1 (HDAC1) knockdown OS cells, but MTA1 overexpression increased the stability and activity of ATF4 protein via ATF4 deacetylation by HDAC1. ATF4 in turn enhanced the expression of MTA1 and HDAC1 at the transcription level, suggesting a positive feedback loop between ATF4 and MTA1/HDAC1. Clinically, the level of ATF4 was positively correlated with that of MTA1 in OS. Mice injected with ATF4-overexpressing cells exhibited a higher rate of tumor growth, and the average weight of these tumors was ~90% greater than the controls. Taken together, these data establish a direct correlation between ATF4-induced OS progression and MTA1/HDAC1-associated metastasis, and support the potential therapeutic value of targeting ATF4 in the treatment of OS.

  14. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells.

    PubMed

    Sinha, Pratima; Clements, Virginia K; Fulton, Amy M; Ostrand-Rosenberg, Suzanne

    2007-05-01

    A causative relationship between chronic inflammation and cancer has been postulated for many years, and clinical observations and laboratory experiments support the hypothesis that inflammation contributes to tumor onset and progression. However, the precise mechanisms underlying the relationship are not known. We recently reported that the proinflammatory cytokine, interleukin-1beta, induces the accumulation and retention of myeloid-derived suppressor cells (MDSC), which are commonly found in many patients and experimental animals with cancer and are potent suppressors of adaptive and innate immunity. This finding led us to hypothesize that inflammation leads to cancer through the induction of MDSC, which inhibit immunosurveillance and thereby allow the unchecked persistence and proliferation of premalignant and malignant cells. We now report that host MDSC have receptors for prostaglandin E2 (PGE2) and that E-prostanoid receptor agonists, including PGE2, induce the differentiation of Gr1(+)CD11b(+) MDSC from bone marrow stem cells, whereas receptor antagonists block differentiation. BALB/c EP2 knockout mice inoculated with the spontaneously metastatic BALB/c-derived 4T1 mammary carcinoma have delayed tumor growth and reduced numbers of MDSC relative to wild-type mice, suggesting that PGE2 partially mediates MDSC induction through the EP2 receptor. Treatment of 4T1-tumor-bearing wild-type mice with the cyclooxygenase 2 inhibitor, SC58236, delays primary tumor growth and reduces MDSC accumulation, further showing that PGE2 induces MDSC and providing a therapeutic approach for reducing this tumor-promoting cell population.

  15. Interleukin-17 Could Promote Breast Cancer Progression at Several Stages of the Disease.

    PubMed

    Welte, Thomas; Zhang, Xiang H-F

    2015-01-01

    Metastatic disease accounts for more than 90% of deaths from breast cancer. Yet the factors that trigger metastasis, often years after primary tumor removal, are not understood well. Recently the proinflammatory cytokine interleukin- (IL-) 17 family has been associated with poor prognosis in breast cancer. Here we review current literature on the pathogenic mechanisms driven by IL-17 during breast cancer progression and connect these findings to metastasis. These include (1) direct effects of IL-17 on tumor cells promoting tumor cell survival and invasiveness, (2) regulation of tumor angiogenesis, and (3) interaction with myeloid derived suppressor cells (MDSCs) to inhibit antitumor immune response and collaborate at the distant metastatic site. Furthermore, IL-17 might also be a culprit in bone destruction caused by late stage bone metastasis. Interestingly, in addition to these potential prometastasis functions, there is also evidence for an opposite, antitumor role of IL-17 during cancer therapies. We hypothesize that these contradictory roles may be due to chronic, imbalanced versus acute transient nature of the immune reactions, as well as differences in the cells that interact with IL-17(+) cells under different circumstances.

  16. The HIF/PHF8/AR axis promotes prostate cancer progression

    PubMed Central

    Tong, D; Liu, Q; Liu, G; Yuan, W; Wang, L; Guo, Y; Lan, W; Zhang, D; Dong, S; Wang, Y; Xiao, H; Mu, J; Mao, C; Wong, J; Jiang, J

    2016-01-01

    Recent studies provide strong evidence that the androgen receptor (AR) signaling pathway remains active in castration-resistant prostate cancer (CRPC). However, the underlying mechanisms are not well understood. In this study, we demonstrate that plant homeo domain finger protein 8 (PHF8 )interacts with and functions as an essential histone demethylase activity-dependent AR coactivator. Furthermore, we demonstrate that the expression of PHF8 is induced by hypoxia in various prostate cancer cell lines. Knockdown of either hypoxia-inducible factor HIF2α or HIF1α almost completely abolished hypoxia-induced PHF8 expression. Importantly, we observed that PHF8 is highly expressed in clinical androgen deprived prostate cancer samples and expression of PHF8 correlates with increased levels of HIF1α and HIF2α. Moreover, elevated PHF8 is associated with higher grade prostate cancers and unfavorable outcomes. Our findings support a working model in which hypoxia in castrated prostate cancer activates HIF transcription factors which then induces PHF8 expression. The elevated PHF8 in turn promotes the AR signaling pathway and prostate cancer progression. Therefore, the HIF/PHF8/AR axis could serve as a potential biomarker for CRPC and is also a promising therapeutic target in combating CRPC. PMID:27991916

  17. Radiation promotes malignant progression of glioma cells through HIF-1alpha stabilization.

    PubMed

    Kim, Young-Heon; Yoo, Ki-Chun; Cui, Yan-Hong; Uddin, Nizam; Lim, Eun-Jung; Kim, Min-Jung; Nam, Seon-Young; Kim, In-Gyu; Suh, Yongjoon; Lee, Su-Jae

    2014-11-01

    Given its contribution to malignant phenotypes of cancer, tumor hypoxia has been considered as a potential therapeutic problem. In the stressful microenvironment condition, hypoxia inducible factor 1 (HIF1) is well known to mediate the transcriptional adaptation of cells to hypoxia and acts as a central player for the process of hypoxia-driven malignant cancer progression. Here, we found that irradiation causes the HIF1α protein to stabilize, even in normoxia condition through activation of p38 MAPK, thereby promoting angiogenesis in tumor microenvironment and infiltrative property of glioma cells. Notably, irradiation reduced hydroxylation of HIF1α through destabilization of prolyl hydroxylases (PHD)-2. Moreover, radiation also decreased the half-life of protein von Hippel-Lindau (pVHL), which is a specific E3 ligase for HIF1α. Of note, inhibition of p38 MAPK attenuated radiation-induced stabilization of HIF1α through destabilization of PHD-2 and pVHL. In agreement with these results, targeting of either p38 MAPK, HIF1α, pVHL or PHD-2 effectively mitigated the radiation-induced tube formation of human brain-derived micro-vessel endothelial cells (HB-MEC) and infiltration of glioma cells. Taken together, our findings suggest that targeting HIF1α in combination with ionizing radiation might increase the efficacy of radiotherapy for glioma treatment. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. Ataxia-telangiectasia mutated (ATM) silencing promotes neuroblastoma progression through a MYCN independent mechanism.

    PubMed

    Mandriota, Stefano J; Valentijn, Linda J; Lesne, Laurence; Betts, David R; Marino, Denis; Boudal-Khoshbeen, Mary; London, Wendy B; Rougemont, Anne-Laure; Attiyeh, Edward F; Maris, John M; Hogarty, Michael D; Koster, Jan; Molenaar, Jan J; Versteeg, Rogier; Ansari, Marc; Gumy-Pause, Fabienne

    2015-07-30

    Neuroblastoma, a childhood cancer with highly heterogeneous biology and clinical behavior, is characterized by genomic aberrations including amplification of MYCN. Hemizygous deletion of chromosome 11q is a well-established, independent marker of poor prognosis. While 11q22-q23 is the most frequently deleted region, the neuroblastoma tumor suppressor in this region remains to be identified. Chromosome bands 11q22-q23 contain ATM, a cell cycle checkpoint kinase and tumor suppressor playing a pivotal role in the DNA damage response. Here, we report that haploinsufficiency of ATM in neuroblastoma correlates with lower ATM expression, event-free survival, and overall survival. ATM loss occurs in high stage neuroblastoma without MYCN amplification. In SK-N-SH, CLB-Ga and GI-ME-N human neuroblastoma cells, stable ATM silencing promotes neuroblastoma progression in soft agar assays, and in subcutaneous xenografts in nude mice. This effect is dependent on the extent of ATM silencing and does not appear to involve MYCN. Our findings identify ATM as a potential haploinsufficient neuroblastoma tumor suppressor, whose inactivation mirrors the increased aggressiveness associated with 11q deletion in neuroblastoma.

  19. Ataxia-telangiectasia mutated (ATM) silencing promotes neuroblastoma progression through a MYCN independent mechanism

    PubMed Central

    Mandriota, Stefano J.; Valentijn, Linda J.; Lesne, Laurence; Betts, David R.; Marino, Denis; Boudal-Khoshbeen, Mary; London, Wendy B.; Rougemont, Anne-Laure; Attiyeh, Edward F.; Maris, John M.; Hogarty, Michael D.; Koster, Jan; Molenaar, Jan J.; Versteeg, Rogier

    2015-01-01

    Neuroblastoma, a childhood cancer with highly heterogeneous biology and clinical behavior, is characterized by genomic aberrations including amplification of MYCN. Hemizygous deletion of chromosome 11q is a well-established, independent marker of poor prognosis. While 11q22-q23 is the most frequently deleted region, the neuroblastoma tumor suppressor in this region remains to be identified. Chromosome bands 11q22-q23 contain ATM, a cell cycle checkpoint kinase and tumor suppressor playing a pivotal role in the DNA damage response. Here, we report that haploinsufficiency of ATM in neuroblastoma correlates with lower ATM expression, event-free survival, and overall survival. ATM loss occurs in high stage neuroblastoma without MYCN amplification. In SK-N-SH, CLB-Ga and GI-ME-N human neuroblastoma cells, stable ATM silencing promotes neuroblastoma progression in soft agar assays, and in subcutaneous xenografts in nude mice. This effect is dependent on the extent of ATM silencing and does not appear to involve MYCN. Our findings identify ATM as a potential haploinsufficient neuroblastoma tumor suppressor, whose inactivation mirrors the increased aggressiveness associated with 11q deletion in neuroblastoma. PMID:26053094

  20. Interleukin-17 Could Promote Breast Cancer Progression at Several Stages of the Disease

    PubMed Central

    Welte, Thomas; Zhang, Xiang H.-F.

    2015-01-01

    Metastatic disease accounts for more than 90% of deaths from breast cancer. Yet the factors that trigger metastasis, often years after primary tumor removal, are not understood well. Recently the proinflammatory cytokine interleukin- (IL-) 17 family has been associated with poor prognosis in breast cancer. Here we review current literature on the pathogenic mechanisms driven by IL-17 during breast cancer progression and connect these findings to metastasis. These include (1) direct effects of IL-17 on tumor cells promoting tumor cell survival and invasiveness, (2) regulation of tumor angiogenesis, and (3) interaction with myeloid derived suppressor cells (MDSCs) to inhibit antitumor immune response and collaborate at the distant metastatic site. Furthermore, IL-17 might also be a culprit in bone destruction caused by late stage bone metastasis. Interestingly, in addition to these potential prometastasis functions, there is also evidence for an opposite, antitumor role of IL-17 during cancer therapies. We hypothesize that these contradictory roles may be due to chronic, imbalanced versus acute transient nature of the immune reactions, as well as differences in the cells that interact with IL-17+ cells under different circumstances. PMID:26783383

  1. Kindlin-2 in pancreatic stellate cells promotes the progression of pancreatic cancer.

    PubMed

    Yoshida, Naoki; Masamune, Atsushi; Hamada, Shin; Kikuta, Kazuhiro; Takikawa, Tetsuya; Motoi, Fuyuhiko; Unno, Michiaki; Shimosegawa, Tooru

    2017-04-01

    Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis associated with pancreatic ductal adenocarcinoma (PDAC). Kindlin-2 is a focal adhesion protein that regulates the activation of integrins. This study aimed to clarify the role of kindlin-2 in PSCs in pancreatic cancer. Kindlin-2 expression in 79 resected pancreatic cancer tissues was examined by immunohistochemical staining. Kindlin-2-knockdown immortalized human PSCs were established using small interfering RNA. Pancreatic cancer cells were treated with conditioned media of PSCs, and the cell proliferation and migration were examined. SUIT-2 pancreatic cancer cells were subcutaneously injected into nude mice alone or with PSCs and the size of the tumors was monitored. Kindlin-2 expression was observed in PDAC and the peritumoral stroma. Stromal kindlin-2 expression was associated with shorter recurrence-free survival time after R0 resection. Knockdown of kindlin-2 resulted in decreased proliferation, migration, and cytokine expression in PSCs. The PSC-induced proliferation and migration of pancreatic cancer cells were suppressed by kindlin-2 knockdown in PSCs. In vivo, co-injection of PSCs increased the size of the tumors, but this effect was abolished by kindlin-2 knockdown in PSCs. In conclusion, kindlin-2 in PSCs promoted the progression of pancreatic cancer.

  2. Tuberatolide B Suppresses Cancer Progression by Promoting ROS-Mediated Inhibition of STAT3 Signaling

    PubMed Central

    Choi, Youn Kyung; Kim, Junseong; Lee, Kang Min; Choi, Yu-Jeong; Ye, Bo-Ram; Kim, Min-Sun; Ko, Seong-Gyu; Lee, Seung-Hong; Kang, Do-Hyung; Heo, Soo-Jin

    2017-01-01

    Tuberatolide B (TTB, C27H34O4) is a diastereomeric meroterpenoid isolated from the Korean marine algae Sargassum macrocarpum. However, the anticancer effects of TTB remain unknown. In this study, we demonstrate that TTB inhibits tumor growth in breast, lung, colon, prostate, and cervical cancer cells. To examine the mechanism by which TTB suppresses cell growth, we determined the effect of TTB on apoptosis, ROS generation, DNA damage, and signal transduction. TTB induced ROS production in MDA-MB-231, A549, and HCT116 cells. Moreover, TTB enhanced DNA damage by inducing γH2AX foci formation and the phosphorylation of DNA damage-related proteins such as Chk2 and H2AX. Furthermore, TTB selectively inhibited STAT3 activation, which resulted in a reduction in cyclin D1, MMP-9, survivin, VEGF, and IL-6. In addition, TTB-induced ROS generation caused STAT3 inhibition, DNA damage, and apoptotic cell death. Therefore, TTB suppresses cancer progression by promoting ROS-mediated inhibition of STAT3 signaling, suggesting that TTB is useful for the treatment of cancer. PMID:28245605

  3. Tuberatolide B Suppresses Cancer Progression by Promoting ROS-Mediated Inhibition of STAT3 Signaling.

    PubMed

    Choi, Youn Kyung; Kim, Junseong; Lee, Kang Min; Choi, Yu-Jeong; Ye, Bo-Ram; Kim, Min-Sun; Ko, Seong-Gyu; Lee, Seung-Hong; Kang, Do-Hyung; Heo, Soo-Jin

    2017-02-25

    Tuberatolide B (TTB, C27H34O₄) is a diastereomeric meroterpenoid isolated from the Korean marine algae Sargassum macrocarpum. However, the anticancer effects of TTB remain unknown. In this study, we demonstrate that TTB inhibits tumor growth in breast, lung, colon, prostate, and cervical cancer cells. To examine the mechanism by which TTB suppresses cell growth, we determined the effect of TTB on apoptosis, ROS generation, DNA damage, and signal transduction. TTB induced ROS production in MDA-MB-231, A549, and HCT116 cells. Moreover, TTB enhanced DNA damage by inducing γH2AX foci formation and the phosphorylation of DNA damage-related proteins such as Chk2 and H2AX. Furthermore, TTB selectively inhibited STAT3 activation, which resulted in a reduction in cyclin D1, MMP-9, survivin, VEGF, and IL-6. In addition, TTB-induced ROS generation caused STAT3 inhibition, DNA damage, and apoptotic cell death. Therefore, TTB suppresses cancer progression by promoting ROS-mediated inhibition of STAT3 signaling, suggesting that TTB is useful for the treatment of cancer.

  4. Long Noncoding RNA PVT1 Promotes Melanoma Progression Via Endogenous Sponging MiR-26b.

    PubMed

    Wang, Bao-Juan; Ding, Hong-Wei; Ma, Guo-An

    2017-04-12

    Melanoma is an extremely aggressive and high mortality skin malignant tumor, and various long noncoding RNAs (lncRNAs)have been reported to be associated with the oncogenesis of melanoma. The purpose of this study is to investigate the potential roles of lncRNA PVT1 in melanoma progression and to explore the possible mechanisms. A total of 35 patients who were diagnosed as malignant melanoma were enrolled in this study. Expression of PVT1 was significantly up-regulated in melanoma tissue and associated with poor prognosis. Loss-of-function experiments showed that PVT1 knock-down markedly suppressed the proliferation activity, induced cell cycle arrest at G0/G1 phase, and enhanced the apoptosis of melanoma cell lines. Bioinformatics analysis and dual-luciferase reporter assay revealed that PVT1 directly bound to miR-26b, which had been verified as a tumor suppressor in melanoma. Moreover, further functional rescue experiments revealed that PVT1 knock-down could observably reverse the tumor-promoting role of miR-26b inhibitor. Overall, our study demonstrates the oncogenic role of PVT1 as a miR-26b sponge, possibly providing a novel therapeutic target for melanoma.

  5. TLR4 promotes fibrosis but attenuates tubular damage in progressive renal injury.

    PubMed

    Pulskens, Wilco P; Rampanelli, Elena; Teske, Gwendoline J; Butter, Loes M; Claessen, Nike; Luirink, Ilse K; van der Poll, Tom; Florquin, Sandrine; Leemans, Jaklien C

    2010-08-01

    Toll-like receptors (TLRs) can orchestrate an inflammatory response upon activation by pathogen-associated motifs and release of endogenous stress ligands during tissue injury. The kidney constitutively expresses most TLRs, including TLR4. The function of TLR4 during the inflammation, tubular atrophy, and fibrosis that accompany progressive renal injury is unknown. Here, we subjected wild-type (WT) and TLR4-deficient mice to unilateral ureteral obstruction and observed elevated levels of TLR4 mRNA in the kidney after obstruction. One day after unilateral ureteral obstruction, TLR4-deficient mice had fewer proliferating tubular epithelial cells and more tubular damage than WT mice; however, TLR4-deficient mice developed considerably less renal fibrosis despite decreased matrix metalloproteinase activity and without significant differences in myofibroblast accumulation. In vitro, TLR4-deficient primary tubular epithelial cells and myofibroblasts produced significantly less type I collagen mRNA after TGF-beta stimulation than WT cells. The reduced fibrosis in TLR4-deficient mice associated with an upregulation of Bambi, a negative regulator of TGF-beta signaling. In conclusion, TLR4 attenuates tubular damage but promotes renal fibrosis by modulating the susceptibility of renal cells to TGF-beta. These data suggest that TLR4 signaling may be a therapeutic target for the prevention of renal fibrosis.

  6. Defining and implementing arsenic policies in Bangladesh: possible roles for public and private sector actors.

    PubMed

    Mahmood, Shakeel Ahmed Ibne; Ball, Carolyn

    2004-01-01

    A UN report warned up to 50% of Bangladesh's population (57 million) are at risk of arsenic poisoning from naturally occurring arsenic in well water. This article explores how this problem occurred, assesses what factors impede progress eliminating this problem and recommends governmental measures for prevention of arsenic poisoning.

  7. Mesenchymal stem cells promote colorectal cancer progression through AMPK/mTOR-mediated NF-κB activation

    PubMed Central

    Wu, Xiao-Bing; Liu, Yang; Wang, Gui-Hua; Xu, Xiao; Cai, Yang; Wang, Hong-Yi; Li, Yan-Qi; Meng, Hong-Fang; Dai, Fu; Jin, Ji-De

    2016-01-01

    Mesenchymal stem cells (MSCs) exert a tumor-promoting effect in a variety of human cancers. This study was designed to identify the molecular mechanisms related to the tumor-promoting effect of MSCs in colorectal cancer. In vitro analysis of colorectal cancer cell lines cultured in MSC conditioned media (MSC-CM) showed that MSC-CM significantly promoted the progression of the cancer cells by enhancing cell proliferation, migration and colony formation. The tumorigenic effect of MSC-CM was attributed to altered expression of cell cycle regulatory proteins and inhibition of apoptosis. Furthermore, MSC-CM induced high level expression of a number of pluripotency factors in the cancer cells. ELISAs revealed MSC-CM contained higher levels of IL-6 and IL-8, which are associated with the progression of cancer. Moreover, MSC-CM downregulated AMPK mRNA and protein phosphorylation, but upregulated mTOR mRNA and protein phosphorylation. The NF-κB pathway was activated after addition of MSC-CM. An in vivo model in Balb/C mice confirmed the ability of MSC-CM to promote the invasion and proliferation of colorectal cancer cells. This study indicates that MSCs promote the progression of colorectal cancer via AMPK/mTOR-mediated NF-κB activation. PMID:26892992

  8. Massive acute arsenic poisonings.

    PubMed

    Lech, Teresa; Trela, Franciszek

    2005-07-16

    Arsenic poisonings are still important in the field of toxicology, though they are not as frequent as about 20-30 years ago. In this paper, the arsenic concentrations in ante- and post-mortem materials, and also forensic and anatomo-pathological aspects in three cases of massive acute poisoning with arsenic(III) oxide (two of them with unexplained criminalistic background, in which arsenic was taken for amphetamine and one suicide), are presented. Ante-mortem blood and urine arsenic concentrations ranged from 2.3 to 6.7 microg/ml, respectively. Post-mortem tissue total arsenic concentrations were also detected in large concentrations. In case 3, the contents of the duodenum contained as much as 30.1% arsenic(III) oxide. The high concentrations of arsenic detected in blood and tissues in all presented cases are particularly noteworthy in that they are very rarely detected at these concentrations in fatal arsenic poisonings.

  9. Activity of the AtMRP3 promoter in transgenic Arabidopsis thaliana and Nicotiana tabacum plants is increased by cadmium, nickel, arsenic, cobalt and lead but not by zinc and iron.

    PubMed

    Zientara, Katarzyna; Wawrzyńska, Anna; Lukomska, Jolanta; López-Moya, José Rafael; Liszewska, Frantz; Assunção, Ana G L; Aarts, Mark G M; Sirko, Agnieszka

    2009-02-05

    Characterization of the function, regulation and metal-specificity of metal transporters is one of the basic steps needed for the understanding of transport and accumulation of toxic metals and metalloids by plants. In this work GUS was used as a reporter for monitoring the activity of the promoter of the AtMRP3 gene from Arabidopsis thaliana, a gene encoding an ABC-transporter, expression of which is induced by heavy metals. The AtMRP3 promoter-GUS fusion expression cassette was introduced into the genome of two model plants, A. thaliana and Nicotiana tabacum. The promoter induces GUS activity in the roots as well as in the shoots upon metal exposure. Similar responses of the AtMRP3 promoter to the presence of the selected metals was observed in both plant species. Cadmium, nickel, arsenic, cobalt and lead strongly activated the transcription of the reporter gene, while zinc and iron had no impact. The AtMRP3 promoter thus seems to be a useful new tool in designing plants that can be used for biomonitoring of environmental contaminations.

  10. The ecology of arsenic

    USGS Publications Warehouse

    Oremland, Ronald S.; Stolz, John F.

    2003-01-01

    Arsenic is a metalloid whose name conjures up images of murder. Nonetheless, certain prokaryotes use arsenic oxyanions for energy generation, either by oxidizing arsenite or by respiring arsenate. These microbes are phylogenetically diverse and occur in a wide range of habitats. Arsenic cycling may take place in the absence of oxygen and can contribute to organic matter oxidation. In aquifers, these microbial reactions may mobilize arsenic from the solid to the aqueous phase, resulting in contaminated drinking water. Here we review what is known about arsenic-metabolizing bacteria and their potential impact on speciation and mobilization of arsenic in nature.

  11. Autophagy Inhibition by Sustained Over-production of IL-6 Contributes to Arsenic Carcinogenesis

    PubMed Central

    Qi, Yuanlin; Zhang, Mingfang; Li, Hui; Frank, Jacqueline A.; Dai, Lu; Liu, Huijuan; Zhang, Zhuo; Wang, Chi; Chen, Gang

    2014-01-01

    Chronic inflammation has been implicated as an etiological factor in cancer, whereas autophagy may help preserve cancer cell survival but exert anti-inflammatory effects. How these phenomena interact during carcinogenesis remains unclear. We explored this question in a human bronchial epithelial cell-based model of lung carcinogenesis that is mediated by sub-chronic exposure to arsenic. We found that sustained overexpression of the pro-inflammatory interleukin IL-6 promoted arsenic-induced cell transformation by inhibiting autophagy. Conversely, strategies to enhance autophagy counteracted the effect of IL-6 in the model. These findings were confirmed and extended in a mouse model of arsenic-induced lung cancer. Mechanistic investigations suggested that mTOR inhibition contributed to the activation of autophagy, whereas IL-6 overexpression was sufficient to block autophagy by supporting Beclin-1/Mcl-1 interaction. Overall, our findings argued that chronic inflammatory states driven by IL-6 could antagonize autophagic states that may help preserve cancer cell survival and promote malignant progression, suggesting a need to uncouple inflammation and autophagy controls to enable tumor progression. PMID:24830721

  12. CB-08KIF3A IS ESSENTIAL FOR CILIOGENESIS, CILIA FUNCTION AND PROMOTES GLIOBLASTOMA PROGRESSION

    PubMed Central

    Hoang-Minh, Lan; Deleyrolle, Loic; Ugartemendia, George; Breunig, Joshua; Semple-Rowland, Susan; Reynolds, Brent; Sarkisian, Matthew

    2014-01-01

    Despite recent findings that cilia transduce diverse signaling pathways affecting cell proliferation, migration and survival, little is known about the influence of cilia or cilia-associated proteins in glioblastoma multiforme (GBM). We recently showed that primary cilia project from subsets of cells in GBM patient biopsies and derived cell lines. To determine if cilia contribute to GBM growth, we blocked ciliogenesis using a lentivirus expressing a dominant negative form of KIF3A, an essential ciliogenesis protein. We generated stable GBM cell lines (L0 and S3; representing different molecular subclasses) whereby dnKIF3A+ cells exhibited virtual complete loss of cilia compared to controls (confirmed by immunostaining and EM). Canonically, secreted Sonic hedgehog (SHH) ligand binds and activates receptor signaling cascades (e.g., smoothened (SMO)) within cilia to promote normal cell proliferation and tumor cell growth in specific developmental and pathological contexts, respectively. To examine the role of SHH in GBM proliferation, we exposed control and dnKIF3A+ L0 and S3 cells to saline or recombinant SHH. We found the number of L0 control cells significantly increased after SHH compared to saline, an effect blocked by pretreatment with cyclopamine (SMO inhibitor). However, SHH did not increase the number of L0 dnKIF3A+ cells. Interestingly, SHH exposure had no effect on S3 control cell numbers, despite observations that SHH signaling components (SMO and Gli3) were recruited to their cilia in response to SHH. This suggests GBM cilia are SHH-responsive but the downstream consequences of ciliary signaling may differ between cell lines. Notably, mice intracranially xenografted with L0 cells expressing dnKIF3A survived significantly longer than mice receiving control cells, and retained the loss of cilia phenotype in the tumors. Collectively, these data suggest KIF3A promotes GBM tumor progression, but the extent to which the effects are mediated by cilia and the

  13. Upregulation of long non-coding RNA DQ786243 promotes the progression of gastric cancer.

    PubMed

    Shan, Ting; Fan, Juanyun; Zhao, Qin; Deng, Kaiyuan; Xia, Jiazeng

    2017-10-01

    Long non‑coding RNAs (lncRNAs) have been identified as key regulatory factors in various biological processes. Their dysregulation has been observed in several types of human cancer, including gastric cancer (GC). The aim of the present study was to investigate the putative roles of the lncRNA DQ786243 in the progression of GC, as well as evaluate its diagnostic and therapeutic potential in GC. The expression of DQ786243 in 82 pairs of GC tissues and adjacent healthy tissues, as well as in three GC cell lines and a human normal gastric epithelial cell line, was assessed using reverse transcription‑quantitative polymerase chain reaction. In addition, the putative correlation between the expression of DQ786243 and various clinicopathological features of GC was investigated. Furthermore, the effects of silencing DQ786243 in GC cells were examined using RNA interference. Colony formation and Cell Counting kit‑8 assays were used to evaluate the effects of DQ786243 on GC cell proliferation, and Transwell and wound healing assays were used to examine GC cell migration and invasion. The results of the present study demonstrated that the expression of DQ786243 was significantly upregulated in GC tissues and cell lines compared with healthy control tissues and cells. Correlation analysis revealed a significant association between the expression of DQ786243 and the TNM stage, tumor size, depth of invasion and presence of lymph node metastasis in patients with GC. Furthermore, silencing the DQ786243 was demonstrated to inhibit proliferation, and impair the migration and invasion of GC cells. The present results suggested that DQ786243 may function as an oncogenic regulator via promoting the proliferation and metastasis of GC cells. Therefore, DQ786243 may have potential as a novel biomarker for the diagnosis of GC, and may also be a promising candidate for the development of novel therapeutic approaches for the treatment of patients with GC.

  14. A novel biomarker C6orf106 promotes the malignant progression of breast cancer.

    PubMed

    Jiang, Guiyang; Zhang, Xiupeng; Zhang, Yong; Wang, Liang; Fan, Chuifeng; Xu, Hongtao; Miao, Yuan; Wang, Enhua

    2015-09-01

    C6orf106 (chromosome 6 open reading frame 106) is a recently discovered protein encoded by the 6th chromosome. Though many proteins encoded by chromosome 6 are reportedly related to cancer, schizophrenia, autoimmunity and many other diseases, the function of C6orf106 was not well demonstrated so far. As measured by immunohistochemical staining, C6orf106 was positive in normal breast duct myoepithelial cells (92.31 %, 72/78), but negative in normal breast duct glandular epithelial cells (3.85 %, 3/78). In breast ductal carcinoma in situ, C6orf106 showed weakly or moderately positive (77.97 %, 46/59), but it was significantly strongly positive in invasive ductal carcinoma (79.57 %, 148/186). The expression intensity of C6orf106 seemed increased significantly along with the malignancy of breast cancer (p < 0.001). Additionally, C6orf106 expression was significantly correlated with TNM stage (p = 0.001 and p = 0.004) and lymph node metastasis (p = 0.018 and p = 0.025) of the overall and the triple-negative breast cancer, respectively. Consistently, we found that the interference of C6orf106 was able to inhibit cell proliferation and invasion of two triple-negative breast cancer cell lines, MDA-MB-231 and BT-549, accompanied by the decrease of cyclin A2, cyclin B1, c-myc, and N-cadherin and the increase of E-cadherin. Collectively, these results indicate that C6orf106 may promote tumor progression in the invasive breast cancer, particularly in triple-negative breast cancer, and C6orf106 might serve as a novel therapeutic target of breast cancer, especially for triple-negative breast cancer.

  15. Arsenic and cardiovascular disease.

    PubMed

    States, J Christopher; Srivastava, Sanjay; Chen, Yu; Barchowsky, Aaron

    2009-02-01

    Chronic arsenic exposure is a worldwide health problem. Although arsenic-induced cancer has been widely studied, comparatively little attention has been paid to arsenic-induced vascular disease. Epidemiological studies have shown that chronic arsenic exposure is associated with increased morbidity and mortality from cardiovascular disease. In addition, studies suggest that susceptibility to arsenic-induced vascular disease may be modified by nutritional factors in addition to genetic factors. Recently, animal models for arsenic-induced atherosclerosis and liver sinusoidal endothelial cell dysfunction have been developed. Initial studies in these models show that arsenic exposure accelerates and exacerbates atherosclerosis in apolipoprotein E-knockout mice. Microarray studies of liver mRNA and micro-RNA abundance in mice exposed in utero suggest that a permanent state of stress is induced by the arsenic exposure. Furthermore, the livers of the arsenic-exposed mice have activated pathways involved in immune responses suggesting a pro-hyperinflammatory state. Arsenic exposure of mice after weaning shows a clear dose-response in the extent of disease exacerbation. In addition, increased inflammation in arterial wall is evident. In response to arsenic-stimulated oxidative signaling, liver sinusoidal endothelium differentiates into a continuous endothelium that limits nutrient exchange and waste elimination. Data suggest that nicotinamide adenine dinucleotide phosphate oxidase-derived superoxide or its derivatives are essential second messengers in the signaling pathway for arsenic-stimulated vessel remodeling. The recent findings provide future directions for research into the cardiovascular effects of arsenic exposure.

  16. Daily goal progress is facilitated by spousal support and promotes psychological, physical, and relational well-being throughout adulthood

    PubMed Central

    Jakubiak, Brittany K.; Feeney, Brooke C.

    2016-01-01

    In two daily-diary studies, we tested the consequences and precursors of daily goal progress throughout the adult lifespan. Attachment theory posits that exploration—including the pursuit of autonomous goals—promotes well-being across the lifespan and is facilitated by support from close others. For both young-adult newlyweds (Study 1) and married couples in late adulthood (Study 2), daily independent goal progress predicted same-day and next-day improvements in psychological, physical, and relational well-being. Specifically, when participants made more progress on their goals than usual on one day, they reported increases in positive affect, sleep quality, and relationship quality, and decreased physical symptoms, the following day (as well as concurrently). Additionally, spousal support (i.e., availability, encouragement, and noninterference) enabled same-day and next-day goal progress. Mediational analyses showed indirect links between spousal support and well-being through goal progress. Some effects were moderated by attachment orientation in the newlywed sample; individuals with greater insecure attachment benefited most from goal progress, and spousal support enabled goal progress most strongly for individuals with less anxious attachment. Overall, these results support and extend attachment theoretical propositions regarding the importance of the exploration system across the adult lifespan. They contribute to existing literature by demonstrating wide-ranging consequences of successful exploration for well-being and by providing evidence for the importance of both exploration and support for exploration into late adulthood. PMID:27560610

  17. Arsenic Trioxide Injection

    MedlinePlus

    ... of the white blood cells).Arsenic trioxide may cause a serious or life-threatening group of symptoms ... medications to treat the syndrome.Arsenic trioxide may cause QT prolongation (heart muscles take longer to recharge ...

  18. Arsenic Treatment Technology Demonstrations

    EPA Pesticide Factsheets

    EPA’s research for the new Arsenic Rule focused on the development and evaluation of innovative methods and cost-effective technologies for improving the assessment and control of arsenic contamination.

  19. Cryptic exposure to arsenic.

    PubMed

    Rossy, Kathleen M; Janusz, Christopher A; Schwartz, Robert A

    2005-01-01

    Arsenic is an odorless, colorless and tasteless element long linked with effects on the skin and viscera. Exposure to it may be cryptic. Although human intake can occur from four forms, elemental, inorganic (trivalent and pentavalent arsenic) and organic arsenic, the trivalent inorganic arsenicals constitute the major human hazard. Arsenic usually reaches the skin from occupational, therapeutic, or environmental exposure, although it still may be employed as a poison. Occupations involving new technologies are not exempt from arsenic exposure. Its acute and chronic effects are noteworthy. Treatment options exist for arsenic-induced pathology, but prevention of toxicity remains the main focus. Vitamin and mineral supplementation may play a role in the treatment of arsenic toxicity.

  20. Fact Sheet on Arsenic

    EPA Pesticide Factsheets

    Arsenic is a naturally occurring element that is found in combination with either inorganic or organic substances to form many different compounds. Inorganic arsenic compounds are found in soils, sediments, and groundwater.

  1. Characterization of the cystatin B gene promoter harboring the dodecamer repeat expanded in progressive myoclonus epilepsy, EPM1.

    PubMed

    Alakurtti, K; Virtaneva, K; Joensuu, T; Palvimo, J J; Lehesjoki, A E

    2000-01-25

    Mutations in the gene encoding cystatin B (CSTB) are responsible for the primary defect in progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1). A novel and unique type of disease-causing mutation, an unstable dodecamer repeat expansion, accounts for the majority of EPM1 patients world-wide. This minisatellite repeat expansion, located in the putative promoter of CSTB 175 bp upstream from the translation initiation codon, appears to downregulate CSTB gene expression in vivo. We report here the characterization of the CSTB promoter using different promoter-luciferase gene constructs. Transient transfections of cultured mammalian cells suggest that the region from -670 to -1 bp from the translation initiation codon functions as the CSTB promoter. Active binding to five Sp1 and four AP1 sites as well as weak binding to an androgen response element (ARE) half site was demonstrated by electrophoretic mobility shift assays. The effect of the minisatellite expansion on the promoter activity was evaluated by comparing the activity of constructs containing wild-type and expanded alleles. An increase in the number of dodecamer units from three to 19 repeats lowered transcription in vitro by 10-fold. Northern analysis of lymphoblastoid RNA from individuals with 'premutation' length dodecamer repeat (12-17 copies) expansions showed decreased levels of CSTB mRNA expression. These data indicate that expansion of the dodecamer repeat located in the proximal promoter of CSTB severely disrupts the function of the promoter and thereby reduces transcription of CSTB.

  2. ARSENIC SOURCES AND ASSESSMENT

    EPA Science Inventory

    Recent research has identified a number of potential and current links between environmental arsenic releases and the management of operational and abandoned landfills. Many landfills will receive an increasing arsenic load due to the disposal of arsenic-bearing solid residuals ...

  3. ARSENIC REMOVAL TECHNOLOGY

    EPA Science Inventory

    Presentation will discuss the state-of-art technology for removal of arsenic from drinking water. Presentation includes results of several EPA field studies on removal of arsenic from existing arsenic removal plants and key results from several EPA sponsored research studies. T...

  4. ARSENIC REMOVAL TECHNOLOGY

    EPA Science Inventory

    Presentation will discuss the state-of-art technology for removal of arsenic from drinking water. Presentation includes results of several EPA field studies on removal of arsenic from existing arsenic removal plants and key results from several EPA sponsored research studies. T...

  5. ARSENIC SOURCES AND ASSESSMENT

    EPA Science Inventory

    Recent research has identified a number of potential and current links between environmental arsenic releases and the management of operational and abandoned landfills. Many landfills will receive an increasing arsenic load due to the disposal of arsenic-bearing solid residuals ...

  6. ARSENIC TREATMENT TECHNOLOGY

    EPA Science Inventory

    Presentation will discuss the state-of-the-art technology for removal of arsenic from drinking water. Presentation also includes results of several EPA field studies on removal of arsenic from existing arsenic removal plants and key results from several EPA sponsored research st...

  7. Case studies--arsenic.

    PubMed

    Chou, C H Selene J; De Rosa, Christopher T

    2003-08-01

    Arsenic is found naturally in the environment. People may be exposed to arsenic by eating food, drinking water, breathing air, or by skin contact with soil or water that contains arsenic. In the U.S., the diet is a predominant source of exposure for the general population with smaller amounts coming from drinking water and air. Children may also be exposed to arsenic because of hand to mouth contact or eating dirt. In addition to the normal levels of arsenic in air, water, soil, and food, people could by exposed to higher levels in several ways such as in areas containing unusually high natural levels of arsenic in rocks which can lead to unusually high levels of arsenic in soil or water. People living in an area like this could take in elevated amounts of arsenic in drinking water. Workers in an occupation that involves arsenic production or use (for example, copper or lead smelting, wood treatment, pesticide application) could be exposed to elevated levels of arsenic at work. People who saw or sand arsenic-treated wood could inhale/ingest some of the sawdust which contains high levels of arsenic. Similarly, when pressure-treated wood is burned, high levels of arsenic could be released in the smoke. In agricultural areas where arsenic pesticides were used on crops the soil could contain high levels of arsenic. Some hazardous waste sites contain large quantities of arsenic. Arsenic ranks #1 on the ATSDR/EPA priority list of hazardous substances. Arsenic has been found in at least 1,014 current or former NPL sites. At the hazardous waster sites evaluated by ATSDR, exposure to arsenic in soil predominated over exposure to water, and no exposure to air had been recorded. However, there is no information on morbidity or mortality from exposure to arsenic in soil at hazardous waste sites. Exposure assessment, community and tribal involvement, and evaluation and surveillance of health effects are among the ATSDR future Superfund research program priority focus areas

  8. RPS27a promotes proliferation, regulates cell cycle progression and inhibits apoptosis of leukemia cells

    SciTech Connect

    Wang, Houcai; Yu, Jing; Zhang, Lixia; Xiong, Yuanyuan; Chen, Shuying; Xing, Haiyan; Tian, Zheng; Tang, Kejing; Wei, Hui; Rao, Qing; Wang, Min; Wang, Jianxiang

    2014-04-18

    Highlights: • RPS27a expression was up-regulated in advanced-phase CML and AL patients. • RPS27a knockdown changed biological property of K562 and K562/G01 cells. • RPS27a knockdown affected Raf/MEK/ERK, P21 and BCL-2 signaling pathways. • RPS27a knockdown may be applicable for new combination therapy in CML patients. - Abstract: Ribosomal protein S27a (RPS27a) could perform extra-ribosomal functions besides imparting a role in ribosome biogenesis and post-translational modifications of proteins. The high expression level of RPS27a was reported in solid tumors, and we found that the expression level of RPS27a was up-regulated in advanced-phase chronic myeloid leukemia (CML) and acute leukemia (AL) patients. In this study, we explored the function of RPS27a in leukemia cells by using CML cell line K562 cells and its imatinib resistant cell line K562/G01 cells. It was observed that the expression level of RPS27a was high in K562 cells and even higher in K562/G01 cells. Further analysis revealed that RPS27a knockdown by shRNA in both K562 and K562G01 cells inhibited the cell viability, induced cell cycle arrest at S and G2/M phases and increased cell apoptosis induced by imatinib. Combination of shRNA with imatinib treatment could lead to more cleaved PARP and cleaved caspase-3 expression in RPS27a knockdown cells. Further, it was found that phospho-ERK(p-ERK) and BCL-2 were down-regulated and P21 up-regulated in RPS27a knockdown cells. In conclusion, RPS27a promotes proliferation, regulates cell cycle progression and inhibits apoptosis of leukemia cells. It appears that drugs targeting RPS27a combining with tyrosine kinase inhibitor (TKI) might represent a novel therapy strategy in TKI resistant CML patients.

  9. Arsenic pollution sources.

    PubMed

    Garelick, Hemda; Jones, Huw; Dybowska, Agnieszka; Valsami-Jones, Eugenia

    2008-01-01

    Arsenic is a widely dispersed element in the Earth's crust and exists at an average concentration of approximately 5 mg/kg. There are many possible routes of human exposure to arsenic from both natural and anthropogenic sources. Arsenic occurs as a constituent in more than 200 minerals, although it primarily exists as arsenopyrite and as a constituent in several other sulfide minerals. The introduction of arsenic into drinking water can occur as a result of its natural geological presence in local bedrock. Arsenic-containing bedrock formations of this sort are known in Bangladesh, West Bengal (India), and regions of China, and many cases of endemic contamination by arsenic with serious consequences to human health are known from these areas. Significant natural contamination of surface waters and soil can arise when arsenic-rich geothermal fluids come into contact with surface waters. When humans are implicated in causing or exacerbating arsenic pollution, the cause can almost always be traced to mining or mining-related activities. Arsenic exists in many oxidation states, with arsenic (III) and (V) being the most common forms. Similar to many metalloids, the prevalence of particular species of arsenic depends greatly on the pH and redox conditions of the matrix in which it exists. Speciation is also important in determining the toxicity of arsenic. Arsenic minerals exist in the environment principally as sulfides, oxides, and phosphates. In igneous rocks, only those of volcanic origin are implicated in high aqueous arsenic concentrations. Sedimentary rocks tend not to bear high arsenic loads, and common matrices such as sands and sandstones contain lower concentrations owing to the dominance of quartz and feldspars. Groundwater contamination by arsenic arises from sources of arsenopyrite, base metal sulfides, realgar and orpiment, arsenic-rich pyrite, and iron oxyhydroxide. Mechanisms by which arsenic is released from minerals are varied and are accounted for by

  10. Force engages vinculin and promotes tumor progression by enhancing PI3-kinase activation of phosphatidylinositol (3,4,5)-triphosphate

    PubMed Central

    Rubashkin, MG; Cassereau, L; Bainer, R; DuFort, CC; Yui, Y; Ou, G; Paszek, MJ; Davidson, MW; Chen, YY; Weaver, VM

    2014-01-01

    Extracellular matrix stiffness induces focal adhesion assembly to drive malignant transformation and tumor metastasis. Nevertheless, how force alters focal adhesions to promote tumor progression remains unclear. Here, we explored the role of the focal adhesion protein vinculin, a force-activated mechano-transducer, in mammary epithelial tissue transformation and invasion. We found that extracellular matrix stiffness stabilizes the assembly of a vinculin-talin-actin scaffolding complex that facilitates PI3-kinase mediated phosphatidylinositol (3,4,5)-triphosphate phosphorylation. Using defined two and three dimensional matrices, a mouse model of mammary tumorigenesis with vinculin mutants and a novel super resolution imaging approach, we established that ECM stiffness, per se, promotes the malignant progression of a mammary epithelium by activating and stabilizing vinculin and enhancing Akt signaling at focal adhesions. Our studies also revealed that vinculin strongly co-localizes with activated Akt at the invasive border of human breast tumors, where the ECM is stiffest and we detected elevated mechano-signaling. Thus, extracellular matrix stiffness could induce tumor progression by promoting the assembly of signaling scaffolds; a conclusion underscored by the significant association we observed between highly expressed focal adhesion plaque proteins and malignant transformation across multiple types of solid cancer. PMID:25183785

  11. Redox controls on arsenic enrichment and release from aquifer sediments in central Yangtze River Basin

    NASA Astrophysics Data System (ADS)

    Schaefer, Michael V.; Guo, Xinxin; Gan, Yiqun; Benner, Shawn G.; Griffin, Aron M.; Gorski, Christopher A.; Wang, Yanxin; Fendorf, Scott

    2017-05-01

    More than 100 million people in Asia are presently exposed to groundwater with arsenic (As) concentrations exceeding the World Health Organization standard of 10 μg L-1. Arsenic contaminated groundwater within basins of the central portion of the Yangtze River has recently been reported, but the processes controlling arsenic concentrations have yet to be resolved. We examined the hydrologic and geochemical factors controlling arsenic within the Jianghan Plain, an inland sedimentary basin of the Yangtze River, where arsenic concentrations exhibit strong seasonal variability driven by surface and groundwater mixing (Schaefer et al., 2016). Hydrologic fluctuations alter redox conditions in the aquifer, leading to oscillations between arsenic/iron reduction and oxidation. Here we investigate the depth-distribution of solid and aqueous phase iron and arsenic species and, through a series of laboratory manipulations, constrain the biogeochemical processes controlling seasonal changes in groundwater arsenic concentrations. In sediment incubations from ∼20 m below the surface, where solid-phase arsenic concentrations exceed 100 mg kg-1, both unamended and glucose-amended sediment samples result in arsenic release to the aqueous phase. In situ carbon was capable of promoting As release in the sediment. In contrast, sediment batch incubations from other depths resulted in limited As release. Solid phase arsenic in the enriched zone was relatively oxidized but may become reduced over short time periods. In sediments below the As-enriched zone, glucose amendment resulted in arsenic reduction, but arsenic release to the aqueous phase was restricted by the subsequent formation of arsenic sulfide minerals. Buried sedimentary arsenic coupled with anaerobic microbial respiration of subsurface organic carbon within the Jianghan Plain aquifer leads to rapid release of As to groundwater. Arsenic release from sediments at ∼20 m depth is sufficient to explain arsenic concentrations

  12. Promotion

    PubMed Central

    Alam, Hasan B.

    2013-01-01

    This article gives an overview of the promotion process in an academic medical center. A description of different promotional tracks, tenure and endowed chairs, and the process of submitting an application is provided. Finally, some practical advice about developing skills and attributes that can help with academic growth and promotion is dispensed. PMID:24436683

  13. MGMT promoter methylation is associated with temozolomide response and prolonged progression-free survival in disseminated cutaneous melanoma.

    PubMed

    Tuominen, Rainer; Jewell, Rosalyn; van den Oord, Joost J; Wolter, Pascal; Stierner, Ulrika; Lindholm, Christer; Hertzman Johansson, Carolina; Lindén, Diana; Johansson, Hemming; Frostvik Stolt, Marianne; Walker, Christy; Snowden, Helen; Newton-Bishop, Julia; Hansson, Johan; Egyházi Brage, Suzanne

    2015-06-15

    To investigate the predictive and prognostic value of O(6) -methylguanine DNA methyltransferase (MGMT) inactivation by analyses of promoter methylation in pretreatment tumor biopsies from patients with cutaneous melanoma treated with dacarbazine (DTIC) or temozolomide (TMZ) were performed. The patient cohorts consisted of Belgian and Swedish disseminated melanoma patients. Patients were subdivided into those receiving single-agent treatment with DTIC/TMZ (cohort S, n = 74) and those treated with combination chemotherapy including DTIC/TMZ (cohort C, n = 79). Median follow-up was 248 and 336 days for cohort S and cohort C, respectively. MGMT promoter methylation was assessed by three methods. The methylation-related transcriptional silencing of MGMT mRNA expression was assessed by real-time RT-PCR. Response to chemotherapy and progression-free survival (PFS) and overall survival were correlated to MGMT promoter methylation status. MGMT promoter methylation was detected in tumor biopsies from 21.5 % of the patients. MGMT mRNA was found to be significantly lower in tumors positive for MGMT promoter methylation compared to tumors without methylation in both treatment cohorts (p < 0.005). DTIC/TMZ therapy response rate was found to be significantly associated with MGMT promoter methylation in cohort S (p = 0.0005), but did not reach significance in cohort C (p = 0.16). Significantly longer PFS was observed among patients with MGMT promoter-methylated tumors (p = 0.002). Multivariate Cox regression analysis identified presence of MGMT promoter methylation as an independent variable associated with longer PFS. Together, this implies that MGMT promoter methylation is associated with response to single-agent DTIC/TMZ and longer PFS in disseminated cutaneous melanoma.

  14. Dual therapeutic functions of F-5 fragment in burn wounds: preventing wound progression and promoting wound healing in pigs.

    PubMed

    Bhatia, Ayesha; O'Brien, Kathryn; Chen, Mei; Wong, Alex; Garner, Warren; Woodley, David T; Li, Wei

    2016-01-01

    Burn injuries are a leading cause of morbidity including prolonged hospitalization, disfigurement, and disability. Currently there is no Food and Drug Administration-approved burn therapeutics. A clinical distinction of burn injuries from other acute wounds is the event of the so-called secondary burn wound progression within the first week of the injury, in which a burn expands horizontally and vertically from its initial boundary to a larger area. Therefore, an effective therapeutics for burns should show dual abilities to prevent the burn wound progression and thereafter promote burn wound healing. Herein we report that topically applied F-5 fragment of heat shock protein-90α is a dual functional agent to promote burn wound healing in pigs. First, F-5 prevents burn wound progression by protecting the surrounding cells from undergoing heat-induced caspase 3 activation and apoptosis with increased Akt activation. Accordingly, F-5-treated burn and excision wounds show a marked decline in inflammation. Thereafter, F-5 accelerates burn wound healing by stimulating the keratinocyte migration-led reepithelialization, leading to wound closure. This study addresses a topical agent that is capable of preventing burn wound progression and accelerating burn wound healing.

  15. Dual therapeutic functions of F-5 fragment in burn wounds: preventing wound progression and promoting wound healing in pigs

    PubMed Central

    Bhatia, Ayesha; O’Brien, Kathryn; Chen, Mei; Wong, Alex; Garner, Warren; Woodley, David T.; Li, Wei

    2016-01-01

    Burn injuries are a leading cause of morbidity including prolonged hospitalization, disfigurement, and disability. Currently there is no Food and Drug Administration-approved burn therapeutics. A clinical distinction of burn injuries from other acute wounds is the event of the so-called secondary burn wound progression within the first week of the injury, in which a burn expands horizontally and vertically from its initial boundary to a larger area. Therefore, an effective therapeutics for burns should show dual abilities to prevent the burn wound progression and thereafter promote burn wound healing. Herein we report that topically applied F-5 fragment of heat shock protein-90α is a dual functional agent to promote burn wound healing in pigs. First, F-5 prevents burn wound progression by protecting the surrounding cells from undergoing heat-induced caspase 3 activation and apoptosis with increased Akt activation. Accordingly, F-5–treated burn and excision wounds show a marked decline in inflammation. Thereafter, F-5 accelerates burn wound healing by stimulating the keratinocyte migration-led reepithelialization, leading to wound closure. This study addresses a topical agent that is capable of preventing burn wound progression and accelerating burn wound healing. PMID:27382602

  16. The arsenic-based cure of acute promyelocytic leukemia promotes cytoplasmic sequestration of PML and PML/RARA through inhibition of PML body recycling.

    PubMed

    Lång, Emma; Grudic, Amra; Pankiv, Serhiy; Bruserud, Oystein; Simonsen, Anne; Bjerkvig, Rolf; Bjørås, Magnar; Bøe, Stig Ove

    2012-07-26

    Arsenic in the form of arsenic trioxide (ATO) is used as a therapeutic drug for treatment of acute promyelocytic leukemia (APL). The mechanism by which this agent cures this disease was previously shown to involve direct interactions between ATO and the promyelocytic leukemia protein (PML), as well as accelerated degradation of the APL-associated fusion oncoprotein PML/retinoic acid receptor α (RARA). Here we investigated the fate of PML-generated nuclear structures called PML bodies in ATO-treated cells. We found that ATO inhibits formation of progeny PML bodies while it stabilizes cytoplasmic precursor compartments, referred to as cytoplasmic assemblies of PML and nucleoporins (CyPNs), after cell division. This block in PML body recycling is readily detected at pharmacologic relevant ATO concentrations (0.02-0.5μM) that do not cause detectable cell-cycle defects, and it does not require modification of PML by SUMOylation. In addition, PML and PML/RARA carrying mutations previously identified in ATO-resistant APL patients are impeded in their ability to become sequestered within CyPNs. Thus, ATO may inhibit nuclear activities of PML and PML/RARA in postmitotic cells through CyPN-dependent cytoplasmic sequestration.

  17. ARSENIC MINERALS AS INDICATORS OF CONDITIONS OF GOLD DEPOSITION IN CARLIN-TYPE GOLD DEPOSITS.

    USGS Publications Warehouse

    Rytuba, James J.

    1984-01-01

    Arsenic minerals commonly occurring in Carlin-type gold deposits include orpiment and realgar and, more rarely, native arsenic and arsenopyrite. Other arsenic-bearing phases present include arsenian pyrite and stibnite and a number of thallium and mercury sulfides. Under conditions of constant temperature and pressure, the relative stability of arsenic minerals is a function of sulfur activity. At high sulfur activity, orpiment is the stable phase. As sulfur activity is decreased, more sulfur-deficient arsenic phases become stable with the progressive formation of realgar, native arsenic, arsenopyrite, and finally, loellingite at very low sulfur activity. Three univariant equilibrium assemblages: orpiment plus realgar, realgar plus native arsenic and native arsenic plus arsenopyrite are useful indicators of sulfur activity and commonly occur in the epithermal environment.

  18. DNA methylation of heparanase promoter influences its expression and associated with the progression of human breast cancer.

    PubMed

    Jiao, Fei; Bai, Shi-Yu; Ma, Ying; Yan, Zhong-Hai; Yue, Zhen; Yu, Yuan; Wang, Xin; Wang, Juan

    2014-01-01

    Heparanase promotes tumor invasion and metastasis in several malignancies including breast cancer. However, the roles and regulation mechanisms of heparanase during breast cancer progression are still not fully understood. The aim of this study is to determine the differential regulation of heparanase gene expression in specific stages of breast cancer by DNA methylation. We detected levels of heparanase expression and DNA methylation patterns of its promoter in breast cancer cell lines (MCF-7 and MDA-MB-435) and clinical tissues, respectively. It has been observed that heparanase is highly expressed in the invasive MDA-MB-435 cells with low methylation modification in the heparanase promoter. In contrast, lower expression of heparanase in MCF-7 cells is accompanied by higher methylation in the promoter. Treatment of MCF-7 cells with 5-aza-2'-deoxycytidine (5-aza-dC), a potent demethylating agent, results in induction of heparanase expression and higher invasion potential in vitro and leads to an advantage of tumor formation in vivo. In 54 tissue samples, cancer samples at late stages (stage IV) showed the highest heparanase expression accomplished by little DNA methylation. On the contrary, methylation prevalence is highest in normal tissue and inversely correlated with heparanase expression. A significant correlation between DNA methylation and clinical stage was demonstrated (p = 0.012). Collectively, these results demonstrate that DNA methylation play the regulation role in heparanase gene in different stages of breast cancer and present a direct effect on tumor progression.

  19. The -786T>C promoter polymorphism of the NOS3 gene is associated with prostate cancer progression

    PubMed Central

    Marangoni, Karina; Araújo, Thaíse G; Neves, Adriana F; Goulart, Luiz R

    2008-01-01

    Background There is no biological or epidemiological data on the association between NOS3 promoter polymorphisms and prostate cancer. The polymorphisms in the promoter region of NOS3 gene may be responsible for variations in the plasma NO, which may promote cancer progression by providing a selective growth advantage to tumor cells by angiogenic stimulus and by direct DNA damage. Methods This study aimed evaluating the NOS3 promoter polymorphisms by PCR-SSCP and sequencing, associating genotypes and haplotypes with NOS3 expression levels through semi-quantitative RT-PCR, and with PCA3 mRNA detection, a specific tumor biomarker, in the peripheral blood of pre-surgical samples from 177 patients; 83 PCa and 94 BPH. Results Three novel SNPs were identified -764A>G, -714G>T and -649G>A in the NOS3 gene promoter region, which together with the -786T>C generated four haplotypes (N, T, C, A). NOS3 gene expression levels were affected by the -786T>C polymorphism, and there was a 2-fold increase in NOS3 levels favored by the incorporation of each C allele. NOS3 levels higher than 80% of the constitutive gene expression level (B2M) presented a 4-fold increase in PCa occurrence. Conclusion The -786T>C polymorphism was the most important promoter alteration of the NOS3 gene that may affect the PCa progression, but not its occurrence, and the incorporation of the C allele is associated with increased levels of NOS3 transcripts. The NOS3 transcript levels presented a bimodal behavior in tumor development and may be used as a biomarker together with the PCA3 marker for molecular staging of the prostate cancer. PMID:18823560

  20. The -786T>C promoter polymorphism of the NOS3 gene is associated with prostate cancer progression.

    PubMed

    Marangoni, Karina; Araújo, Thaíse G; Neves, Adriana F; Goulart, Luiz R

    2008-09-29

    There is no biological or epidemiological data on the association between NOS3 promoter polymorphisms and prostate cancer. The polymorphisms in the promoter region of NOS3 gene may be responsible for variations in the plasma NO, which may promote cancer progression by providing a selective growth advantage to tumor cells by angiogenic stimulus and by direct DNA damage. This study aimed evaluating the NOS3 promoter polymorphisms by PCR-SSCP and sequencing, associating genotypes and haplotypes with NOS3 expression levels through semi-quantitative RT-PCR, and with PCA3 mRNA detection, a specific tumor biomarker, in the peripheral blood of pre-surgical samples from 177 patients; 83 PCa and 94 BPH. Three novel SNPs were identified -764A>G, -714G>T and -649G>A in the NOS3 gene promoter region, which together with the -786T>C generated four haplotypes (N, T, C, A). NOS3 gene expression levels were affected by the -786T>C polymorphism, and there was a 2-fold increase in NOS3 levels favored by the incorporation of each C allele. NOS3 levels higher than 80% of the constitutive gene expression level (B2M) presented a 4-fold increase in PCa occurrence. The -786T>C polymorphism was the most important promoter alteration of the NOS3 gene that may affect the PCa progression, but not its occurrence, and the incorporation of the C allele is associated with increased levels of NOS3 transcripts. The NOS3 transcript levels presented a bimodal behavior in tumor development and may be used as a biomarker together with the PCA3 marker for molecular staging of the prostate cancer.

  1. Ageing and recurrent episodes of neuroinflammation promote progressive experimental autoimmune encephalomyelitis in Biozzi ABH mice.

    PubMed

    Peferoen, Laura A N; Breur, Marjolein; van de Berg, Sarah; Peferoen-Baert, Regina; Boddeke, Erik H W G M; van der Valk, Paul; Pryce, Gareth; van Noort, Johannes M; Baker, David; Amor, Sandra

    2016-10-01

    Current therapies for multiple sclerosis (MS) reduce the frequency of relapses by modulating adaptive immune responses but fail to limit the irreversible neurodegeneration driving progressive disability. Experimental autoimmune encephalomyelitis (EAE) in Biozzi ABH mice recapitulates clinical features of MS including relapsing-remitting episodes and secondary-progressive disability. To address the contribution of recurrent inflammatory events and ageing as factors that amplify progressive neurological disease, we examined EAE in 8- to 12-week-old and 12-month-old ABH mice. Compared with the relapsing-remitting (RREAE) and secondary progressive (SPEAE) EAE observed in young mice, old mice developed progressive disease from onset (PEAE) associated with pronounced axonal damage and increased numbers of CD3(+) T cells and microglia/macrophages, but not B cells. Whereas the clinical neurological features of PEAE and SPEAE were comparable, the pathology was distinct. SPEAE was associated with significantly reduced perivascular infiltrates and T-cell numbers in the central nervous system (CNS) compared with PEAE and the acute phase of RREAE. In contrast to perivascular infiltrates that declined during progression from RREAE into SPEAE, the numbers of microglia clusters remained constant. Similar to what is observed during MS, the microglia clusters emerging during EAE were associated with axonal damage and oligodendrocytes expressing heat-shock protein B5, but not lymphocytes. Taken together, our data reveal that the course of EAE is dependent on the age of the mice. Younger mice show a relapsing-remitting phase followed by progressive disease, whereas old mice immediately show progression. This indicates that recurrent episodes of inflammation in the CNS, as well as age, contribute to progressive neurological disease. © 2016 John Wiley & Sons Ltd.

  2. Promoting Lifelong Ocean Education-2 Years Later: Charting Progress and Adjusting Course

    NASA Technical Reports Server (NTRS)

    Meeson, Blanche; McDougall, Carrie; Simms, Eric; Walker, Sharon; Keener-Chavis, Paula

    2006-01-01

    Session participants will identify how their regional or national efforts contribute to the overall progress on the education recommendations in the USCOP and the work that remains. They will examine progress, identify shortcomings, and suggest course corrections in current and planned efforts. This session will build upon VADM Lautenbacher's keynote presentation on ocean education. Examples, such as ocean literacy efforts at regional and national levels, will be highlighted to stimulate discussion on progress, challenges, and solutions. Working in small groups, participants will consider actions that they, their organizations, or NMEA might take to further the ocean and aquatic education agenda.

  3. Th17 Cells in Protection from Tumor or Promotion of Tumor Progression

    PubMed Central

    Young, M. Rita I.

    2016-01-01

    The roles of inflammation and inflammatory cells such as Th17 cells in the development and progression of cancer have been extensively studied. However, the results have been varied, with conflicting conclusions. Most studies have focused on changes in inflammatory phenotypes once cancers have developed and disease is progressing. Far fewer studies have looked at the immune phenotypic changes that occur during progression of premalignant lesions to cancer. The impact of inflammation and, in particular, Th17 cells on tumor biology is summarized in this review, with a focus on the differences in the outcomes of studies. Possible explanations for the contradictory conclusions are also suggested. PMID:27453801

  4. Promoting Lifelong Ocean Education-2 Years Later: Charting Progress and Adjusting Course

    NASA Technical Reports Server (NTRS)

    Meeson, Blanche; McDougall, Carrie; Simms, Eric; Walker, Sharon; Keener-Chavis, Paula

    2006-01-01

    Session participants will identify how their regional or national efforts contribute to the overall progress on the education recommendations in the USCOP and the work that remains. They will examine progress, identify shortcomings, and suggest course corrections in current and planned efforts. This session will build upon VADM Lautenbacher's keynote presentation on ocean education. Examples, such as ocean literacy efforts at regional and national levels, will be highlighted to stimulate discussion on progress, challenges, and solutions. Working in small groups, participants will consider actions that they, their organizations, or NMEA might take to further the ocean and aquatic education agenda.

  5. Availability of arsenic in human milk in women and its correlation with arsenic in urine of breastfed children living in arsenic contaminated areas in Bangladesh.

    PubMed

    Islam, Md Rafiqul; Attia, John; Alauddin, Mohammad; McEvoy, Mark; McElduff, Patrick; Slater, Christine; Islam, Md Monirul; Akhter, Ayesha; d'Este, Catherine; Peel, Roseanne; Akter, Shahnaz; Smith, Wayne; Begg, Stephen; Milton, Abul Hasnat

    2014-12-04

    Early life exposure to inorganic arsenic may be related to adverse health effects in later life. However, there are few data on postnatal arsenic exposure via human milk. In this study, we aimed to determine arsenic levels in human milk and the correlation between arsenic in human milk and arsenic in mothers and infants urine. Between March 2011 and March 2012, this prospective study identified a total of 120 new mother-baby pairs from Kashiani (subdistrict), Bangladesh. Of these, 30 mothers were randomly selected for human milk samples at 1, 6 and 9 months post-natally; the same mother baby pairs were selected for urine sampling at 1 and 6 months. Twelve urine samples from these 30 mother baby pairs were randomly selected for arsenic speciation. Arsenic concentration in human milk was low and non-normally distributed. The median arsenic concentration in human milk at all three time points remained at 0.5 μg/L. In the mixed model estimates, arsenic concentration in human milk was non-significantly reduced by -0.035 μg/L (95% CI: -0.09 to 0.02) between 1 and 6 months and between 6 and 9 months. With the progression of time, arsenic concentration in infant's urine increased non-significantly by 0.13 μg/L (95% CI: -1.27 to 1.53). Arsenic in human milk at 1 and 6 months was not correlated with arsenic in the infant's urine at the same time points (r = -0.13 at 1 month and r = -0.09 at 6 month). Arsenite (AsIII), arsenate (AsV), monomethyl arsonic acid (MMA), dimethyl arsinic acid (DMA) and arsenobetaine (AsB) were the constituents of total urinary arsenic; DMA was the predominant arsenic metabolite in infant urine. We observed a low arsenic concentration in human milk. The concentration was lower than the World Health Organization's maximum permissible limit (WHO Permissible Limit 15 μg/kg-bw/week). Our findings support the safety of breastfeeding even in arsenic contaminated areas.

  6. Arsenic removal from water

    DOEpatents

    Moore, Robert C.; Anderson, D. Richard

    2007-07-24

    Methods for removing arsenic from water by addition of inexpensive and commonly available magnesium oxide, magnesium hydroxide, calcium oxide, or calcium hydroxide to the water. The hydroxide has a strong chemical affinity for arsenic and rapidly adsorbs arsenic, even in the presence of carbonate in the water. Simple and commercially available mechanical methods for removal of magnesium hydroxide particles with adsorbed arsenic from drinking water can be used, including filtration, dissolved air flotation, vortex separation, or centrifugal separation. A method for continuous removal of arsenic from water is provided. Also provided is a method for concentrating arsenic in a water sample to facilitate quantification of arsenic, by means of magnesium or calcium hydroxide adsorption.

  7. Arsenic cardiotoxicity: An overview.

    PubMed

    Alamolhodaei, Nafiseh Sadat; Shirani, Kobra; Karimi, Gholamreza

    2015-11-01

    Arsenic, a naturally ubiquitous element, is found in foods and environment. Cardiac dysfunction is one of the major causes of morbidity and mortality in the world. Arsenic exposure is associated with various cardiopathologic effects including ischemia, arrhythmia and heart failure. Possible mechanisms of arsenic cardiotoxicity include oxidative stress, DNA fragmentation, apoptosis and functional changes of ion channels. Several evidences have shown that mitochondrial disruption, caspase activation, MAPK signaling and p53 are the pathways for arsenic induced apoptosis. Arsenic trioxide is an effective and potent antitumor agent used in patients with acute promyelocytic leukemia and produces dramatic remissions. As2O3 administration has major limitations such as T wave changes, QT prolongation and sudden death in humans. In this review, we discuss the underlying pathobiology of arsenic cardiotoxicity and provide information about cardiac health effects associated with some medicinal plants in arsenic toxicity. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Arsenic: homicidal intoxication

    SciTech Connect

    Massey, E.W.; Wold, D.; Heyman, A.

    1984-07-01

    Arsenic-induced deaths have been known to occur from accidental poisoning, as a result of medical therapy, and from intentional poisonings in homicide and suicide. Twenty-eight arsenic deaths in North Carolina from 1972 to 1982 included 14 homicides and seven suicides. In addition, 56 hospitalized victims of arsenic poisoning were identified at Duke Medical Center from 1970 to 1980. Four case histories of arsenic poisoning in North Carolina are presented and clinical manifestations are discussed. In view of the continued widespread use of arsenic in industry and agriculture, and its ubiquity in the environment, arsenic poisoning will continue to occur. A need for knowledge of its toxicity and of the clinical manifestations of acute and chronic arsenic poisoning will also continue.

  9. Arsenic geochemistry and health.

    PubMed

    Duker, Alfred A; Carranza, E J M; Hale, Martin

    2005-07-01

    Arsenic occurs naturally in the earth's crust and is widely distributed in the environment. Natural mineralization and activities of microorganisms enhance arsenic mobilization in the environment but human intervention has exacerbated arsenic contamination. Although arsenic is useful for industrial, agricultural, medicinal and other purposes, it exerts a toxic effect in a variety of organisms, including humans. Arsenic exposure may not only affect and disable organs of the body, especially the skin, but may also interfere with the proper functioning of the immune system. This paper, therefore, generally highlights the toxic effects of arsenic as well as its mobilization in the natural environment and possible controls. It also briefly attempts to outline the impact of arsenic on the immune system, whose alteration could lead to viral/bacterial infections.

  10. PRL-3 Promotes the Malignant Progression of Melanoma via Triggering Dephosphorylation and Cytoplasmic Localization of NHERF1.

    PubMed

    Fang, Xian-Ying; Song, Ran; Chen, Wei; Yang, Yuan-Yuan; Gu, Yan-Hong; Shu, Yong-Qian; Wu, Xu-Dong; Wu, Xue-Feng; Sun, Yang; Shen, Yan; Xu, Qiang

    2015-09-01

    Phosphatase of regenerating liver-3 (PRL-3) has been reported to have a critical role in metastatic progression of cancers. Here, we investigate how PRL-3 increases the malignant degree of melanoma cells. The expression of PRL-3 increased gradually during the malignant progression of melanoma. The phosphorylation of Akt was elevated in highly malignant melanoma cells, which was accompanied by a decrease in nuclear phosphatase and tensin homolog (PTEN). The phosphorylation of NHERF1 in the serine site was regulated by PRL-3 and showed cytoplasmic translocation upon dephosphorylation, which resulted in a decrease in nuclear PTEN. The co-translocation of NHERF1 and PTEN from the nucleus to the cytoplasm was observed during the malignant progression of melanoma cells. Tumor growth was inhibited significantly, and the survival was prolonged upon knockdown of cytoplasmic NHERF1 in B16BL6 cells prior to the inoculation into mice. Taken together, to our knowledge previously unreported, we have identified NHERF1 as a potential substrate of PRL-3. Its phosphorylation status as well as its change in cellular localization and association with PTEN correlated with the malignant progression of melanoma. Our data provide an explanation for how PRL-3 promotes the malignant progression of melanoma, as well as a diagnostic marker or therapeutic target for malignant melanoma.

  11. Androgen receptor (AR) suppresses miRNA-145 to promote renal cell carcinoma (RCC) progression independent of VHL status.

    PubMed

    Chen, Yuan; Sun, Yin; Rao, Qun; Xu, Hua; Li, Lei; Chang, Chawnshang

    2015-10-13

    Mutational inactivation of the VHL tumor suppressor plays key roles in the development of renal cell carcinoma (RCC), and mutated VHL-mediated VEGF induction has become the main target for the current RCC therapy. Here we identified a signal pathway of VEGF induction by androgen receptor (AR)/miRNA-145 as a new target to suppress RCC progression. Mechanism dissection revealed that AR might function through binding to the androgen receptor element (ARE) located on the promoter region of miRNA-145 to suppress p53's ability to induce expression of miRNA-145 that normally suppresses expression of HIF2α/VEGF/MMP9/CCND1. Suppressing AR with AR-shRNA or introducing exogenous miRNA-145 mimic can attenuate RCC progression independent of VHL status. MiR-145 mimic in preclinical RCC orthotopic xenograft mouse model revealed its efficacy in suppression of RCC progression. These results together identified signals by AR-suppressed miRNA-145 as a key player in the RCC progression via regulating HIF2α/VEGF/MMP9/CCND1 expression levels. Blockade of the newly identified signal by AR inhibition or miRNA-145 mimics has promising therapeutic benefit to suppress RCC progression.

  12. Androgen receptor (AR) suppresses miRNA-145 to promote renal cell carcinoma (RCC) progression independent of VHL status

    PubMed Central

    Chen, Yuan; Sun, Yin; Rao, Qun; Xu, Hua; Li, Lei; Chang, Chawnshang

    2015-01-01

    Mutational inactivation of the VHL tumor suppressor plays key roles in the development of renal cell carcinoma (RCC), and mutated VHL-mediated VEGF induction has become the main target for the current RCC therapy. Here we identified a signal pathway of VEGF induction by androgen receptor (AR)/miRNA-145 as a new target to suppress RCC progression. Mechanism dissection revealed that AR might function through binding to the androgen receptor element (ARE) located on the promoter region of miRNA-145 to suppress p53's ability to induce expression of miRNA-145 that normally suppresses expression of HIF2α/VEGF/MMP9/CCND1. Suppressing AR with AR-shRNA or introducing exogenous miRNA-145 mimic can attenuate RCC progression independent of VHL status. MiR-145 mimic in preclinical RCC orthotopic xenograft mouse model revealed its efficacy in suppression of RCC progression. These results together identified signals by AR-suppressed miRNA-145 as a key player in the RCC progression via regulating HIF2α/VEGF/MMP9/CCND1 expression levels. Blockade of the newly identified signal by AR inhibition or miRNA-145 mimics has promising therapeutic benefit to suppress RCC progression. PMID:26304926

  13. Model systems for defining initiation, promotion, and progression of skin neoplasms.

    PubMed

    Boutwell, R K

    1989-01-01

    A number of items that must be considered in designing and choosing a suitable model for initiation and promotion testing have been described. Although these items may seem complex, tests for initiation and promotion are, in reality, quite simple and provide a rational approach to carcinogen testing. Several tests have been described here and Eastin, elsewhere in this book, describes the validation of a simple and highly recommended test. The processes involved in initiation and promotion are qualitatively different. The criteria for concern about possible human hazards as well as for regulation of initiators and promoters should be based on these qualitative differences. Realistic appraisal of the risk must be based on the level and nature of the potential hazard. In particular, it must be recognized that promoting action is reversible, that a threshold exists, and that promotion is readily inhibited. Therefore, animal tests that differentiate between potential initiators and promoters are essential to enable a logical assessment of human risk and the implementation of appropriate protective measures based on scientific facts.

  14. PUMA promotes apoptosis of hematopoietic progenitors driving leukemic progression in a mouse model of myelodysplasia.

    PubMed

    Guirguis, A A; Slape, C I; Failla, L M; Saw, J; Tremblay, C S; Powell, D R; Rossello, F; Wei, A; Strasser, A; Curtis, D J

    2016-06-01

    Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis with resultant cytopenias. Increased apoptosis and aberrantly functioning progenitors are thought to contribute to this phenotype. As is the case for other malignancies, overcoming apoptosis is believed to be important in progression toward acute myeloid leukemia (AML). Using the NUP98-HOXD13 (NHD13) transgenic mouse model of MDS, we previously reported that overexpression of the anti-apoptotic protein BCL2, blocked apoptosis and improved cytopenias, paradoxically, delaying leukemic progression. To further understand this surprising result, we examined the role of p53 and its pro-apoptotic effectors, PUMA and NOXA in NHD13 mice. The absence of p53 or PUMA but not NOXA reduced apoptosis and expanded the numbers of MDS-repopulating cells. Despite a similar effect on apoptosis and cell numbers, the absence of p53 and PUMA had diametrically opposed effects on progression to AML: absence of p53 accelerated leukemic progression, while absence of PUMA significantly delayed progression. This may be explained in part by differences in cellular responses to DNA damage. The absence of p53 led to higher levels of γ-H2AX (indicative of persistent DNA lesions) while PUMA-deficient NHD13 progenitors resolved DNA lesions in a manner comparable to wild-type cells. These results suggest that targeting PUMA may improve the cytopenias of MDS without a detrimental effect on leukemic progression thus warranting further investigation.

  15. Estrogen related receptor alpha in castration-resistant prostate cancer cells promotes tumor progression in bone

    PubMed Central

    Delliaux, Carine; Gervais, Manon; Kan, Casina; Benetollo, Claire; Pantano, Francesco; Vargas, Geoffrey; Bouazza, Lamia; Croset, Martine; Bala, Yohann; Leroy, Xavier; Rosol, Thomas J; Rieusset, Jennifer; Bellahcène, Akeila; Castronovo, Vincent; Aubin, Jane E; Clézardin, Philippe; Duterque-Coquillaud, Martine; Bonnelye, Edith

    2016-01-01

    Bone metastases are one of the main complications of prostate cancer and they are incurable. We investigated whether and how estrogen receptor-related receptor alpha (ERRα) is involved in bone tumor progression associated with advanced prostate cancer. By meta-analysis, we first found that ERRα expression is correlated with castration-resistant prostate cancer (CRPC), the hallmark of progressive disease. We then analyzed tumor cell progression and the associated signaling pathways in gain-of-function/loss-of-function CRPC models in vivo and in vitro. Increased levels of ERRα in tumor cells led to rapid tumor progression, with both bone destruction and formation, and direct impacts on osteoclasts and osteoblasts. VEGF-A, WNT5A and TGFβ1 were upregulated by ERRα in tumor cells and all of these factors also significantly and positively correlated with ERRα expression in CRPC patient specimens. Finally, high levels of ERRα in tumor cells stimulated the pro-metastatic factor periostin expression in the stroma, suggesting that ERRα regulates the tumor stromal cell microenvironment to enhance tumor progression. Taken together, our data demonstrate that ERRα is a regulator of CRPC cell progression in bone. Therefore, inhibiting ERRα may constitute a new therapeutic strategy for prostate cancer skeletal-related events. PMID:27776343

  16. ARSENIC (+3 OXIDATION STATE) METHYLTRANSFERASE AND THE METHYLATION OF ARSENICALS

    EPA Science Inventory

    Metabolic conversion of inorganic arsenic into methylated products is a multistep process that yields mono, di, and trimethylated arsenicals. In recent years, it has become apparent that formation of methylated metabolites of inorganic arsenic is not necessarily a detoxification...

  17. ARSENIC (+3 OXIDATION STATE) METHYLTRANSFERASE AND THE METHYLATION OF ARSENICALS

    EPA Science Inventory

    Metabolic conversion of inorganic arsenic into methylated products is a multistep process that yields mono, di, and trimethylated arsenicals. In recent years, it has become apparent that formation of methylated metabolites of inorganic arsenic is not necessarily a detoxification...

  18. Reduction and Coordination of Arsenic in Indian Mustard1

    PubMed Central

    Pickering, Ingrid J.; Prince, Roger C.; George, Martin J.; Smith, Robert D.; George, Graham N.; Salt, David E.

    2000-01-01

    The bioaccumulation of arsenic by plants may provide a means of removing this element from contaminated soils and waters. However, to optimize this process it is important to understand the biological mechanisms involved. Using a combination of techniques, including x-ray absorption spectroscopy, we have established the biochemical fate of arsenic taken up by Indian mustard (Brassica juncea). After arsenate uptake by the roots, possibly via the phosphate transport mechanism, a small fraction is exported to the shoot via the xylem as the oxyanions arsenate and arsenite. Once in the shoot, the arsenic is stored as an AsIII-tris-thiolate complex. The majority of the arsenic remains in the roots as an AsIII-tris-thiolate complex, which is indistinguishable from that found in the shoots and from AsIII-tris-glutathione. The thiolate donors are thus probably either glutathione or phytochelatins. The addition of the dithiol arsenic chelator dimercaptosuccinate to the hydroponic culture medium caused a 5-fold-increased arsenic level in the leaves, although the total arsenic accumulation was only marginally increased. This suggests that the addition of dimercaptosuccinate to arsenic-contaminated soils may provide a way to promote arsenic bioaccumulation in plant shoots, a process that will be essential for the development of an efficient phytoremediation strategy for this element. PMID:10759512

  19. Cancer-associated fibroblasts promote the progression of endometrial cancer via the SDF-1/CXCR4 axis.

    PubMed

    Teng, Fei; Tian, Wen-Yan; Wang, Ying-Mei; Zhang, Yan-Fang; Guo, Fei; Zhao, Jing; Gao, Chao; Xue, Feng-Xia

    2016-02-06

    Cancer-associated fibroblasts (CAFs) are believed to play an essential role in cancer initiation and development. However, little research has been undertaken to evaluate the role of CAFs in endometrial cancer (EC) progression. We aim to detect the functional contributions of CAFs to promote progression of EC. Stromal fibroblasts were isolated from endometrioid adenocarcinomas and normal endometrial tissues. The conditioned media of cultured CAFs and normal fibroblasts (NFs) were collected to detect the level of stromal cell-derived factor-1alpha (SDF-1α), macrophage chemoattractant protein-1 (MCP-1), migration inhibitory factor (MIF), colony stimulating factor-1 (CSF-1), and interleukin-1 (IL-1) by ELISA. The CAFs or NFs were cocultured with EC cell lines to determine the proliferation, migration, and invasion by MTT assays and transwell chambers. Xenograft models were used to observe tumor growth. Matrix metalloproteinases (MMP)-2 and MMP-9 activity was evaluated by zymography. AMD3100 (a chemokine receptor 4 (CXCR4) antagonist) was used to block the SDF-1/CXCR4 axis. Neutralizing antibodies were used to detect PI3K/Akt and MAPK/Erk pathways by western blotting. SDF-1α and CXCR4 expressions were analyzed in xenotransplanted tumors and 348 cases by immunohistochemistry. CAFs promoted proliferation, migration, and invasion as well as in vivo tumorigenesis of admixed EC cells significantly more than NFs by secreting SDF-1α. These effects were significantly inhibited by AMD3100. CAFs promoted EC progression via the SDF-1α/CXCR4 axis to activate the PI3K/Akt and MAPK/Erk signalings in a paracrine-dependent manner or increase MMP-2 and MMP-9 secretion in an autocrine-dependent manner. SDF-1α and CXCR4 expression upregulation accompanied clinical EC development and progression. High SDF-1α expression levels were associated with deep myometrial invasion, lymph node metastasis, and poor prognosis in EC. Our data indicated that CAFs derived from EC tissues promoted

  20. Tetra-arsenic tetra-sulfide (As4S 4) promotes apoptosis in retinoid acid -resistant human acute promyelocytic leukemic NB4-R1 cells through downregulation of SET protein.

    PubMed

    Liu, Yanfeng; He, Pengcheng; Liu, Feng; Zhou, Naicen; Cheng, Xiaoyan; Shi, Lili; Zhu, Huachao; Zhao, Jing; Wang, Yuan; Zhang, Mei

    2014-04-01

    Tetra-arsenic tetra-sulfide (As4S4) is an arsenic compound with antitumor activity, especially in acute promyelocytic leukemia (APL) that are resistant to retinoic acid (RA). Although recent studies have revealed that the therapeutic action of As4S4 is closely associated with the induction of cellular apoptosis, the exact molecular mechanism underlying this action in RA-resistant APL remains to be clarified. In this study, we found that As4S4-induced apoptosis was accompanied by reduced mRNA and protein expression of SET gene in RA-resistant NB4-R1 cells. Moreover, RNAi knockdown of SET gene further promoted As4S4-induced apoptosis, while SET overexpression recovered the cell viability, suggesting that As4S4 induces apoptosis through the reduction of SET protein in NB4-R1 cells. We also observed that the knockdown of SET gene resulted in the upregulation of protein phosphatase 2 (PP2A) expression and the downregulation of promyelocytic leukemia and retinoic acid receptor α fusion gene (PML-RARα) expression, which were enhanced by As4S4 treatments. By contrast, overexpression of SET gene resulted in PP2A downregulation and PML-RARα upregulation, which were abolished by As4S4 pretreatment. Since PP2A is a proapoptotic factor and PML-RARα is an antiapoptotic factor, our results suggest that As4S4-induced apoptosis in RA-resistant NB4-R1 cells is through the downregulation of SET protein expression, which, in turn, increases PP2A and reduces PML-RARα expressions to lead to cell apoptosis.

  1. Tissue damage-associated "danger signals" influence T-cell responses that promote the progression of preneoplasia to cancer.

    PubMed

    He, Ying; Zha, Jikun; Wang, Yamin; Liu, Wenhua; Yang, Xuanming; Yu, Ping

    2013-01-15

    T-cell responses may be shaped by sterile "danger signals" that are constituted by damage-associated molecular patterns (DAMP). However, whether and what type of adaptive immune responses are triggered in vivo by DAMPs induced by tumor progression are not well characterized. In this study, we report that the production of HMGB1, an established DAMP released by dying cells, was critical for tumor progression in an established mouse model of prostate cancer. HMGB1 was required for the activation and intratumoral accumulation of T cells that expressed cytokine lymphotoxinα(1)β(2) (LT) on their surface. Intriguingly, these tumor-activated T cells recruited macrophages to the lesion and were essential to promote the preneoplasia to invasive carcinoma in an LTβ receptor (LTβR)-dependent manner. Taken together, our findings suggest that the release of HMGB1 as an endogenous danger signal is important for priming an adaptive immune response that promotes malignant progression, with implications for cancer prevention and therapy.

  2. Promotion of progressive mobility activities with ventricular assist and extracorporeal membrane oxygenation devices in a cardiothoracic intensive care unit.

    PubMed

    Chavez, Jennifer; Bortolotto, Shannon Johnson; Paulson, Martha; Huntley, Nicole; Sullivan, Breandan; Babu, Ashok

    2015-01-01

    Progressive mobility (PM) is a clinical intervention that influences complications experienced throughout critical illness. Early PM is a relevant topic in critical care practice literature and was principle to introducing a PM care guideline in an acute cardiothoracic/cardiovascular intensive care unit. A noted challenge in the cardiothoracic/cardiovascular intensive care unit is caring for acute cardiac and pulmonary failure. Often, these patients require prolonged mechanical circulatory support via extracorporeal mechanical oxygenation or a ventricular assist device. This article describes safe and effective progressive mobilization for patients experiencing MCS in a case study format. This article also highlights how a multidisciplinary clinical team supports mobility practice in specific critical care roles. Post-intensive care syndrome is composed of various health implications that occur following critical illness. Recent data suggest improved care outcomes when critically ill patients are awake and participate in active physical rehabilitation as early as clinically possible. The case studies presented indicate that mobility, to the point of ambulation, is a feasible clinical expectation when patients present with substantial acute respiratory and cardiac failure and are managed with MCS. Development of a PM guideline uses a critical appraisal of practice evidence, highlights multidisciplinary collaboration, and increases progression to ambulation. Mobility for complex patients is attainable, as demonstrated in the postguideline outcomes. The PM guideline provides structure to primary caregivers and promotes safe practices. The PM guideline facilitates an advanced level of care, promotes safe practices, champions holistic recovery, and encourages active patient involvement, goals satisfying to both patients and staff.

  3. Epigenetic silencing of HIC1 promotes epithelial-mesenchymal transition and drives progression in esophageal squamous cell carcinoma

    PubMed Central

    Li, Pei; Liu, Xiang; Dong, Zi-Ming; Ling, Zhi-Qiang

    2015-01-01

    Downregulation of the novel tumor suppressor gene HIC1 (hypermethylated in cancer 1) occurs frequently in various tumors where it causes tumor progression and metastasis. In this study, we investigated a role of HIC1 in esophageal squamous cell carcinoma (ESCC) and the underlying mechanisms. Downregulation of HIC1 occurred in approximately 70% of primary ESCCs at both mRNA and protein level where it was associated significantly with vascular invasion, advanced clinical stage, lymph node metastasis, and poor disease free survival (DFS). The promoter methylation analyses suggested that loss of HIC1 expression was mediated by epigenetic mechanisms. Functional studies established that ectopic re-expression of HIC1 in ESCC cells inhibited cell proliferation, clonogenicity, cell motility, tumor formation and epithelial-mesenchymal transition (EMT). Our results decipher the mechanism through which HIC1 deficiency induce ESCC cells to undergo EMT and promote tumor progression and metastasis through activation of EphA2 signaling pathway. Together, loss of the regulation of EphA2 pathway through HIC1 epigenetic silencing could be an important mechanism in the ESCC progression. We identify a novel pathway that linking HIC1 downregulation to EphA2-inducing EMT in ESCC cells and may shed light on the development of novel anti-tumor therapeutics. PMID:26510908

  4. Identification of an arsenic resistance and arsenic-sensing system in Campylobacter jejuni.

    PubMed

    Wang, Liping; Jeon, Byeonghwa; Sahin, Orhan; Zhang, Qijing

    2009-08-01

    Arsenic is commonly present in the natural environment and is also used as a feed additive for animal production. Poultry is a major reservoir for Campylobacter jejuni, a major food-borne human pathogen causing gastroenteritis. It has been shown that Campylobacter isolates from poultry are highly resistant to arsenic compounds, but the molecular mechanisms responsible for the resistance have not been determined, and it is unclear if the acquired arsenic resistance affects the susceptibility of Campylobacter spp. to other antimicrobials. In this study, we identified a four-gene operon that contributes to arsenic resistance in Campylobacter. This operon encodes a putative membrane permease (ArsP), a transcriptional repressor (ArsR), an arsenate reductase (ArsC), and an efflux protein (Acr3). PCR analysis of various clinical C. jejuni isolates indicated a significant association of this operon with elevated resistance to arsenite and arsenate. Gene-specific mutagenesis confirmed the role of the ars operon in conferring arsenic resistance. It was further shown that this operon is subject to regulation by ArsR, which directly binds to the ars promoter and inhibits the transcription of the operon. Arsenite inhibits the binding of ArsR to the ars promoter DNA and induces the expression of the ars genes. Mutation of the ars genes did not affect the susceptibility of C. jejuni to commonly used antibiotics. These results identify the ars operon as an important mechanism for arsenic resistance and sensing in Campylobacter.

  5. Exosomes derived from gastric cancer cells activate NF-κB pathway in macrophages to promote cancer progression.

    PubMed

    Wu, Lijun; Zhang, Xu; Zhang, Bin; Shi, Hui; Yuan, Xiao; Sun, Yaoxiang; Pan, Zhaoji; Qian, Hui; Xu, Wenrong

    2016-09-01

    Exosomes are nano-sized membrane vesicles secreted by both normal and cancer cells. Emerging evidence indicates that cancer cells derived exosomes contribute to cancer progression through the modulation of tumor microenvironment. However, the effects of exosomes derived from gastric cancer cells on macrophages are not well understood. In this study, we investigated the biological role of gastric cancer cells derived exosomes in the activation of macrophages. We demonstrated that gastric cancer cells derived exosomes activated macrophages to express increased levels of proinflammatory factors, which in turn promoted tumor cell proliferation and migration. In addition, gastric cancer cells derived exosomes remarkably upregulated the phosphorylation of NF-κB in macrophages. Inhibiting the activation of NF-κB reversed the upregulation of proinflammatory factors in macrophages and blocked their promoting effects on gastric cancer cells. Moreover, we found that gastric cancer cells derived exosomes could also activate macrophages from human peripheral blood monocytes through the activation of NF-κB. In conclusion, our results suggest that gastric cancer cells derived exosomes stimulate the activation of NF-κB pathway in macrophages to promote cancer progression, which provides a potential therapeutic approach for gastric cancer by interfering with the interaction between exosomes and macrophages in tumor microenvironment.

  6. A Salt-Induced Reno-Cerebral Reflex Activates Renin-Angiotensin Systems and Promotes CKD Progression

    PubMed Central

    Cao, Wei; Li, Aiqing; Wang, Liangliang; Zhou, Zhanmei; Su, Zhengxiu; Bin, Wei; Wilcox, Christopher S.

    2015-01-01

    Salt intake promotes progression of CKD by uncertain mechanisms. We hypothesized that a salt-induced reno-cerebral reflex activates a renin-angiotensin axis to promote CKD. Sham-operated and 5/6-nephrectomized rats received a normal-salt (0.4%), low-salt (0.02%), or high-salt (4%) diet for 2 weeks. High salt in 5/6-nephrectomized rats increased renal NADPH oxidase, inflammation, BP, and albuminuria. Furthermore, high salt activated the intrarenal and cerebral, but not the systemic, renin-angiotensin axes and increased the activity of renal sympathetic nerves and neurons in the forebrain of these rats. Renal fibrosis was increased 2.2-fold by high versus low salt, but intracerebroventricular tempol, losartan, or clonidine reduced this fibrosis by 65%, 69%, or 59%, respectively, and renal denervation or deafferentation reduced this fibrosis by 43% or 38%, respectively (all P<0.05). Salt-induced fibrosis persisted after normalization of BP with hydralazine. These data suggest that the renal and cerebral renin-angiotensin axes are interlinked by a reno-cerebral reflex that is activated by salt and promotes oxidative stress, fibrosis, and progression of CKD independent of BP. PMID:25635129

  7. Long noncoding RNA PVT1 promotes cervical cancer progression through epigenetically silencing miR-200b.

    PubMed

    Zhang, Shaorong; Zhang, Guanli; Liu, Jingying

    2016-08-01

    Long noncoding RNA PVT1 has been reported to be dysregulated and play vital roles in a variety of cancers. However, the functions and molecular mechanisms of PVT1 in cervical cancer remain unclear. The objective of this study was to investigate the expression, clinical significance, biological roles, and underlying functional mechanisms of PVT1 in cervical cancer. Our results revealed that PVT1 is upregulated in cervical cancer tissues. Enhanced expression of PVT1 is associated with larger tumor size, advanced International Federation of Gynecology and Obstetrics stage, and poor prognosis of cervical cancer patients. Using gain-of-function and loss-of-function approaches, we demonstrated that overexpression of PVT1 promotes cervical cancer cells proliferation, cell cycle progression and migration, and depletion of PVT1 inhibits cervical cancer cell proliferation, cell cycle progression, and migration. Mechanistically, we verified that PVT1 binds to EZH2, recruits EZH2 to the miR-200b promoter, increases histone H3K27 trimethylation level on the miR-200b promoter, and inhibits miR-200b expression. Furthermore, the effects of PVT1 on cervical cell proliferation and migration depend upon silencing of miR-200b. Taken together, our findings confirmed that PVT1 functions as an oncogene in cervical cancer and indicated that PVT1 is not only an important prognostic marker, but also a potential therapy target for cervical cancer.

  8. Evidence for arsenic essentiality.

    PubMed

    Uthus, E O

    1992-06-01

    Although numerous studies with rats, hamsters, minipigs, goats and chicks have indicated that arsenic is an essential nutrient, the physiological role of arsenic is open to conjecture. Recent studies have suggested that arsenic has a physiological role that affects the formation of various metabolites of methionine metabolism including taurine and the polyamines. The concentration of plasma taurine is decreased in arsenic-deprived rats and hamsters. The hepatic concentration of polyamines and the specific activity of an enzyme necessary for the synthesis of spermidine and spermine, S-adenosylmethionine decarboxylase, are also decreased in arsenic-deprived rats. Thus, evidence has been obtained which indicates that arsenic is of physiological importance, especially when methionine metabolism is stressed (e.g. pregnancy, lactation, methionine deficiency, vitamin B6 deprivation). Any possible nutritional requirement by humans can be estimated only by using data from animal studies. The arsenic requirement for growing chicks and rats has been suggested to be near 25 ng g(-1) diet. Thus, a possible human requirement is 12 μg day(-1). The reported arsenic content of diets from various parts of the world indicates that the average intake of arsenic is in the range of 12-40 μg. Fish, grain and cereal products contribute most arsenic to the diet.

  9. Development and Use of a Tool to Guide Junior Faculty in Their Progression Toward Promotion and Tenure

    PubMed Central

    Garand, Linda; Matthews, Judith T.; Courtney, Karen L.; Davies, Marilyn; Lingler, Jennifer H.; Schlenk, Elizabeth A.; Yang, Kyeongra; Bender, Catherine M.; Burke, Lora E.

    2011-01-01

    Junior faculty have multiple roles and need to participate in a variety of activities that increase their likelihood of achieving promotion and tenure. Yet, these faculty often struggle when deciding how and when to expend effort along their career trajectory. In response to the need for structured guidance when setting priorities and making decisions about time management, faculty from a school of nursing at a research university have developed and begun to use a faculty progression tool. Introduced during orientation, this tool helps junior faculty weigh the relative importance of engaging in specific activities by offering a time frame and suggestions for prioritizing and pacing efforts to accomplish critical milestones. Although primarily aimed at tenure stream faculty in a research-intensive environment, this faculty progression tool serves as a model that may be modified for environments with less focus on research. Likewise, it may provide a foundation for development of a similar tool for nontenure stream faculty. PMID:20637442

  10. Increased Tumor Necrosis Factor (TNF)-α and Its Promoter Polymorphisms Correlate with Disease Progression and Higher Susceptibility towards Vitiligo

    PubMed Central

    Laddha, Naresh C.; Dwivedi, Mitesh; Begum, Rasheedunnisa

    2012-01-01

    Abstract Tumor Necrosis Factor (TNF)-α, is a paracrine inhibitor of melanocytes, which plays a critical role in the pathogenesis of several autoimmune diseases including vitiligo, as abnormal immune responses have frequently been observed in vitiligo patients. Moreover, vitiligo patients show higher lesion levels of TNF-α. Genetic polymorphisms in the promoter region of TNF-α are involved in the regulation of its expression. The present study explores TNF-α promoter polymorphisms and correlates them with TNF-α transcript and protein levels in vitiligo patients and controls of Gujarat along with its effect on disease onset and progression. PCR-RFLP technique was used for genotyping of these polymorphisms in 977 vitiligo patients and 990 controls. TNF-α transcript and protein levels were measured by Real time PCR and ELISA respectively. The genotype and allele frequencies for the investigated polymorphisms were significantly associated with vitiligo patients. The study revealed significant increase in TNF-α transcript and protein levels in vitiligo patients compared to controls. In particular, haplotypes: AATCC, AACCT, AGTCT, GATCT, GATCC and AGCCT were found to increase the TNF-α levels in vitiligo patients. Analysis of TNF-α levels based on the gender and disease progression suggests that female patients and patients with active vitiligo had higher levels of TNF-α. Also, the TNF-α levels were high in patients with generalized vitiligo as compared to localized vitiligo. Age of onset analysis of the disease suggests that the haplotypes: AACAT, AACCT, AATCC and AATCT had a profound effect in the early onset of the disease. Moreover, the analysis suggests that female patients had an early onset of vitiligo. Overall, our results suggest that TNF-α promoter polymorphisms may be genetic risk factors for susceptibility and progression of the disease. The up-regulation of TNF-α transcript and protein levels in individuals with susceptible haplotypes advocates

  11. Integrated genomic analysis of colorectal cancer progression reveals activation of EGFR through demethylation of the EREG promoter

    PubMed Central

    Qu, X; Sandmann, T; Frierson, H; Fu, L; Fuentes, E; Walter, K; Okrah, K; Rumpel, C; Moskaluk, C; Lu, S; Wang, Y; Bourgon, R; Penuel, E; Pirzkall, A; Amler, L; Lackner, M R; Tabernero, J; Hampton, G M; Kabbarah, O

    2016-01-01

    Key molecular drivers that underlie transformation of colonic epithelium into colorectal adenocarcinoma (CRC) are well described. However, the mechanisms through which clinically targeted pathways are activated during CRC progression have yet to be elucidated. Here, we used an integrative genomics approach to examine CRC progression. We used laser capture microdissection to isolate colonic crypt cells, differentiated surface epithelium, adenomas, carcinomas and metastases, and used gene expression profiling to identify pathways that were differentially expressed between the different cell types. We identified a number of potentially important transcriptional changes in developmental and oncogenic pathways, and noted a marked upregulation of EREG in primary and metastatic cancer cells. We confirmed this pattern of gene expression by in situ hybridization and observed staining consistent with autocrine expression in the tumor cells. Upregulation of EREG during the adenoma–carcinoma transition was associated with demethylation of two key sites within its promoter, and this was accompanied by an increase in the levels of epidermal growth factor receptor (EGFR) phosphorylation, as assessed by reverse-phase protein analysis. In CRC cell lines, we demonstrated that EREG demethylation led to its transcriptional upregulation, higher levels of EGFR phosphorylation, and sensitization to EGFR inhibitors. Low levels of EREG methylation in patients who received cetuximab as part of a phase II study were associated with high expression of the ligand and a favorable response to therapy. Conversely, high levels of promoter methylation and low levels of EREG expression were observed in tumors that progressed after treatment. We also noted an inverse correlation between EREG methylation and expression levels in several other cancers, including those of the head and neck, lung and bladder. Therefore, we propose that upregulation of EREG expression through promoter demethylation

  12. USP39, a direct target of microRNA-133a, promotes progression of pancreatic cancer via the AKT pathway.

    PubMed

    Cai, Jing; Liu, Tiande; Huang, Peng; Yan, Wei; Guo, Changkuo; Xiong, Le; Liu, Anwen

    2017-04-22

    Ubiquitin specific protease 39 (USP39) is one of the deubiquitinating enzymes without ubiquitin protease activity, which has been implicated in the progression of several cancers. However, the role of USP39 in pancreatic cancer (PC) is largely unknown. In present study, we found that USP39 expression was elevated in PC tissues than adjacent non-tumor tissues. Importantly, we demonstrated that overexpression of USP39 is closely correlated with tumor progression and poor survival in PC patients. Furthermore, high USP39 expression was observed in PC cell lines and ectopic expression of USP39 significantly enhanced in vitro cell proliferation and promoted in vivo tumor growth, whereas silencing USP39 suppressed growth of PC cells. Besides, our experimental data revealed that knockdown of USP39 induced cell apoptosis through inhibition of AKT signaling pathway in PC cells. Moreover, USP39 was a direct target of miR-133a, a microRNA that has been reported to be involved in progression of PC. Taken together, our data provide a novel PC regulatory axis that is miR-133a/USP39, the dysfunction of which drives diverse aspects of the progression of PC.

  13. Stanniocalcin-2 (STC2): A potential lung cancer biomarker promotes lung cancer metastasis and progression.

    PubMed

    Na, Sang-su; Aldonza, Mark Borris; Sung, Hye-Jin; Kim, Yong-In; Son, Yeon Sung; Cho, Sukki; Cho, Je-Yoel

    2015-06-01

    The homodimeric glycoprotein, stanniocalcin 2 (STC2) is previously known to be involved in the regulation of calcium and phosphate transport in the kidney and also reported to play multiple roles in several cancers. However, its function and clinical significance in lung cancer have never been reported and still remain uncertain. Here, we investigated the possibility of STC2 as a lung cancer biomarker and identified its potential role in lung cancer cell growth, metastasis and progression. Proteomic analysis of secretome of primary cultured lung cancer cells revealed higher expression of STC2 in cancers compared to that of adjacent normal cells. RT-PCR and Western blot analyses showed higher mRNA and protein expressions of STC2 in lung cancer tissues compared to the adjacent normal tissues. Knockdown of STC2 in H460 lung cancer cells slowed down cell growth progression and colony formation. Further analysis revealed suppression of migration, invasion and delayed G0/G1 cell cycle progression in the STC2 knockdown cells. STC2 knockdown also attenuated the H202-induced oxidative stress on H460 cell viability with a subsequent increase in intracellular ROS levels, which suggest a protective role of STC2 in redox regulatory system of lung cancer. These findings suggest that STC2 can be a potential lung cancer biomarker and plays a positive role in lung cancer metastasis and progression. This article is part of a Special Issue entitled: Medical Proteomics. Copyright © 2015. Published by Elsevier B.V.

  14. Factors that Promote Progression in Schools Functioning as Professional Learning Community

    ERIC Educational Resources Information Center

    Leclerc, Martine; Moreau, Andre C.; Dumouchel, Catherine; Sallafranque-St-Louis, Francois

    2012-01-01

    The purpose of this research is to identify factors that influence the functioning of a school working as a Professional Learning Community (PLC) and to analyze the links between these factors and the school's progression. This research was developed within the context of an interpretative research paradigm. The primary data collection tool…

  15. Labor Unions as a Means of Promoting Leadership and Black Progress.

    ERIC Educational Resources Information Center

    Stepp, Marc

    1985-01-01

    Describes Black participation in the history, governance, and activities of the United Automobile Workers Union. Calls for organized labor in general to support more actively equal employment for Blacks and to make a greater commitment to economic equality and progress. (GC)

  16. Adrenergic receptor β2 activation by stress promotes breast cancer progression through macrophages M2 polarization in tumor microenvironment.

    PubMed

    Qin, Jun-fang; Jin, Feng-jiao; Li, Ning; Guan, Hai-tao; Lan, Lan; Ni, Hong; Wang, Yue

    2015-05-01

    Stress and its related hormones epinephrine (E) and norepinephrine (NE) play a crucial role in tumor progression. Macrophages in the tumor microenvironment (TME) polarized to M2 is also a vital pathway for tumor deterioration. Here, we explore the underlying role of macrophages in the effect of stress and E promoting breast cancer growth. It was found that the weight and volume of tumor in tumor bearing mice were increased, and dramatically accompanied with the rising E level after chronic stress using social isolation. What is most noteworthy, the number of M2 macrophages inside tumor was up-regulated with it. The effects of E treatment appear to be directly related to the change of M2 phenotype is reproduced in vitro. Moreover, E receptor ADRβ2 involved in E promoting M2 polarization was comprehended simultaneously. Our results imply psychological stress is influential on specific immune system, more essential for the comprehensive treatment against tumors.

  17. Arsenic treatment considerations

    SciTech Connect

    Chen, H.W.; Frey, M.M.; Clifford, D.; McNeill, L.S.; Edwards, M.

    1999-03-01

    The best arsenic treatment technique for a given utility will depend on arsenic concentration and species in source water, other constituents in the water, existing treatment processes, treatment costs, and handling of residuals. To evaluate these issues, a national survey investigated arsenic occurrence and speciation in US drinking water sources. In general, total arsenic concentration was higher in groundwater than in surface water supplies. Particulate arsenic was more abundant than previously suspected, and more arsenate than arsenite was present. The cost of arsenic treatment increased in the following order: modified conventional treatment {much_lt} activated alumina or anion exchange < reverse osmosis. Nevertheless, the most cost-effective treatment still might not be best, because secondary treatment benefits and residuals handling should also be taken into account.

  18. Quantitative imaging of arsenic and its species in goat following long term oral exposure.

    PubMed

    Patra, Pabitra Hriday; Bandyopadhyay, Samiran; Kumar, Rakesh; Datta, Bakul Kumar; Maji, Chinmoy; Biswas, Suman; Dash, Jeevan Ranjan; Sar, Tapas Kumar; Sarkar, Samar; Manna, Sanjib K; Chakraborty, Animesh Kumar; Mandal, Tapan Kumar

    2012-06-01

    Severity of arsenic toxicity was reported to vary depending on its species. The present study reflects the status of different species of arsenic in goat following long-term exposure of arsenic leading to hepatic damage. The experiment was conducted with six black Bengal goats, which were administered with sodium arsenite orally at a dose rate of 2 mgkg(-1) daily for 84 days. Faeces, urine, hair and blood samples were collected from those animals at 14 days interval. Excretion of total arsenic was reduced from 56 days onwards through both faeces and urine indicating higher accumulation of arsenic in body. The speciation study revealed that urinary arsenic was mainly of organic type, whereas hair accumulated almost equal proportion of arsenite, arsenate and organo arsenicals. Goats excreted high proportion of organo arsenicals through faeces possibly due to hepatobiliary secretion of organo arsenic into the gut. Significantly elevated serum alanine aminotransferase and aspartate aminotransferase activities (p<0.05) along with histopathological changes in liver indicated hepatotoxicity. The arsenite fraction increased and organic proportion decreased in urine as the time progressed, which indicates that arsenite gets methylated in liver of goat. The study thus alluded that the toxicity of arsenic would aggravate if the animals were exposed for long time as the hepatotoxicity progressed resulting in decreased methylation and formation of organo arsenicals and decreased excretions through urine. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Arsenic-Induced Pancreatitis

    PubMed Central

    Connelly, Sean; Zancosky, Krysia; Farah, Katie

    2011-01-01

    The introduction of all-trans retinoic acid (ATRA) and arsenic trioxide has brought about tremendous advancement in the treatment of acute promyelocytic myelogenous leukemia (APML). In most instances, the benefits of these treatments outweigh the risks associated with their respective safety profiles. Although acute pancreatitis is not commonly associated with arsenic toxicity, it should be considered as a possible side effect. We report a case of arsenic-induced pancreatitis in a patient with APML. PMID:22606427

  20. Tissue-Resident Macrophages in Pancreatic Ductal Adenocarcinoma Originate from Embryonic Hematopoiesis and Promote Tumor Progression.

    PubMed

    Zhu, Yu; Herndon, John M; Sojka, Dorothy K; Kim, Ki-Wook; Knolhoff, Brett L; Zuo, Chong; Cullinan, Darren R; Luo, Jingqin; Bearden, Audrey R; Lavine, Kory J; Yokoyama, Wayne M; Hawkins, William G; Fields, Ryan C; Randolph, Gwendalyn J; DeNardo, David G

    2017-08-15

    Tumor-associated macrophages (TAMs) are essential components of the cancer microenvironment and play critical roles in the regulation of tumor progression. Optimal therapeutic intervention requires in-depth understanding of the sources that sustain macrophages in malignant tissues. In this study, we investigated the ontogeny of TAMs in murine pancreatic ductal adenocarcinoma (PDAC) models. We identified both inflammatory monocytes and tissue-resident macrophages as sources of TAMs. Unexpectedly, significant portions of pancreas-resident macrophages originated from embryonic development and expanded through in situ proliferation during tumor progression. Whereas monocyte-derived TAMs played more potent roles in antigen presentation, embryonically derived TAMs exhibited a pro-fibrotic transcriptional profile, indicative of their role in producing and remodeling molecules in the extracellular matrix. Collectively, these findings uncover the heterogeneity of TAM origin and functions and could provide therapeutic insight for PDAC treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Inhibitory mechanism of dimercaptopropanesulfonic acid (DMPS) in the cellular biomethylation of arsenic.

    PubMed

    Wang, Shuping; Shi, Nan; Geng, Zhirong; Li, Xiangli; Hu, Xin; Wang, Zhilin

    2014-11-01

    Dimercaptopropanesulfonic acid (DMPS) has been approved for the treatment of arsenic poisoning through promoting arsenic excretion and modulating arsenic species. To clarify how DMPS regulates the excretion of arsenic species, we investigated the effects of DMPS on the biomethylation of arsenite (As(3+)) in HepG2 cells. In the experiments, we found that DMPS at low concentrations dramatically decreased the content of arsenic in HepG2 cells and inhibited the cellular methylation of As(3+). Three aspects, the expression of human arsenic (III) methyltransferase (hAS3MT), the accumulation of cellular reactive oxygen species (ROS) and the in vitro enzymatic methylation of arsenic, were considered to explain the reasons for the inhibition of DMPS in arsenic metabolism. The results suggested that DMPS competitively coordinated with As(3+) and monomethylarsonous acid (MMA(3+)) to inhibit the up-regulation of arsenic on the expression of hAS3MT and block arsenic involving in the enzymatic methylation. Moreover, DMPS eliminated arsenic-induced accumulation of ROS, which might contribute to the antidotal effects of DMPS on arsenic posing.

  2. EGFR-induced phosphorylation of type Iγ phosphatidylinositol phosphate kinase promotes pancreatic cancer progression

    PubMed Central

    Xue, Junli; Xiong, Xunhao; Huang, Yan; Hu, Jinghua; Ling, Kun

    2017-01-01

    Pancreatic cancer is one of the deadliest malignancies and effective treatment has always been lacking. In current study, we investigated how the type Iγ phosphatidylinositol phosphate kinase (PIPKIγ) participates in the progression of pancreatic ductal adenocarcinoma (PDAC) for novel therapeutic potentials against this lethal disease. We found that PIPKIγ is up-regulated in all tested PDAC cell lines. The growth factor (including EGFR)-induced tyrosine phosphorylation of PIPKIγ is significantly elevated in in situ and metastatic PDAC tissues. Loss of PIPKIγ inhibits the aggressiveness of PDAC cells by restraining the activities of AKT and STAT3, as well as MT1-MMP expression. Therefore when planted into the pancreas of nude mice, PIPKIγ-depleted PDAC cells exhibits substantially repressed tumor growth and metastasis comparing to control PDAC cells. Results from further studies showed that the phosphorylation-deficient PIPKIγ mutant, unlike its wild-type counterpart, cannot rescue PDAC progression inhibited by PIPKIγ depletion. These findings indicate that PIPKIγ, functioning downstream of EGFR signaling, is critical to the progression of PDAC, and suggest that PIPKIγ is potentially a valuable therapeutic target for PDAC treatment. PMID:28388589

  3. Knockdown of TWIST1 enhances arsenic trioxide- and ionizing radiation-induced cell death in lung cancer cells by promoting mitochondrial dysfunction

    SciTech Connect

    Seo, Sung-Keum; Kim, Jae-Hee; Choi, Ha-Na; Choe, Tae-Boo; Hong, Seok-Il; Yi, Jae-Youn; Hwang, Sang-Gu; Lee, Hyun-Gyu; Lee, Yun-Han; Park, In-Chul

    2014-07-11

    Highlights: • Knockdown of TWIST1 enhanced ATO- and IR-induced cell death in NSCLCs. • Intracellular ROS levels were increased in cells treated with TWIST1 siRNA. • TWIST1 siRNA induced MMP loss and mitochondrial fragmentation. • TWIST1 siRNA upregulated the fission-related proteins FIS1 and DRP1. - Abstract: TWIST1 is implicated in the process of epithelial mesenchymal transition, metastasis, stemness, and drug resistance in cancer cells, and therefore is a potential target for cancer therapy. In the present study, we found that knockdown of TWIST1 by small interfering RNA (siRNA) enhanced arsenic trioxide (ATO)- and ionizing radiation (IR)-induced cell death in non-small-cell lung cancer cells. Interestingly, intracellular reactive oxygen species levels were increased in cells treated with TWIST1 siRNA and further increased by co-treatment with ATO or IR. Pretreatment of lung cancer cells with the antioxidant N-acetyl-cysteine markedly suppressed the cell death induced by combined treatment with TWIST1 siRNA and ATO or IR. Moreover, treatment of cells with TWIST1 siRNA induced mitochondrial membrane depolarization and significantly increased mitochondrial fragmentation (fission) and upregulated the fission-related proteins FIS1 and DRP1. Collectively, our results demonstrate that siRNA-mediated TWIST1 knockdown induces mitochondrial dysfunction and enhances IR- and ATO-induced cell death in lung cancer cells.

  4. Prolyl-4-hydroxylase α subunit 2 promotes breast cancer progression and metastasis by regulating collagen deposition.

    PubMed

    Xiong, Gaofeng; Deng, Lei; Zhu, Jieqing; Rychahou, Piotr G; Xu, Ren

    2014-01-02

    Increased collagen deposition provides physical and biochemical signals to support tumor growth and invasion during breast cancer development. Therefore, inhibition of collagen synthesis and deposition has been considered a strategy to suppress breast cancer progression. Collagen prolyl-4-hydroxylase α subunit 2 (P4HA2), an enzyme hydroxylating proline residues in -X-Pro-Gly- sequences, is a potential therapeutic target for the disorders associated with increased collagen deposition. However, expression and function of P4HA2 in breast cancer progression are not well investigated. Gene co-expression analysis was performed in the published microarray datasets to identify potential regulators of collagen I, III, and IV in human breast cancer tissue. Expression of P4HA2 was silenced by shRNAs, and its activity was inhibited by 1, 4-DPCA, a prolyl-4-hydroxylase inhibitor. Three-dimensional culture assay was used to analyze roles of P4HA2 in regulating malignant phenotypes of breast cancer cells. Reduced deposition of collagen I and IV was detected by Western blotting and immunofluorescence. Control and P4HA2-silenced breast cancer cells were injected into fat pad and tail vein of SCID mice to examine effect of P4HA2 on tumor growth and lung metastasis. Using gene co-expression analysis, we showed that P4HA2 was associated with expression of Col1A1, Col3A1, and Col4A1 during breast cancer development and progression. P4HA2 mRNA levels were significantly upregulated in breast cancer compared to normal mammary tissue. Increased mRNA levels of P4HA2 correlated with poor clinical outcome in breast cancer patients, which is independent of estrogen receptor status. Silencing P4HA2 expression or treatment with the P4HA inhibitor significantly inhibited cell proliferation and suppressed aggressive phenotypes of breast cancer cells in 3D culture, accompanied by reduced deposition of collagen I and IV. We also found that knockdown of P4HA2 inhibited mammary tumor growth and

  5. Aberrant hypomethylation-mediated CD147 overexpression promotes aggressive tumor progression in human prostate cancer.

    PubMed

    Liang, Yu-Xiang; Mo, Ru-Jun; He, Hui-Chan; Chen, Jia-Hong; Zou, Jun; Han, Zhao-Dong; Lu, Jian-Ming; Cai, Chao; Zeng, Yan-Ru; Zhong, Wei-De; Wu, Chin-Lee

    2015-05-01

    Our previous study revealed the potential role of CD147 in human prostate cancer (PCa). Here, we investigated the CD147 promoter methylation status and the correlation with tumorigenicity in human PCa. CD147 mRNA and protein expression levels were both significantly higher in the 4 PCa cell lines, than in the 2 non-tumorigenic benign human prostatic epithelial cell lines (all P<0.01). We showed hypomethylation of promoter regions of CD147 in PCa cell lines with significant CD147 expression as compared to non-tumorigenic benign human prostatic epithelial cell lines slowly expressing CD147. Additionally, the treatment of methylated cell lines with 5-aza-2'-deoxycytidine increased CD147 expression significantly in low-expressing cell lines and also activated the expression of matrix metalloproteinase (MMP)-2, which may be one of the most important downstream targets of CD147. Furthermore, PCa tissues displayed decreased DNA methylation in the promoter region of CD147 compared to the corresponding non-cancerous prostate tissues, and methylation intensity correlated inversely with the CD147 mRNA levels. There was a significant negative correlation between CD147 mRNA levels and the number of methylated sites in PCa tissues (r=-0.467, P<0.01). In conclusion, our data offer convincing evidence for the first time that the DNA promoter hypomethylation of CD147 may be one of the regulatory mechanisms involved in the cancer-related overexpression of CD147 and may play a crucial role in the tumorigenesis of PCa.

  6. Downregulation of HSP60 disrupts mitochondrial proteostasis to promote tumorigenesis and progression in clear cell renal cell carcinoma

    PubMed Central

    Tang, Haiping; Chen, Yuling; Liu, Xiaohui; Wang, Shiyu; Lv, Yang; Wu, Di; Wang, Qingtao; Luo, Minkui; Deng, Haiteng

    2016-01-01

    In the present study, we demonstrate that HSP60 is unequivocally downregulated in clear cell renal cell carcinoma (ccRCC) tissues compared to pericarcinous tissues. Overexpression of HSP60 in ccRCC cancer cells suppresses cell growth. HSP60 knockdown increases cell growth and proliferation in both cell culture and nude mice xenografts, and drives cells to undergo epithelial to mesenchymal transition (EMT). Our results propose that HSP60 silencing disrupts the integrity of the respiratory complex I and triggers the excessive ROS production, which promotes tumor progression in the following aspects: (1) ROS activates the AMPK pathway that promotes acquisition of the Warburg phenotype in HSP60-KN cells; (2) ROS generated by HSP60 knockdown or by rotenone inhibition drives cells to undergo EMT; and (3) the high level of ROS may also fragment the Fe-S clusters that up regulates ADHFe1 expression and the 2-hydroxygluterate (2-HG) production leading to changes in DNA methylation. These results suggest that the high level of ROS is needed for tumorigenesis and progression in tumors with the low HSP60 expression and HSP60 is a potential diagnostic biomarker as well as a therapeutic target in ccRCC. PMID:27246978

  7. Dynein axonemal heavy chain 8 promotes androgen receptor activity and associates with prostate cancer progression

    PubMed Central

    Wang, Yu; Ledet, Russell J.; Imberg-Kazdan, Keren; Logan, Susan K.; Garabedian, Michael J.

    2016-01-01

    To gain insight into cellular factors regulating AR action that could promote castration resistant prostate cancer (CRPC), we performed a genome-wide RNAi screen for factors that promote ligand-independent AR transcriptional activity and integrated clinical databases for candidate genes that are positively associated with prostate cancer metastasis and recurrence. From this analysis, we identified Dynein Axonemal Heavy Chain 8 (DNAH8) as an AR regulator that displayed higher mRNA expression in metastatic than in primary tumors, and showed high expression in patients with poor prognosis. Axonemal dyneins function in cellular motility, but the function of DNAH8 in prostate cancer or other cell types has not been reported. DNAH8 is on chromosome 6q21.2, a cancer-associated amplicon, and is primarily expressed in prostate and testis. Its expression is higher in primary tumors compared to normal prostate, and is further increased in metastatic prostate cancers. Patients expressing high levels of DNAH8 have a greater risk of relapse and a poor prognosis after prostatectomy. Depletion of DNAH8 in prostate cancer cells suppressed AR transcriptional activity and proliferation. Androgen treatment increased DNAH8 mRNA expression, and AR bound the DNAH8 promoter sequence indicating DNAH8 is an AR target gene. Thus, DNAH8 is a new regulator of AR associated with metastatic tumors and poor prognosis. PMID:27363033

  8. HnRNP-L promotes prostate cancer progression by enhancing cell cycling and inhibiting apoptosis.

    PubMed

    Zhou, Xumin; Li, Qi; He, Jincan; Zhong, Liren; Shu, Fangpeng; Xing, Rongwei; Lv, Daojun; Lei, Bin; Wan, Bo; Yang, Yu; Wu, Huayan; Mao, Xiangming; Zou, Yaguang

    2016-12-27

    Expression of the RNA-binding protein HnRNP-L was previously shown to associate with tumorigenesis in liver and lung cancer. In this study, we examined the role of HnRNP-L in prostate cancer (Pca). We found that HnRNP-L is overexpressed in prostate tissue samples from 160 PC patients compared with tissue samples from 32 donors with cancers other than Pca. Moreover, HnRNP-L positively correlated with aggressive tumor characteristics. HnRNP-L knockdown inhibited cell proliferation and promoted cell apoptosis of Pca cell lines in vitro, and suppressed tumor growth when the cells were subcutaneously implanted in an athymic mouse model. Conversely, overexpression of HnRNP-L promoted cell proliferation and tumor growth while prohibiting cell apoptosis. HnRNP-L promoted cell proliferation and tumor growth in Pca in part by interacting with endogenous p53 mRNA, which was closely associated with cyclin p21. In addition, HnRNP-L affected cell apoptosis by directly binding the classical apoptosis protein BCL-2. These observations suggest HnRNP-L is an important regulatory factor that exerts pro-proliferation and anti-apoptosis effects in Pca through actions affecting the cell cycle and intrinsic apoptotic signaling. Thus HnRNP-L could potentially serve as a valuable molecular biomarker or therapeutic target in the treatment of Pca.

  9. NMU signaling promotes endometrial cancer cell progression by modulating adhesion signaling

    PubMed Central

    Lin, Ting-Yu; Wu, Fang-Ju; Chang, Chia-Lin; Li, Zhongyou; Luo, Ching-Wei

    2016-01-01

    Neuromedin U (NMU) was originally named based on its strong uterine contractile activity, but little is known regarding its signaling/functions in utero. We identified that NMU and one of its receptors, NMUR2, are not only present in normal uterine endometrium but also co-expressed in endometrial cancer tissues, where the NMU level is correlated with the malignant grades and survival of patients. Cell-based assays further confirmed that NMU signaling can promote cell motility and proliferation of endometrial cancer cells derived from grade II tumors. Activation of NMU pathway in these endometrial cancer cells is required in order to sustain expression of various adhesion molecules, such as CD44 and integrin alpha1, as well as production of their corresponding extracellular matrix ligands, hyaluronan and collagen IV; it also increased the activity of SRC and its downstream proteins RHOA and RAC1. Thus, it is concluded that NMU pathway positively controls the adhesion signaling-SRC-Rho GTPase axis in the tested endometrial cancer cells and that changes in cell motility and proliferation can occur when there is manipulation of NMU signaling in these cells either in vitro or in vivo. Intriguingly, this novel mechanism also explains how NMU signaling promotes the EGFR-driven and TGFβ receptor-driven mesenchymal transitions. Through the above axis, NMU signaling not only can promote malignancy of the tested endometrial cancer cells directly, but also helps these cells to become more sensitive to niche growth factors in their microenvironment. PMID:26849234

  10. The arsenic hyperaccumulator fern Pteris vittata L.

    PubMed

    Xie, Qing-En; Yan, Xiu-Lan; Liao, Xiao-Yong; Li, Xia

    2009-11-15

    Arsenic (As) contaminated soils and waters are becoming major global environmental and human health risks. The identification of natural hyperaccumulators of As opens the door for phytoremediation of the arsenic contaminant. Pteris vittata is the first identified naturally evolving As hyperaccumulator. More than a decade after its discovery, we have made great progress in understanding the uptake, transport, and detoxification of As in the fern. The molecular mechanisms controlling As accumulation in P. vittata are now beginning to be recognized. In this review, we will try to summarize what we have learned about this As accumulator, with particular emphasis on the current knowledge of the physiological and molecular mechanisms of arsenic phytoremediation. We also discuss the potential strategies to further enhance phytoextraction abilities of P. vittata.

  11. Chronic arsenic toxicity: studies in West Bengal, India.

    PubMed

    Guha Mazumder, Debendranath; Dasgupta, U B

    2011-09-01

    Chronic arsenic toxicity (arsenicosis) as a result of drinking arsenic-contaminated groundwater is a major environmental health hazard throughout the world, including India. A lot of research on health effects, including genotoxic effect of chronic arsenic toxicity in humans, have been carried out in West Bengal during the last 2 decades. A review of literature including information available from West Bengal has been made to characterize the problem. Scientific journals, monographs, and proceedings of conferences with regard to human health effects, including genotoxicity, of chronic arsenic toxicity have been reviewed. Pigmentation and keratosis are the specific skin diseases characteristic of chronic arsenic toxicity. However, in West Bengal, it was found to produce various systemic manifestations, such as chronic lung disease, characterized by chronic bronchitis, chronic obstructive and/or restrictive pulmonary disease, and bronchiectasis; liver diseases, such as non cirrhotic portal fibrosis; polyneuropathy; peripheral vascular disease; hypertension; nonpitting edema of feet/hands; conjunctival congestion; weakness; and anemia. High concentrations of arsenic, greater than or equal to 200 μg/L, during pregnancy were found to be associated with a sixfold increased risk for stillbirth. Cancers of skin, lung, and urinary bladder are the important cancers associated with this toxicity. Of the various genotoxic effects of arsenic in humans, chromosomal aberration and increased frequency of micronuclei in different cell types have been found to be significant. Various probable mechanisms have been incriminated to cause DNA damage because of chronic arsenic toxicity. The results of the study in West Bengal suggest that deficiency in DNA repair capacity, perturbation of methylation of promoter region of p53 and p16 genes, and genomic methylation alteration may be involved in arsenic-induced disease manifestation in humans. P53 polymorphism has been found to be

  12. Dissolution of arsenic minerals mediated by dissimilatory arsenate reducing bacteria: estimation of the physiological potential for arsenic mobilization.

    PubMed

    Lukasz, Drewniak; Liwia, Rajpert; Aleksandra, Mantur; Aleksandra, Sklodowska

    2014-01-01

    The aim of this study was characterization of the isolated dissimilatory arsenate reducing bacteria in the context of their potential for arsenic removal from primary arsenic minerals through reductive dissolution. Four strains, Shewanella sp. OM1, Pseudomonas sp. OM2, Aeromonas sp. OM4, and Serratia sp. OM17, capable of anaerobic growth with As (V) reduction, were isolated from microbial mats from an ancient gold mine. All of the isolated strains: (i) produced siderophores that promote dissolution of minerals, (ii) were resistant to dissolved arsenic compounds, (iii) were able to use the dissolved arsenates as the terminal electron acceptor, and (iii) were able to use copper minerals containing arsenic minerals (e.g., enargite) as a respiratory substrate. Based on the results obtained in this study, we postulate that arsenic can be released from some As-bearing polymetallic minerals (such as copper ore concentrates or middlings) under reductive conditions by dissimilatory arsenate reducers in indirect processes.

  13. Dissolution of Arsenic Minerals Mediated by Dissimilatory Arsenate Reducing Bacteria: Estimation of the Physiological Potential for Arsenic Mobilization

    PubMed Central

    Lukasz, Drewniak; Liwia, Rajpert; Aleksandra, Mantur; Aleksandra, Sklodowska

    2014-01-01

    The aim of this study was characterization of the isolated dissimilatory arsenate reducing bacteria in the context of their potential for arsenic removal from primary arsenic minerals through reductive dissolution. Four strains, Shewanella sp. OM1, Pseudomonas sp. OM2, Aeromonas sp. OM4, and Serratia sp. OM17, capable of anaerobic growth with As (V) reduction, were isolated from microbial mats from an ancient gold mine. All of the isolated strains: (i) produced siderophores that promote dissolution of minerals, (ii) were resistant to dissolved arsenic compounds, (iii) were able to use the dissolved arsenates as the terminal electron acceptor, and (iii) were able to use copper minerals containing arsenic minerals (e.g., enargite) as a respiratory substrate. Based on the results obtained in this study, we postulate that arsenic can be released from some As-bearing polymetallic minerals (such as copper ore concentrates or middlings) under reductive conditions by dissimilatory arsenate reducers in indirect processes. PMID:24724102

  14. Arsenic and chromium in drinking water promote tumorigenesis in a mouse colitis-associated colorectal cancer model and the potential mechanism is ROS-mediated Wnt/β-catenin signaling pathway

    SciTech Connect

    Wang, Xin; Mandal, Ardhendu K.; Saito, Hiroshi; Pulliam, Joseph F.; Lee, Eun Y.; Ke, Zun-Ji; Lu, Jian; Ding, Songze; Li, Li; Shelton, Brent J.; Tucker, Thomas; Evers, B. Mark; Zhang, Zhuo; Shi, Xianglin

    2012-07-01

    Exposure to carcinogenic metals, such as trivalent arsenic [As(III)] and hexavalent chromium [Cr(VI)], through drinking water is a major global public health problem and is associated with various cancers. However, the mechanism of their carcinogenicity remains unclear. In this study, we used azoxymethane/dextran sodium sulfate (AOM/DSS)-induced mouse colitis-associated colorectal cancer model to investigate their tumorigenesis. Our results demonstrate that exposure to As(III) or Cr(VI), alone or in combination, together with AOM/DSS pretreatment has a promotion effect, increasing the colorectal tumor incidence, multiplicity, size, and grade, as well as cell inflammatory response. Two-dimensional differential gel electrophoresis coupled with mass spectrometry revealed that As(III) or Cr(VI) treatment alone significantly changed the density of proteins. The expression of β-catenin and phospho-GSK was increased by treatment of carcinogenic metals alone. Concomitantly, the expression of NADPH oxidase1 (NOX1) and the level of 8-OHdG were also increased by treatment of carcinogenic metals alone. Antioxidant enzymes, such as superoxide dismutase (SOD) and catalase, were decreased. Similarly, in an in vitro system, exposure of CRL-1807 to carcinogenic metals increased reactive oxygen species (ROS) generation, the expression of β-catenin, phospho-GSK, and NOX1. Inhibition of ROS generation by addition of SOD or catalase inhibited β-catenin expression and activity. Our study provides a new animal model to study the carcinogenicity of As(III) and Cr(VI) and suggests that As(III) and Cr(VI) promote colorectal cancer tumorigenesis, at least partly, through ROS-mediated Wnt/β-catenin signaling pathway. -- Highlights: ► Carcinogenic metals in drinking water promote colorectal tumor formation in vivo. ► Carcinogenic metals induce β-catenin activation in vivo and in vitro. ► ROS generation induced by carcinogenic metals mediated β-catenin activation.

  15. Overexpression of paxillin induced by miR-137 suppression promotes tumor progression and metastasis in colorectal cancer

    PubMed Central

    Xu, Rui-Hua

    2013-01-01

    The deregulation of paxillin (PXN) has been involved in the progression and metastasis of different malignancies including colorectal cancer (CRC). miR-137 is frequently suppressed in CRC. PXN is predicted to be a direct target of miR-137 in CRC cells. On this basis, we hypothesized that overexpression of PXN induced by suppression of miR-137 may promote tumor progression and metastasis and predicts poor prognosis. We detected the expression of PXN and miR-137 in clinical tumor tissues by immunohistochemical analysis and real-time PCR, positive PXN staining was observed in 198 of the 247 (80.1%) cases, whereas no or weak PXN staining was observed in the adjacent non-cancerous area. Higher level of PXN messenger RNA (mRNA) and lower level of miR-137 was observed in cancer tissues than adjacent non-cancerous tissues. High expression of PXN and low expression of miR-137 was associated with aggressive tumor phenotype and adverse prognosis. Moreover, the expression of PXN was negatively correlated with miR-137 expression. A dual-luciferase reporter gene assay validated that PXN was a direct target of miR-137. The use of miR-137 mimics or inhibitor could decrease or increase PXN mRNA and protein levels in CRC cell lines. Knockdown of PXN or ectopic expression of miR-137 could markedly inhibit cell proliferation, migration and invasion in vitro and repress tumor growth and metastasis in vivo. Taken together, these results demonstrated that overexpression of PXN induced by suppression of miR-137 promotes tumor progression and metastasis and could serve as an independent prognostic indicator in CRC patients. PMID:23275153

  16. MFHAS1 promotes colorectal cancer progress by regulating polarization of tumor-associated macrophages via STAT6 signaling pathway

    PubMed Central

    Zhong, Jing; Wang, Huihui; Weng, Meilin; Cheng, Qian; Wu, Qichao; Sun, Zhirong; Jiang, Hui; Zhu, Minmin; Ren, Yu; Xu, Pingbo; Chen, Jiawei; Miao, Changhong

    2016-01-01

    Malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) is a predicted oncoprotein that demonstrates tumorigenic activity in vivo; however, the mechanisms involved are unknown. Macrophages are divided into the pro-inflammatory M1 and anti-inflammatory/protumoral M2 subtypes. Tumor cells can induce M2 polarization of tumor-associated macrophages (TAMs) to promote metastasis; but the underlying pathways require to be elucidated. In this study, we detected a positive association between MFHAS1 expression in TAMs and human colorectal cancer (CRC) TNM stage. Supernatant of CT26 murine CRC cells induced MFHAS1 expression in RAW264.7 murine macrophages. Additionally, CT26 supernatant induced the M2 marker CD206 and activated the pro-M2 STAT6 and KLF4 signaling in control but not MFHAS1-silenced RAW264.7 macrophages. Moreover, supernatant of control, but not MFHAS1-silenced macrophages promoted CT26 cell proliferation, migration and epithelial-mesenchymal transition. Compared with control macrophages, MFHAS1-silenced macrophages showed significantly reduced protumoral effects in vivo. Together, these results suggested that CRC cells induce M2 polarization of TAMs through MFHAS1 induction and subsequent STAT6 and KLF4 activation to promote CRC progress. Finally, similar to CT26 supernatant stimulation, peroxisome proliferator-activated receptor-γ (PPARγ) activation by rosiglitazone induced M2 polarization of RAW264.7 macrophages through MFHAS1-dependent pathway. Our results highlight the role of MFHAS1 as a regulator of macrophages polarization and CRC progress. PMID:27783989

  17. Nuclear vasohibin-2 promotes cell proliferation by inducing G0/G1 to S phase progression.

    PubMed

    Ge, Qianqian; Zhou, Jia; Tu, Min; Xue, Xiaofeng; Li, Zhanjun; Lu, Zipeng; Wei, Jishu; Song, Guoxin; Chen, Jianmin; Guo, Feng; Jiang, Kuirong; Miao, Yi; Gao, Wentao

    2015-09-01

    As a member of the vasohibin (VASH2) family, VASH2 is localized intracellularly as a nuclear and cytoplasmic type. Cytoplasmic VASH2 is associated with carcinoma angiogenesis and malignant transformation and promotes cancer growth. However, the function of nuclear VASH2 has yet to be investigated. The aim of the present study was to detect the nuclear VASH2 expression profile in human organs and tissues by protein microarray technique. To examine the function of nuclear VASH2, we analyzed the relationship between nuclear VASH2 and Ki-67, and stably constructed VASH2 overexpression and knockdown in LO2 and HepG2 cell lines, based on a previous study in hepatic cells. The study was conducted using bromodeoxyuridine, immunofluorescent staining, western blot analysis and flow cytometry. Nuclear VASH2 was highly expressed in actively dividing cells in normal and cancer tissues. There was a significant positive correlation between nuclear VASH2 and Ki-67, indicating that nuclear VASH2 positively correlated with cell proliferation in normal and cancer tissues. The bromodeoxyuridine (BrdU) proliferation test showed that nuclear VASH2 increased the S-phase population and promoted cell proliferation, while VASH2 knockdown reduced BrdU absorbance. Cell cycle analysis revealed that nuclear VASH2 overexpression increased the S-phase population in LO2 and HepG2 cells, while nuclear VASH2 knockdown reduced the S-phase population and increased the G0/G1 population. The findings of this study challenge the classic view of VASH2, which was previously reported as an angiogenesis factor. Furthermore, to the best of our knowledge, these results are the first clinical data indicating that nuclear VASH2, but not cytoplasmic VASH2, promotes cell proliferation by driving the cell cycle from the G0/G1 to S phase.

  18. Developing sense of coherence in educational contexts: making progress in promoting mental health in children.

    PubMed

    Krause, Christina

    2011-12-01

    The notion of salutogenesis was developed by Aaron Antonovsky to achieve a fundamental innovative approach to promoting mental health. Within the concept of salutogenesis, the author defined the sense of coherence (SOC) as a global life orientation, and he suggests that it emerges in the early years of childhood. In order to develop coherence and its components it is necessary to explore certain health resources. In this paper the following questions will be discussed: (1) which are the individual and social resources to keep healthy, and (2) how can these resources be activated? Selected empirical findings will be presented to respond to these research questions. The results show that resources such as self-worth and a sense of belonging are fundamental health factors. They can be developed most effectively in the early years of childhood and through the formal educational system, e.g. in kindergartens and primary schools. However, the findings show that professionals need to be trained to be able to deliver educational programmes in terms of salutogenesis. At the same time, experience shows that promoting health resources in children successfully depends on the participation of the parents and their support by the professional educators. This paper aims to present new ideas and experiences in the area of a practical realization of the concept of salutogenesis in educational systems. Particularly, health promotion programmes, for example 'The I am I programme' ( Krause, 2009 ), could be implemented successfully in kindergartens with a high quota of children with an immigrant background, due to the fact that this programme includes the reflection and experience of cultural traditions, food, songs, dancing, and family rituals.

  19. Arsenic (+3 oxidation state) methyltransferase and the methylation of arsenicals in the invertebrate chordate Ciona intestinalis

    EPA Science Inventory

    The biotransformation of inorganic arsenic (iAs) involves methylation by an arsenic (+3 oxidation state) methyltransferase (AS3MT), yielding methyl arsenic (MA), dimethyl arsenic (DMA), and trimethylarsenic (TMA). To identify molecular mechanisms that coordinate arsenic biotra...

  20. Arsenic (+3 oxidation state) methyltransferase and the methylation of arsenicals in the invertebrate chordate Ciona intestinalis

    EPA Science Inventory

    The biotransformation of inorganic arsenic (iAs) involves methylation by an arsenic (+3 oxidation state) methyltransferase (AS3MT), yielding methyl arsenic (MA), dimethyl arsenic (DMA), and trimethylarsenic (TMA). To identify molecular mechanisms that coordinate arsenic biotra...

  1. MMSET is dynamically regulated during cell-cycle progression and promotes normal DNA replication

    PubMed Central

    Evans, Debra L.; Zhang, Haoxing; Ham, Hyoungjun; Pei, Huadong; Lee, SeungBaek; Kim, JungJin; Billadeau, Daniel D.; Lou, Zhenkun

    2016-01-01

    ABSTRACT The timely and precise duplication of cellular DNA is essential for maintaining genome integrity and is thus tightly-regulated. During mitosis and G1, the Origin Recognition Complex (ORC) binds to future replication origins, coordinating with multiple factors to load the minichromosome maintenance (MCM) complex onto future replication origins as part of the pre-replication complex (pre-RC). The pre-RC machinery, in turn, remains inactive until the subsequent S phase when it is required for replication fork formation, thereby initiating DNA replication. Multiple myeloma SET domain-containing protein (MMSET, a.k.a. WHSC1, NSD2) is a histone methyltransferase that is frequently overexpressed in aggressive cancers and is essential for normal human development. Several studies have suggested a role for MMSET in cell-cycle regulation; however, whether MMSET is itself regulated during cell-cycle progression has not been examined. In this study, we report that MMSET is degraded during S phase in a cullin-ring ligase 4-Cdt2 (CRL4Cdt2) and proteasome-dependent manner. Notably, we also report defects in DNA replication and a decreased association of pre-RC factors with chromatin in MMSET-depleted cells. Taken together, our results suggest a dynamic regulation of MMSET levels throughout the cell cycle, and further characterize the role of MMSET in DNA replication and cell-cycle progression. PMID:26771714

  2. microRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism

    PubMed Central

    Hajarnis, Sachin; Lakhia, Ronak; Yheskel, Matanel; Williams, Darren; Sorourian, Mehran; Liu, Xueqing; Aboudehen, Karam; Zhang, Shanrong; Kersjes, Kara; Galasso, Ryan; Li, Jian; Kaimal, Vivek; Lockton, Steven; Davis, Scott; Flaten, Andrea; Johnson, Joshua A.; Holland, William L.; Kusminski, Christine M.; Scherer, Philipp E.; Harris, Peter C.; Trudel, Marie; Wallace, Darren P.; Igarashi, Peter; Lee, Edmund C.; Androsavich, John R.; Patel, Vishal

    2017-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of renal failure. Here we identify miR-17 as a target for the treatment of ADPKD. We report that miR-17 is induced in kidney cysts of mouse and human ADPKD. Genetic deletion of the miR-17∼92 cluster inhibits cyst proliferation and PKD progression in four orthologous, including two long-lived, mouse models of ADPKD. Anti-miR-17 treatment attenuates cyst growth in short-term and long-term PKD mouse models. miR-17 inhibition also suppresses proliferation and cyst growth of primary ADPKD cysts cultures derived from multiple human donors. Mechanistically, c-Myc upregulates miR-17∼92 in cystic kidneys, which in turn aggravates cyst growth by inhibiting oxidative phosphorylation and stimulating proliferation through direct repression of Pparα. Thus, miR-17 family is a promising drug target for ADPKD, and miR-17-mediated inhibition of mitochondrial metabolism represents a potential new mechanism for ADPKD progression. PMID:28205547

  3. MMSET is dynamically regulated during cell-cycle progression and promotes normal DNA replication.

    PubMed

    Evans, Debra L; Zhang, Haoxing; Ham, Hyoungjun; Pei, Huadong; Lee, SeungBaek; Kim, JungJin; Billadeau, Daniel D; Lou, Zhenkun

    2016-01-01

    The timely and precise duplication of cellular DNA is essential for maintaining genome integrity and is thus tightly-regulated. During mitosis and G1, the Origin Recognition Complex (ORC) binds to future replication origins, coordinating with multiple factors to load the minichromosome maintenance (MCM) complex onto future replication origins as part of the pre-replication complex (pre-RC). The pre-RC machinery, in turn, remains inactive until the subsequent S phase when it is required for replication fork formation, thereby initiating DNA replication. Multiple myeloma SET domain-containing protein (MMSET, a.k.a. WHSC1, NSD2) is a histone methyltransferase that is frequently overexpressed in aggressive cancers and is essential for normal human development. Several studies have suggested a role for MMSET in cell-cycle regulation; however, whether MMSET is itself regulated during cell-cycle progression has not been examined. In this study, we report that MMSET is degraded during S phase in a cullin-ring ligase 4-Cdt2 (CRL4(Cdt2)) and proteasome-dependent manner. Notably, we also report defects in DNA replication and a decreased association of pre-RC factors with chromatin in MMSET-depleted cells. Taken together, our results suggest a dynamic regulation of MMSET levels throughout the cell cycle, and further characterize the role of MMSET in DNA replication and cell-cycle progression.

  4. microRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism.

    PubMed

    Hajarnis, Sachin; Lakhia, Ronak; Yheskel, Matanel; Williams, Darren; Sorourian, Mehran; Liu, Xueqing; Aboudehen, Karam; Zhang, Shanrong; Kersjes, Kara; Galasso, Ryan; Li, Jian; Kaimal, Vivek; Lockton, Steven; Davis, Scott; Flaten, Andrea; Johnson, Joshua A; Holland, William L; Kusminski, Christine M; Scherer, Philipp E; Harris, Peter C; Trudel, Marie; Wallace, Darren P; Igarashi, Peter; Lee, Edmund C; Androsavich, John R; Patel, Vishal

    2017-02-16

    Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent genetic cause of renal failure. Here we identify miR-17 as a target for the treatment of ADPKD. We report that miR-17 is induced in kidney cysts of mouse and human ADPKD. Genetic deletion of the miR-17∼92 cluster inhibits cyst proliferation and PKD progression in four orthologous, including two long-lived, mouse models of ADPKD. Anti-miR-17 treatment attenuates cyst growth in short-term and long-term PKD mouse models. miR-17 inhibition also suppresses proliferation and cyst growth of primary ADPKD cysts cultures derived from multiple human donors. Mechanistically, c-Myc upregulates miR-17∼92 in cystic kidneys, which in turn aggravates cyst growth by inhibiting oxidative phosphorylation and stimulating proliferation through direct repression of Pparα. Thus, miR-17 family is a promising drug target for ADPKD, and miR-17-mediated inhibition of mitochondrial metabolism represents a potential new mechanism for ADPKD progression.

  5. EML4 promotes the loading of NUDC to the spindle for mitotic progression

    PubMed Central

    Chen, Dan; Ito, Satoko; Yuan, Hong; Hyodo, Toshinori; Kadomatsu, Kenji; Hamaguchi, Michinari; Senga, Takeshi

    2015-01-01

    Echinoderm microtubule-associated protein (EMAP)-like (EML) family proteins are microtubule-associated proteins that have a conserved hydrophobic EMAP-like protein (HELP) domain and multiple WD40 domains. In this study, we examined the role of EML4, which is a member of the EML family, in cell division. Time-lapse microscopy analysis demonstrated that EML4 depletion induced chromosome misalignment during metaphase and delayed anaphase initiation. Further analysis by immunofluorescence showed that EML4 was required for the organization of the mitotic spindle and for the proper attachment of kinetochores to microtubules. We searched for EML4-associating proteins by mass spectrometry analysis and found that the nuclear distribution gene C (NUDC) protein, which is a critical factor for the progression of mitosis, was associated with EML4. This interaction was mediated by the WD40 repeat of EML4 and by the C-terminus of NUDC. In the absence of EML4, NUDC was no longer able to localize to the mitotic spindle, whereas NUDC was dispensable for EML4 localization. Our results show that EML4 is critical for the loading of NUDC onto the mitotic spindle for mitotic progression. PMID:25789526

  6. Radiation Promotes Colorectal Cancer Initiation and Progression by Inducing Senescence-Associated Inflammatory Responses

    PubMed Central

    Kim, Sang Bum; Bozeman, Ronald; Kaisani, Aadil; Kim, Wanil; Zhang, Lu; Richardson, James A.; Wright, Woodring E.; Shay, Jerry W.

    2015-01-01

    Proton radiotherapy is becoming more common since protons induce more precise DNA damage at the tumor site with reduced side effects to adjacent normal tissues. However, the long-term biological effects of proton irradiation in cancer initiation compared to conventional photon irradiation are poorly characterized. In this study, using a human familial adenomatous polyposis syndrome susceptible mouse model, we show that whole body irradiation with protons are more effective in inducing senescence-associated inflammatory responses (SIR) which are involved in colon cancer initiation and progression. After proton irradiation, a subset of SIR genes (Troy, Sox17, Opg, Faim2, Lpo, Tlr2 and Ptges) and a gene known to be involved in invasiveness (Plat), along with the senescence associated gene (P19Arf) are markedly increased. Following these changes loss of Casein kinase Iα (CKIα) and induction of chronic DNA damage and TP53 mutations are increased compared to x-ray irradiation. Proton irradiation also increases the number of colonic polyps, carcinomas and invasive adenocarcinomas. Pretreatment with the non-steroidal anti-inflammatory drug, CDDO-EA, reduces proton irradiation associated SIR and tumorigenesis. Thus, exposure to proton irradiation elicits significant changes in colorectal cancer initiation and progression that can be mitigated using CDDO-EA. PMID:26477319

  7. Deletion of Interstitial Genes between TMPRSS2 and ERG Promotes Prostate Cancer Progression.

    PubMed

    Linn, Douglas E; Penney, Kathryn L; Bronson, Roderick T; Mucci, Lorelei A; Li, Zhe

    2016-04-01

    TMPRSS2-ERG gene fusions that occur frequently in human prostate cancers can be generated either through insertional chromosomal rearrangement or by intrachromosomal deletion. Genetically, a key difference between these two mechanisms is that the latter results in deletion of a ∼3-Mb interstitial region containing genes with unexplored roles in prostate cancer. In this study, we characterized two mouse models recapitulating TMPRSS2-ERG insertion or deletion events in the background of prostate-specific PTEN deficiency. We found that only the mice that lacked the interstitial region developed prostate adenocarcinomas marked by poor differentiation and epithelial-to-mesenchymal transition. Mechanistic investigations identified several interstitial genes, including Ets2 and Bace2, whose reduced expression correlated in the gene homologs in human prostate cancer with biochemical relapse and lethal disease. Accordingly, PTEN-deficient mice with prostate-specific knockout of Ets2 exhibited marked progression of prostate adenocarcinomas that was partly attributed to activation of MAPK signaling. Collectively, our findings established that Ets2 is a tumor suppressor gene in prostate cancer, and its loss along with other genes within the TMPRSS2-ERG interstitial region contributes to disease progression. Cancer Res; 76(7); 1869-81. ©2016 AACR.

  8. High KRT8 expression promotes tumor progression and metastasis of gastric cancer.

    PubMed

    Fang, Jian; Wang, Hao; Liu, Yun; Ding, Fangfang; Ni, Ying; Shao, Shihe

    2017-02-01

    Keratin8 (KRT8) is the major component of the intermediate filament cytoskeleton and predominantly expressed in simple epithelial tissues. Aberrant expression of KRT8 is associated with multiple tumor progression and metastasis. However, the role of KRT8 in gastric cancer (GC) remains unclear. In this study, KRT8 expression was investigated and it was found to be upregulated along with human GC progression and metastasis at both mRNA and protein levels in human gastric cancer tissues. In addition, KRT8 overexpression enhanced the proliferation and migration of human gastric cancer cells, whereas the knock-down of KRT8 by siRNA only inhibited migration of human gastric cancer cells. Integrinβ1-FAK-induced epithelial-mesenchymal-transition (EMT) only existed in the high KRT8 cells. Furthermore, KRT8 overexpression led to increase in p-smad2/3 levels and TGFβ dependent signaling events. KRT8 expression in GC was related to tumor clinical stage and worse survival. Kaplan-Meier analysis proved that KRT8 was associated with overall survival of patients with GC that patients with high KRT8 expression tend to have unfavorable outcome. Moreover, Cox's proportional hazards analysis showed that high KRT8 expression was a prognostic marker of poor outcome. These results provided that KRT8 expression may therefore be a biomarker or potential therapeutic target to identify patients with worse survival.

  9. CB2 cannabinoid receptor activation promotes colon cancer progression via AKT/GSK3β signaling pathway

    PubMed Central

    Martínez-Martínez, Esther; Martín-Ruiz, Asunción; Martín, Paloma; Calvo, Virginia; Provencio, Mariano; García, José M.

    2016-01-01

    The pharmacological activation of the cannabinoid receptor type 2, CB2, has been shown to elicit anti-tumoral mechanisms in different cancer types. However, little is known about its endogenous role in tumor pathophysiology, and different studies have attributed pro-tumorigenic properties to this receptor. In a previous work, we showed that CB2 expression is a poor prognostic factor in colon cancer patients. Here we report that activation of CB2 with low doses of specific agonists induce cell proliferation and favor the acquisition of aggressive molecular features in colon cancer cells. We show that sub-micromolar concentrations of CB2-specific agonists, JWH-133 and HU-308, promote an increase in cell proliferation rate through the activation of AKT/PKB pathway in colon cancer in vitro and in vivo. AKT activation promotes GSK3β inhibition and thus, a more aggressive cell phenotype with the subsequent elevation of SNAIL levels, E-cadherin degradation and β-catenin delocalization from cell membrane. Taken together, our data show that CB2 activation with sub-micromolar doses of agonists, which could be more similar to endogenous levels of cannabinoids, promote colon cancer progression, implicating that CB2 could have a pro-tumorigenic endogenous role in colon cancer. PMID:27634891

  10. Arsenic Concentrations and Speciation in Shellfishes from Korea

    NASA Astrophysics Data System (ADS)

    Yoon, C.; Yoon, H.

    2005-12-01

    Speciation of arsenic has received significant attention over the past 20 years in both mechanistic and exposure assessment research. Because the toxicity of arsenic is related to its oxidation state and its chemical forms, the determination of the total arsenic contents in a sample is not adequate to allow its impact on living organisms to be estimated. The inorganic arsenic species, arsenite (As3+) and arsenate (As5+), have been classified as carcinogenic and the methylated forms, monomethyl arsonic acid (MMA) and dimethyl arsinic acid (DMA) have recently been identified as cancer promoters. The highly methylated compounds like as arsenobetaine (AsB) and arsenocholine (AsC) are considered to be nontoxic. Although organisms in marine environment contain high amounts of total arsenic (ppm level), it is not usually present as inorganic arsenic or simple methylated forms well known as one of the toxic species. Arsenobetaine is the dominant species in marine animals and arsenosugars are most abundant in marine algae. This study aims to clarify those arsenic species present in the whole body of eleven different shellfishes from Korea. And those arsenic species were separated and measured by characterization using high performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) coupled system. The separation of arsenic species was achieved on anion exchange column and cation exchange column using phosphate and pyridine eluent, respectively. The ultrasonic extraction was employed for extraction of arsenic from whole body of shellfishes. The method was validated by analyzing three certified reference materials (DORM-2, TORT-2, 1566b). Total arsenic concentrations ranged from 0.1 mg/kg dry mass to 21.7 mg/kg dry mass. Most marine shellfishes contained higher arsenobetaine and arsenocholine with the exception of two shellfishes living in river. The lower amounts of inorganic arsenic species were also found in the some sample extracts

  11. Androgen receptor (AR) signaling promotes RCC progression via increased endothelial cell proliferation and recruitment by modulating AKT → NF-κB → CXCL5 signaling

    PubMed Central

    Guan, Zhenfeng; Li, Chong; Fan, Jinhai; He, Dalin; Li, Lei

    2016-01-01

    Androgen receptor (AR) signaling may promote renal cell carcinoma (RCC) progression via altered HIF-2α/VEGF signaling. However, it remains unclear whether AR signaling also promotes RCC progression by recruiting vascular endothelial cells (ECs), key players in the development of blood vessels. In our study, AR increased EC proliferation and recruitment to the tumor microenvironment and promoted RCC progression. Mechanistically, AR modulated cytokine CXCL5 expression by altering AKT → NF-κB signaling, and interruption of AKT → NF-κB → CXCL5 signaling using either specific inhibitors or siRNA suppressed AR-enhanced EC recruitment and AR-EC-promoted RCC progression. The results obtained using an in vivo mouse model and a human clinical sample survey confirmed the role of AR in promoting RCC progression through enhancement of EC proliferation and/or recruitment via altered AKT → NF-κB → CXCL5 signaling. Targeting this newly identified AR-induced AKT → NF-κB → CXCL5 pathway may facilitate the development of new therapies for slowing RCC progression. PMID:27848972

  12. Androgen receptor (AR) signaling promotes RCC progression via increased endothelial cell proliferation and recruitment by modulating AKT → NF-κB → CXCL5 signaling.

    PubMed

    Guan, Zhenfeng; Li, Chong; Fan, Jinhai; He, Dalin; Li, Lei

    2016-11-16

    Androgen receptor (AR) signaling may promote renal cell carcinoma (RCC) progression via altered HIF-2α/VEGF signaling. However, it remains unclear whether AR signaling also promotes RCC progression by recruiting vascular endothelial cells (ECs), key players in the development of blood vessels. In our study, AR increased EC proliferation and recruitment to the tumor microenvironment and promoted RCC progression. Mechanistically, AR modulated cytokine CXCL5 expression by altering AKT → NF-κB signaling, and interruption of AKT → NF-κB → CXCL5 signaling using either specific inhibitors or siRNA suppressed AR-enhanced EC recruitment and AR-EC-promoted RCC progression. The results obtained using an in vivo mouse model and a human clinical sample survey confirmed the role of AR in promoting RCC progression through enhancement of EC proliferation and/or recruitment via altered AKT → NF-κB → CXCL5 signaling. Targeting this newly identified AR-induced AKT → NF-κB → CXCL5 pathway may facilitate the development of new therapies for slowing RCC progression.

  13. Semaphorin 4D cooperates with VEGF to promote angiogenesis and tumor progression

    PubMed Central

    Binmadi, Nada O.; Yang, Ying-Hua; Proia, Patrizia

    2013-01-01

    The semaphorins and plexins comprise a family of cysteine-rich proteins implicated in control of nerve growth and development and regulation of the immune response. Our group and others have found that Semaphorin 4D (SEMA4D) and its receptor, Plexin-B1, play an important role in tumor-induced angiogenesis, with some neoplasms producing SEMA4D in a manner analogous to vascular endothelial growth factor (VEGF) in order to attract Plexin-B1-expressing endothelial cells into the tumor for the purpose of promoting growth and vascularity. While anti-VEGF strategies have been the focus of most angiogenesis inhibition research, such treatment can lead to upregulation of pro-angiogenic factors that can compensate for the loss of VEGF, eventually leading to failure of therapy. Here, we demonstrate that SEMA4D cooperates with VEGF to promote angiogenesis in malignancies and can perform the same function in a setting of VEGF blockade. We also show the potential value of inhibiting SEMA4D/Plexin-B1 signaling as a complementary mechanism to anti-VEGF treatment, particularly in VEGF inhibitor–resistant tumors, suggesting that this may represent a novel treatment for some cancers. PMID:22476930

  14. Mechanisms of arsenic biotransformation.

    PubMed

    Vahter, Marie

    2002-12-27

    Inorganic arsenic, a documented human carcinogen, is methylated in the body by alternating reduction of pentavalent arsenic to trivalent and addition of a methyl group from S-adenosylmethionine. Glutathione, and possibly other thiols, serve as reducing agents. The liver is the most important site of arsenic methylation, but most organs show arsenic methylating activity. The end metabolites are methylarsonic acid (MMA) and dimethylarsinic acid (DMA). These are less reactive with tissue constituents than inorganic arsenic and readily excreted in the urine. However, reactive intermediates may be formed. Absorbed arsenate (As(V)) is fairly rapidly reduced in blood to As(III), which implies increased toxicity. Also, intermediate reduced forms of the methylated metabolites, MMA(III) and DMA(III), have been detected in human urine. In particular MMA(III) is highly toxic. To what extent MMA(III) and DMA(III) contribute to the observed toxicity following exposure to inorganic arsenic remains to be elucidated. There are marked differences in the metabolism of arsenic between mammalian species, population groups and individuals. There are indications that subjects with low MMA in urine have faster elimination of ingested arsenic, compared to those with more MMA in urine.

  15. Arsenic activation neutron detector

    DOEpatents

    Jacobs, Eddy L.

    1981-01-01

    A detector of bursts of neutrons from a deuterium-deuteron reaction includes a quantity of arsenic adjacent a gamma detector such as a scintillator and photomultiplier tube. The arsenic is activated by the 2.5 Mev neutrons to release gamma radiation which is detected to give a quantitative representation of detected neutrons.

  16. Arsenic activation neutron detector

    DOEpatents

    Jacobs, E.L.

    1980-01-28

    A detector of bursts of neutrons from a deuterium-deuteron reaction includes a quantity of arsenic adjacent a gamma detector such as a scintillator and photomultiplier tube. The arsenic is activated by the 2.5-MeV neutrons to release gamma radiation which is detected to give a quantitative representation of detected neutrons.

  17. An update on arsenic

    SciTech Connect

    Malachowski, M.E. )

    1990-09-01

    Arsenic poisoning is more than just a medical curiosity. Cases of acute and chronic intoxication continue to occur in the United States. Much is now known about the biochemical mechanisms of injury, which has led to a rational basis for therapy. Most importantly, however, the clinician must stay alert to correctly diagnose and treat cases of arsenic poisoning.23 references.

  18. [Acute arsenic poisoning].

    PubMed

    Montelescaut, Etienne; Vermeersch, Véronique; Commandeur, Diane; Huynh, Sophie; Danguy des Deserts, Marc; Sapin, Jeanne; Ould-Ahmed, Mehdi; Drouillard, Isabelle

    2014-01-01

    Acute arsenic poisoning is a rare cause of suicide attempt. It causes a multiple organs failure caused by cardiogenic shock. We report the case of a patient admitted twelve hours after an ingestion of trioxide arsenic having survived thanks to a premature treatment.

  19. IL-8 promotes HNSCC progression on CXCR1/2-meidated NOD1/RIP2 signaling pathway

    PubMed Central

    Chan, Leong-Perng; Wang, Ling-Feng; Chiang, Feng-Yu; Lee, Ka-Wo; Kuo, Po-Lin; Liang, Chia-Hua

    2016-01-01

    NOD1 (nucleotide-binding oligomerization domain 1) is overexpressed in head and neck squamous cell carcinoma (HNSCC) cells, as is IL-8 in cancer cells. However, the mechanism of the IL-8-mediated overexpression of NOD in HNSCC not been identified. This study determines whether IL-8 promotes tumor progression via the NOD signaling pathway in HNSCC. Higher IL-8, NOD1 and receptor-interacting protein kinase (RIP2) expressions were observed in HNSCC tissue than in non-cancerous matched tissue (NCMT), whereas NOD2 was weakly expressed. Furthermore, IL-8 stimulated the proliferation of HNSCC cells (SCC4, SCC9 and SCC25) but not dysplastic oral mucosa DOK cells. Exposure to IL-8 increased the clonogenicity of HNSCC cells. IL-8 siRNA inhibited cell proliferation and cell colony formation, suggesting that IL-8 is involved in HNSCC cancer progression. The expressions of CXCR1 and CXCR2 were higher in HNSCC tissue than in NCMT. HNSCC cells that were exposed to IL-8 exhibited higher expression of CXCR1/2 than did controls. The blocking of IL-8 by siRNA reduced CXCR1/2 expression in HNSCC cells, suggesting that the cancer progression of HNSCC cells that is induced by IL-8 depends on CXCR1/2. Additionally, IL-8 is associated with increased NOD1 and RIP2 expression and reduced NOD2 expression in three types of HNSCC cells. The blocking of IL-8 by siRNA reduces IL-8, NOD1 and RIP2 expressions in HNSCC cells, but not the level of NOD2. These results suggest that IL-8 has an important role in HNSCC progression via a CXCR1/2-meidated NOD1/RIP2 signaling pathway. PMID:27557518

  20. Prevention and health promotion: decades of progress, new challenges, and an emerging agenda.

    PubMed

    Smith, Timothy W; Orleans, C Tracy; Jenkins, C David

    2004-03-01

    Daily habits (e.g., smoking, diet, and exercise) and their immediate consequences (e.g., obesity) confer risk for most of the major health problems in industrialized nations. Hence, determinants of these behaviors and their modifications have been central topics in health psychology. Considerable scientific and applied progress has been made, but the field faces important challenges and opportunities in the future. These challenges and opportunities include changes in demographics and patterns of health, the need for a more comprehensive model of the domain of health behavior and prevention, the need to integrate behavioral and psychosocial risk and resilience, the incorporation of new technologies, and addressing a variety of professional and economic barriers to the implementation of prevention in health care.

  1. Low severity coal liquefaction promoted by cyclic olefins. Quarterly technical progress report, April--June 1996

    SciTech Connect

    Curtis, C.W.

    1997-12-31

    The goal of this research is to develop a methodology for analyzing the reactivity of cyclic olefins in situ in a high temperature and high pressure infrared cell. Cyclic olefins, such as 1,4,5,8-tetrahydronaphthalene (isotetralin) and 1,4,5,8,9,10-hexahydroanthracene (HHA), are highly reactive donor compounds that readily donate their hydrogen to coal and model acceptors when heated to temperatures of 200{degrees}C and above. These donors are active donors in the low severity liquefaction of coal at 350{degrees}C as shown in the research performed in this project. The infrared studies are being performed in a high temperature infrared cell that was obtained from AABSPEC. Modifications to that cell have been made and have been reported in previous progress reports.

  2. Carcinoembryonic antigen promotes colorectal cancer progression by targeting adherens junction complexes

    SciTech Connect

    Bajenova, Olga; Chaika, Nina; Tolkunova, Elena; Davydov-Sinitsyn, Alexander; Gapon, Svetlana; Thomas, Peter; O’Brien, Stephen

    2014-06-10

    Oncomarkers play important roles in the detection and management of human malignancies. Carcinoembryonic antigen (CEA, CEACAM5) and epithelial cadherin (E-cadherin) are considered as independent tumor markers in monitoring metastatic colorectal cancer. They are both expressed by cancer cells and can be detected in the blood serum. We investigated the effect of CEA production by MIP101 colorectal carcinoma cell lines on E-cadherin adherens junction (AJ) protein complexes. No direct interaction between E-cadherin and CEA was detected; however, the functional relationships between E-cadherin and its AJ partners: α-, β- and p120 catenins were impaired. We discovered a novel interaction between CEA and beta-catenin protein in the CEA producing cells. It is shown in the current study that CEA overexpression alters the splicing of p120 catenin and triggers the release of soluble E-cadherin. The influence of CEA production by colorectal cancer cells on the function of E-cadherin junction complexes may explain the link between the elevated levels of CEA and the increase in soluble E-cadherin during the progression of colorectal cancer. - Highlights: • Elevated level of CEA increases the release of soluble E-cadherin during the progression of colorectal cancer. • CEA over-expression alters the binding preferences between E-cadherin and its partners: α-, β- and p120 catenins in adherens junction complexes. • CEA produced by colorectal cancer cells interacts with beta-catenin protein. • CEA over-expression triggers the increase in nuclear beta-catenin. • CEA over-expression alters the splicing of p120 catenin protein.

  3. Interleukin-33 promotes disease progression in patients with primary biliary cirrhosis.

    PubMed

    Sun, Yongqiang; Zhang, Ji-Yuan; Lv, Sa; Wang, Huan; Gong, Man; Du, Ning; Liu, Honghong; Zhang, Ning; Jing, Jing; Zhou, Chao; Zhang, Fan; Wang, Zongren

    2014-01-01

    Primary biliary cirrhosis (PBC) is a progressive autoimmune liver disease that can cause a series of complications, including cirrhosis, liver failure and hepatocellular carcinoma. Interleukin-33 (IL-33) is expressed in various non-hematopoietic cells and a certain population of immune cells, and exerts its biological effects by binding to the specific receptor, suppression of tumorigenicity 2 (ST2). A soluble form of ST2 (sST2) has been postulated to act as a decoy receptor for IL-33. In this study, we aimed to investigate the role of IL-33 in the pathogenesis of PBC. The study included 20 healthy controls and 68 patients with PBC. We thus found the increased serum IL-33 levels in PBC patients. Its elevated levels were positively correlated with serum alkaline phosphatase levels (a key parameter for the definition of PBC) and with Child-Pugh scores, which were used to determine the prognosis of liver cirrhosis. Moreover, the serum concentrations of sST2 were significantly higher in PBC patients compared with healthy subjects, irrespective of the disease severity. Importantly, the cells that express IL-33 and/or myeloperoxidase (a marker for neutrophils) were accumulated in the livers of PBC patients, and their number increased with the severity of liver lesions. Lastly, in vitro chemotaxis assays revealed that IL-33 enhanced the migration of neutrophils. These data suggest that IL-33 may affect the progress of PBC by recruiting neutrophils to the liver. This expanded knowledge of IL-33 in PBC patients is important for developing therapeutic strategies (e.g., neutralization of IL-33), selecting optimal clinical management, and predicting prognosis.

  4. Enhanced expression of c-myc in hepatocytes promotes initiation and progression of alcoholic liver disease.

    PubMed

    Nevzorova, Yulia A; Cubero, Francisco J; Hu, Wei; Hao, Fengjie; Haas, Ute; Ramadori, Pierluigi; Gassler, Nikolaus; Hoss, Mareike; Strnad, Pavel; Zimmermann, Henning W; Tacke, Frank; Trautwein, Christian; Liedtke, Christian

    2016-03-01

    Progression of alcoholic liver disease (ALD) can be influenced by genetic factors, which potentially include specific oncogenes and tumor suppressors. In the present study, we tested the hypothesis that aberrant expression of the proto-oncogene c-myc might exert a crucial role in the development of ALD. Expression of c-myc was measured in biopsies of patients with ALD by quantitative real-time PCR and immunohistochemistry. Mice with transgenic expression of c-myc in hepatocytes (alb-myc(tg)) and wild-type (WT) controls were fed either control or ethanol (EtOH) containing Lieber-DeCarli diet for 4weeks to induce ALD. Hepatic c-myc was strongly upregulated in human patients with advanced ALD and in EtOH-fed WT mice. Transcriptome analysis indicated deregulation of pathways involved in ER-stress, p53 signaling, hepatic fibrosis, cell cycle regulation, ribosomal synthesis and glucose homeostasis in EtOH-fed alb-myc(tg) mice. Transgenic expression of c-myc in hepatocytes with simultaneous EtOH-uptake led to early ballooning degeneration, increased liver collagen deposition and hepatic lipotoxicity, together with excessive CYP2E1-derived reactive oxygen species (ROS) production. Moreover, EtOH-fed alb-myc(tg) mice exhibited substantial changes in mitochondrial morphology associated with energy dysfunction. Pathway analysis revealed that elevated c-myc expression and ethanol uptake synergistically lead to strong AKT activation, Mdm2 phosphorylation and as a consequence to inhibition of p53. Expression of c-myc and EtOH-uptake synergistically accelerate the progression of ALD most likely due to loss of p53-dependent protection. Thus, c-myc is a new potential marker for the early detection of ALD and identification of risk patients. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  5. Estrogen induces androgen-repressed SOX4 expression to promote progression of prostate cancer cells.

    PubMed

    Yang, Muyi; Wang, Jing; Wang, Lin; Shen, Chengwu; Su, Bo; Qi, Mei; Hu, Jing; Gao, Wei; Tan, Weiwei; Han, Bo

    2015-09-01

    The sex determing region Y-box 4 (SOX4) gene is a critical developmental transcriptional factor that is overexpressed in prostate cancer (PCa). While we and others have investigated the role of SOX4 overexpression in PCa, the molecular mechanism underlying its aberrant expression remains unclear. Immunohistochemistry were utilized to detect SOX4 expression and the correlation between estrogen receptor β (ERβ), androgen receptor (AR) and SOX4 in a cohort of 94 clinical specimens. Real-time quantitative PCR and Western blotting were used to study the transcript and protein expression levels. Immunofluorescence staining and co-immunoprecipitation were performed to assess the interaction and subcellular location of ERβ and AR. Chromatin immunoprecipitation (ChIP) assays and Luciferase reporter assays were performed to explore the binding and transcriptional activities of ERβ and AR to the SOX4 promoter. Cellular function was evaluated by MTS, invasion and wound healing assays. SOX4 expression is up-regulated in Castration-Resistant Prostate Cancer (CRPC) tumors compared to hormone-dependent PCa (HDPC) cases. Increased expression was also observed in PCa cells after long-term androgen-deprivation treatment (ADT). In vitro data indicated that SOX4 is an AR transcriptional target and down-regulated by dihydrotestosterone (DHT) via AR. 17β-estradiol (E2) up-regulates SOX4 expression in the absence of androgen through the formation of a protein complex between ERβ and AR. Knockdown of AR or ERβ blocks the E2-induced SOX4 expression. ChIP assays confirmed that both ERβ and AR bind to the SOX4 promoter in response to E2. Functionally, silencing SOX4 significantly attenuates the proliferative effect, as well as the capacity of migration and invasion of E2 on PCa cells. Clinically, overexpression of SOX4 is significantly associated with ERβ expression in PCa. In addition, this association is still retained in CRPC patients with poor prognosis. These findings suggest

  6. Innovative business approaches for incenting health promotion in sub-Saharan Africa: progress and persisting challenges.

    PubMed

    Patel, Deepak N; Nossel, Craig; Alexander, Eleanore; Yach, Derek

    2013-01-01

    Non-communicable chronic diseases related to behaviors such as tobacco use, overeating, excess alcohol intake and physical inactivity account for increasing morbidity and mortality in South Africa. Over the last 15 years, Discovery Health, the largest private health plan in South Africa, has developed a voluntary health promotion program called Vitality with over 1.5 million members. Vitality was designed with many applications drawn from the growing field of behavioral economics, including the use of incentives and rewards. Incentives offered on the program are aimed at lowering the financial barriers to activities such as visiting the gym, buying healthy food or receiving preventive screening. Members accrue points for engagement which translate into discounts on a range of goods and services. Although the full impact of the program cannot yet be quantified, engagement with the program is continually increasing and there is compelling evidence that this translates into better health and cost outcomes.

  7. ANGPTL4 deficiency in haematopoietic cells promotes monocyte expansion and atherosclerosis progression

    NASA Astrophysics Data System (ADS)

    Aryal, Binod; Rotllan, Noemi; Araldi, Elisa; Ramírez, Cristina M.; He, Shun; Chousterman, Benjamin G.; Fenn, Ashley M.; Wanschel, Amarylis; Madrigal-Matute, Julio; Warrier, Nikhil; Martín-Ventura, Jose L.; Swirski, Filip K.; Suárez, Yajaira; Fernández-Hernando, Carlos

    2016-07-01

    Lipid accumulation in macrophages has profound effects on macrophage gene expression and contributes to the development of atherosclerosis. Here, we report that angiopoietin-like protein 4 (ANGPTL4) is the most highly upregulated gene in foamy macrophages and it's absence in haematopoietic cells results in larger atherosclerotic plaques, characterized by bigger necrotic core areas and increased macrophage apoptosis. Furthermore, hyperlipidemic mice deficient in haematopoietic ANGPTL4 have higher blood leukocyte counts, which is associated with an increase in the common myeloid progenitor (CMP) population. ANGPTL4-deficient CMPs have higher lipid raft content, are more proliferative and less apoptotic compared with the wild-type (WT) CMPs. Finally, we observe that ANGPTL4 deficiency in macrophages promotes foam cell formation by enhancing CD36 expression and reducing ABCA1 localization in the cell surface. Altogether, these findings demonstrate that haematopoietic ANGPTL4 deficiency increases atherogenesis through regulating myeloid progenitor cell expansion and differentiation, foam cell formation and vascular inflammation.

  8. Z‐Scheme Photocatalytic Systems for Promoting Photocatalytic Performance: Recent Progress and Future Challenges

    PubMed Central

    Li, Haijin; Tu, Wenguang

    2016-01-01

    Semiconductor photocatalysts have attracted increased attention due to their great potential for solving energy and environmental problems. The formation of Z‐scheme photocatalytic systems that mimic natural photosynthesis is a promising strategy to improve photocatalytic activity that is superior to single component photocatalysts. The connection between photosystem I (PS I) and photosystem II (PS II) are crucial for constructing efficient Z‐scheme photocatalytic systems using two photocatalysts (PS I and PS II). The present review concisely summarizes and highlights recent state‐of‐the‐art accomplishments of Z‐scheme photocatalytic systems with diverse connection modes, including i) with shuttle redox mediators, ii) without electron mediators, and iii) with solid‐state electron mediators, which effectively increase visible‐light absorption, promote the separation and transportation of photoinduced charge carriers, and thus enhance the photocatalytic efficiency. The challenges and prospects for future development of Z‐scheme photocatalytic systems are also presented. PMID:27980982

  9. ANGPTL4 deficiency in haematopoietic cells promotes monocyte expansion and atherosclerosis progression

    PubMed Central

    Aryal, Binod; Rotllan, Noemi; Araldi, Elisa; Ramírez, Cristina M.; He, Shun; Chousterman, Benjamin G.; Fenn, Ashley M.; Wanschel, Amarylis; Madrigal-Matute, Julio; Warrier, Nikhil; Martín-Ventura, Jose L.; Swirski, Filip K.; Suárez, Yajaira; Fernández-Hernando, Carlos

    2016-01-01

    Lipid accumulation in macrophages has profound effects on macrophage gene expression and contributes to the development of atherosclerosis. Here, we report that angiopoietin-like protein 4 (ANGPTL4) is the most highly upregulated gene in foamy macrophages and it's absence in haematopoietic cells results in larger atherosclerotic plaques, characterized by bigger necrotic core areas and increased macrophage apoptosis. Furthermore, hyperlipidemic mice deficient in haematopoietic ANGPTL4 have higher blood leukocyte counts, which is associated with an increase in the common myeloid progenitor (CMP) population. ANGPTL4-deficient CMPs have higher lipid raft content, are more proliferative and less apoptotic compared with the wild-type (WT) CMPs. Finally, we observe that ANGPTL4 deficiency in macrophages promotes foam cell formation by enhancing CD36 expression and reducing ABCA1 localization in the cell surface. Altogether, these findings demonstrate that haematopoietic ANGPTL4 deficiency increases atherogenesis through regulating myeloid progenitor cell expansion and differentiation, foam cell formation and vascular inflammation. PMID:27460411

  10. Astrocytes promote progression of breast cancer metastases to the brain via a KISS1-mediated autophagy.

    PubMed

    Kaverina, Natalya; Borovjagin, Anton V; Kadagidze, Zaira; Baryshnikov, Anatoly; Baryshnikova, Maria; Malin, Dmitry; Ghosh, Dhimankrishhna; Shah, Nameeta; Welch, Danny R; Gabikian, Patrik; Karseladze, Apollon; Cobbs, Charles; Ulasov, Ilya V

    2017-10-05

    Formation of metastases, also known as cancer dissemination, is an important stage of breast cancer (BrCa) development. KISS1 expression is associated with inhibition of metastases development. Recently we have demonstrated that BrCa metastases to the brain exhibit low levels of KISS1 expression at both mRNA and protein levels. By using multicolor immunofluorescence and coculture techniques here we show that normal adult astrocytes in the brain are capable of promoting metastatic transformation of circulating breast cancer cells localized to the brain through secretion of chemokine CXCL12. The latter was found in this study to downregulate KISS1 expression at the post-transcriptional level via induction of microRNA-345 (MIR345). Furthermore, we demonstrated that ectopic expression of KISS1 downregulates ATG5 and ATG7, 2 key modulators of autophagy, and works concurrently with autophagy inhibitors, thereby implicating autophagy in the mechanism of KISS1-mediated BrCa metastatic transformation. We also found that expression of KISS1 in human breast tumor specimens inversely correlates with that of MMP9 and IL8, implicated in the mechanism of metastatic invasion, thereby supporting the role of KISS1 as a potential regulator of BrCa metastatic invasion in the brain. This conclusion is further supported by the ability of KISS1, ectopically overexpressed from an adenoviral vector in MDA-MB-231Br cells with silenced expression of the endogenous gene, to revert invasive phenotype of those cells. Taken together, our results strongly suggest that human adult astrocytes can promote brain invasion of the brain-localized circulating breast cancer cells by upregulating autophagy signaling pathways via the CXCL12-MIR345- KISS1 axis.

  11. Antibody-Mediated Oligodendrocyte Remyelination Promotes Axon Health in Progressive Demyelinating Disease.

    PubMed

    Wootla, Bharath; Denic, Aleksandar; Watzlawik, Jens O; Warrington, Arthur E; Rodriguez, Moses

    2016-10-01

    Demyelination underlies early neurological symptoms in multiple sclerosis (MS); however, axonal damage is considered critical for permanent chronic deficits. The precise mechanisms by which axonal injury occurs in MS are unclear; one hypothesis is the absence or failure of remyelination, suggesting that promoting remyelination may protect axons from death. This report provides direct evidence that promoting oligodendrocyte remyelination protects axons and maintains transport function. Persistent Theiler's virus infection of Swiss Jim Lambert (SJL)/J mice was used as a model of MS to assess the effects of remyelination on axonal injury following demyelination in the spinal cord. Remyelination was induced using an oligodendrocyte/myelin-specific recombinant human monoclonal IgM, rHIgM22. The antibody is endowed with strong anti-apoptotic and pro-proliferative effects on oligodendrocyte progenitor cells. We used (1)H-magnetic resonance spectroscopy (MRS) at the brainstem to measure N-acetyl-aspartate (NAA) as a surrogate of neuronal health and spinal cord integrity. We found increased brainstem NAA concentrations at 5 weeks post-treatment with rHIgM22, which remained stable out to 10 weeks. Detailed spinal cord morphology studies revealed enhanced remyelination in the rHIgM22-treated group but not in the isotype control antibody- or saline-treated groups. Importantly, we found rHIgM22-mediated remyelination protected small- and medium-caliber mid-thoracic spinal cord axons from damage despite similar demyelination and inflammation across all experimental groups. The most direct confirmation of remyelination-mediated protection of descending neurons was an improvement in retrograde transport. Treatment with rHIgM22 significantly increased the number of retrograde-labeled neurons in the brainstem, indicating that preserved axons are functionally competent. This is direct validation that remyelination preserves spinal cord axons and protects functional axon integrity.

  12. XRCC2 Promotes Colorectal Cancer Cell Growth, Regulates Cell Cycle Progression, and Apoptosis

    PubMed Central

    Xu, Kaiwu; Song, Xinming; Chen, Zhihui; Qin, Changjiang; He, Yulong; Zhan, Wenhua

    2014-01-01

    Abstract X-ray repair complementing defective repair in Chinese hamster cells 2 (XRCC2) and poly(ADP-ribose) polymerase 1 (PARP1) both play important roles in homologous recombination DNA repair. According to the theory of synthetic lethality, XRCC2-deficient cells are more sensitive to PARP1 inhibitors compared to XRCC2-expressing cells. We investigated XRCC2 expression and function in colorectal cancer (CRC), and the characteristics of sensitivity to PARP1 inhibitor in CRC cells with different XRCC2 levels. We enrolled 153 patients with CRC who had undergone surgery in this study. XRCC2 expression was assessed using immunohistochemistry. Stable CRC SW480 cell lines with low or high XRCC2 expression were constructed. Following treatment with the PARP1 inhibitor olaparib, the viability of cells with different XRCC2 levels was determined; cell cycle distribution and apoptosis were analyzed using flow cytometry. B-cell lymphoma-2 (Bcl-2) protein expression was measured by Western blotting. The positive rates of XRCC2 in primary CRC tissue were significantly higher than that in the matched adjacent noncancerous tissue, and XRCC2 expression status in primary CRC was related to tumor site, Dukes’ stage, and tumor-nodes-metastasis (TNM) stage. XRCC2 overexpression inhibited CRC cell apoptosis and promoted proliferation by enriching cells in the G0/G1 phase. Moreover, olaparib suppressed proliferation, and olaparib sensitivity in CRC cells with high XRCC2 expression was greater. High XRCC2 expression promotes CRC cell proliferation and enriches cells in the G0/G1 phase but inhibits apoptosis. High XRCC2 expression cells are more sensitive to olaparib, which inhibits their viability. PMID:25526472

  13. Macrophage migratory inhibitory factor promotes bladder cancer progression via increasing proliferation and angiogenesis

    PubMed Central

    Taylor, John A.

    2013-01-01

    Macrophage migratory inhibitory factor (MIF) is a proinflammatory cytokine shown to promote tumorigenesis. Using the N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) model of bladder cancer, we previously showed that MIF knockout mice display decreased angiogenesis and invasion compared with wild-type. This study examines the role of MIF in bladder cancer via use of oral inhibitors of MIF. In vitro, high-grade bladder cancer cells were treated with recombinant human MIF +/− (rhMIF+/−) inhibitor. Measurements included cell counts, proliferation by 3H-thymidine incorporation (TdR), extracellular signal-regulated kinase (ERK) phosphorylation by western blot analysis, messenger RNA (mRNA) expression by quantitative PCR and protein secretion by enzyme-linked immunosorbent assay. Treatment with rhMIF increased ERK phosphorylation, cell counts, TdR and mRNA expression and protein secretion of vascular endothelial growth factor, which were blocked by specific inhibitors of ERK and MIF. In vivo, 3-month-old male C57Bl/6 mice were given BBN for 22 and 16 weeks in study 1 and study 2, respectively. Mice (n = 8–10 per group) were gavaged with vehicle or doses of MIF inhibitors daily from weeks 16–22 in both studies. Average bladder weights, reflecting tumor mass, tumor stage/burden, mitotic rate and proliferation indices, and microvessel densities were reduced in inhibitor groups versus controls. In summary, MIF promotes bladder cancer via increasing cell proliferation and angiogenesis and oral inhibitors of MIF may prove useful in treatment of this disease. PMID:23825153

  14. Arsenic and chromium in drinking water promote tumorigenesis in a mouse colitis-associated colorectal cancer model and the potential mechanism is ROS-mediated Wnt/β-catenin signaling pathway.

    PubMed

    Wang, Xin; Mandal, Ardhendu K; Saito, Hiroshi; Pulliam, Joseph F; Lee, Eun Y; Ke, Zun-Ji; Lu, Jian; Ding, Songze; Li, Li; Shelton, Brent J; Tucker, Thomas; Evers, B Mark; Zhang, Zhuo; Shi, Xianglin

    2012-07-01

    Exposure to carcinogenic metals, such as trivalent arsenic [As(III)] and hexavalent chromium [Cr(VI)], through drinking water is a major global public health problem and is associated with various cancers. However, the mechanism of their carcinogenicity remains unclear. In this study, we used azoxymethane/dextran sodium sulfate (AOM/DSS)-induced mouse colitis-associated colorectal cancer model to investigate their tumorigenesis. Our results demonstrate that exposure to As(III) or Cr(VI), alone or in combination, together with AOM/DSS pretreatment has a promotion effect, increasing the colorectal tumor incidence, multiplicity, size, and grade, as well as cell inflammatory response. Two-dimensional differential gel electrophoresis coupled with mass spectrometry revealed that As(III) or Cr(VI) treatment alone significantly changed the density of proteins. The expression of β-catenin and phospho-GSK was increased by treatment of carcinogenic metals alone. Concomitantly, the expression of NADPH oxidase1 (NOX1) and the level of 8-OHdG were also increased by treatment of carcinogenic metals alone. Antioxidant enzymes, such as superoxide dismutase (SOD) and catalase, were decreased. Similarly, in an in vitro system, exposure of CRL-1807 to carcinogenic metals increased reactive oxygen species (ROS) generation, the expression of β-catenin, phospho-GSK, and NOX1. Inhibition of ROS generation by addition of SOD or catalase inhibited β-catenin expression and activity. Our study provides a new animal model to study the carcinogenicity of As(III) and Cr(VI) and suggests that As(III) and Cr(VI) promote colorectal cancer tumorigenesis, at least partly, through ROS-mediated Wnt/β-catenin signaling pathway. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Arsenic and chromium in drinking water promote tumorigenesis in a mouse colitis-associated colorectal cancer model and the potential mechanism is ROS-mediated Wnt/β-catenin signaling pathway

    PubMed Central

    Wang, Xin; Mandal, Ardhendu K.; Saito, Hiroshi; Pulliam, Joseph F.; Lee, Eun Y.; Ke, Zun-Ji; Lu, Jian; Ding, Songze; Li, Li; Shelton, Brent J; Tucker, Thomas; Evers, B. Mark; Zhang, Zhuo; Shi, Xianglin

    2015-01-01

    Exposure to carcinogenic metals, such as trivalent arsenic [As(III)] and hexavalent chromium [Cr(VI)], through drinking water is a major global public health problem and is associated with various cancers. However, the mechanism of their carcinogenicity remains unclear. In this study, we used azoxymethane/dextran sodium sulfate (AOM/DSS)-induced mouse colitis-associated colorectal cancer model to investigate their tumorigenesis. Our results demonstrate that exposure to As(III) or Cr(VI), alone or in combination, together with AOM/DSS pretreatment has a promotion effect, increasing the colorectal tumor incidence, multiplicity, size, and grade, as well as cell inflammatory response. Two-dimensional differential gel electrophoresis coupled with mass spectrometry revealed that As(III) or Cr(VI) treatment alone significantly changed the density of proteins. The expression of β-catenin and phospho-GSK was increased by treatment of carcinogenic metals alone. Concomitantly, the expression of NADPH oxidase1 (NOX1) and the level of 8-OHdG were also increased by treatment of carcinogenic metals alone. Antioxidant enzymes, such as superoxide dismutase (SOD) and catalase, were decreased. Similarly, in an in vitro system, exposure of CRL-1807 to carcinogenic metals increased reactive oxygen species (ROS) generation, the expression of β-catenin, phospho-GSK, and NOX1. Inhibition of ROS generation by addition of SOD or catalase inhibited β-catenin expression and activity. Our study provides a new animal model to study the carcinogenicity of As(III) and Cr(VI) and suggest that As(III) and Cr(VI) promote colorectal cancer tumorigenesis, at least partly, through ROS-mediated Wnt/β-catenin signaling pathway. PMID:22552367

  16. Altered Arsenic Disposition in Experimental Nonalcoholic Fatty Liver Disease

    PubMed Central

    Canet, Mark J.; Hardwick, Rhiannon N.; Lake, April D.; Kopplin, Michael J.; Scheffer, George L.; Klimecki, Walter T.; Gandolfi, A. Jay

    2012-01-01

    Nonalcoholic fatty liver disease (NAFLD) is represented by a spectrum of liver pathologies ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Liver damage sustained in the progressive stages of NAFLD may alter the ability of the liver to properly metabolize and eliminate xenobiotics. The purpose of the current study was to determine whether NAFLD alters the disposition of the environmental toxicant arsenic. C57BL/6 mice were fed either a high-fat or a methionine-choline-deficient diet to model simple steatosis and NASH, respectively. At the conclusion of the dietary regimen, all mice were given a single oral dose of either sodium arsenate or arsenic trioxide. Mice with NASH excreted significantly higher levels of total arsenic in urine (24 h) compared with controls. Total arsenic in the liver and kidneys of NASH mice was not altered; however, NASH liver retained significantly higher levels of the monomethyl arsenic metabolite, whereas dimethyl arsenic was retained significantly less in the kidneys of NASH mice. NASH mice had significantly higher levels of the more toxic trivalent form in their urine, whereas the pentavalent form was preferentially retained in the liver of NASH mice. Moreover, hepatic protein expression of the arsenic biotransformation enzyme arsenic (3+ oxidation state) methyltransferase was not altered in NASH animals, whereas protein expression of the membrane transporter multidrug resistance-associated protein 1 was increased, implicating cellular transport rather than biotransformation as a possible mechanism. These results suggest that NASH alters the disposition of arsenical species, which may have significant implications on the overall toxicity associated with arsenic in NASH. PMID:22699396

  17. Interleukin-11 promotes the progress of gastric carcinoma via abnormally expressed versican.

    PubMed

    Zhang, Zhenwei; Zhang, Jianpeng; Miao, Lei; Liu, Ke; Yang, Shengsheng; Pan, Chuanyong; Jiao, Binghua

    2012-01-01

    Versican, a ubiquitous component of the extracellular matrix (ECM), accumulates both in tumor stroma and cancer cells and is highly regulated by various cytokines. The aberrant expression of versican and its isoforms is known to modulate cell proliferation, differentiation, and migration, all of which are features of the invasion and metastasis of cancer; versican is also known to favour the homeostasis of the ECM. Interleukin-11 (IL-11) is an important cytokine that exhibits a wide variety of biological effects in gastric cancer development. Here, we analysed the expression of versican isoforms and found that the major isoforms expressed by both gastric carcinoma tissue and gastric cell lines were V0 and V1, and V1 was significantly higher in gastric carcinoma tissue. The treatment of the gastric cell lines AGS and MKN45 with rhIL-11 resulted in a significant increase in the expression of V0 and V1. Exogenous IL-11 increased migration in AGS and MKN45 cells, whereas these effects were reversed when the expression of V0 and V1 were abolished by siRNA targeting versican V0/V1. Collectively, these findings suggest that the abnormally expressed versican and its isoforms participate, at least in part, in the progress of gastric carcinoma triggered by IL-11.

  18. Ran GTPase promotes cancer progression via Met receptor-mediated downstream signaling

    PubMed Central

    Yuen, Hiu-Fung; Chan, Ka-Kui; Platt-Higgins, Angela; Dakir, El-Habib; Matchett, Kyle B.; Haggag, Yusuf Ahmed; Jithesh, Puthen V.; Habib, Tanwir; Faheem, Ahmed; Dean, Fennell A.; Morgan, Richard; Rudland, Philip S.; El-Tanani, Mohamed

    2016-01-01

    It has been shown previously that cancer cells with an activated oncogenic pathway, including Met activation, require Ran for growth and survival. Here, we show that knockdown of Ran leads to a reduction of Met receptor expression in several breast and lung cancer cell lines. This, in turn suppressed HGF expression and the Met-mediated activation of the Akt pathway, as well as cell adhesion, migration, and invasion. In a cell line model where Met amplification has previously been shown to contribute to gefitinib resistance, Ran knockdown sensitized cells to gefitinib-mediated inhibition of Akt and ERK1/2 phosphorylation and consequently reduced cell proliferation. We further demonstrate that Met reduction-mediated by knockdown of Ran, occurs at the post-transcriptional level, probably via a matrix metalloproteinase. Moreover, the level of immunoreactive Ran and Met are positively associated in human breast cancer specimens, suggesting that a high level of Ran may be a pre-requisite for Met overexpression. Interestingly, a high level of immunoreactive Ran dictates the prognostic significance of Met, indicating that the co-overexpression of Met and Ran may be associated with cancer progression and could be used in combination as a prognostic indicator. PMID:27716616

  19. CSE1L interaction with MSH6 promotes osteosarcoma progression and predicts poor patient survival.

    PubMed

    Cheng, Dong-Dong; Lin, He-Chun; Li, Shi-Jie; Yao, Ming; Yang, Qing-Cheng; Fan, Cun-Yi

    2017-04-07

    To discover tumor-associated proteins in osteosarcoma, a quantitative proteomic analysis was performed to identify proteins that were differentially expressed between osteosarcoma and human osteoblastic cells. Through clinical screening and a functional evaluation, chromosome segregation 1-like (CSE1L) protein was found to be related to the growth of osteosarcoma cells. To date, little is known about the function and underlying mechanism of CSE1L in osteosarcoma. In the present study, we show that knockdown of CSE1L inhibits osteosarcoma growth in vitro and in vivo. By co-immunoprecipitation and RNA-seq analysis, CSE1L was found to interact with mutS homolog 6 (MSH6) and function as a positive regulator of MSH6 protein in osteosarcoma cells. A rescue study showed that decreased growth of osteosarcoma cells by CSE1L knockdown was reversed by MSH6 overexpression, indicating that the activity of CSE1L was an MSH6-dependent function. In addition, depletion of MSH6 hindered cellular proliferation in vitro and in vivo. Notably, CSE1L expression was correlated with MSH6 expression in tumor samples and was associated with poor prognosis in patients with osteosarcoma. Taken together, our results demonstrate that the CSE1L-MSH6 axis has an important role in osteosarcoma progression.

  20. CSE1L interaction with MSH6 promotes osteosarcoma progression and predicts poor patient survival

    PubMed Central

    Cheng, Dong-dong; Lin, He-chun; Li, Shi-jie; Yao, Ming; Yang, Qing-cheng; Fan, Cun-yi

    2017-01-01

    To discover tumor-associated proteins in osteosarcoma, a quantitative proteomic analysis was performed to identify proteins that were differentially expressed between osteosarcoma and human osteoblastic cells. Through clinical screening and a functional evaluation, chromosome segregation 1-like (CSE1L) protein was found to be related to the growth of osteosarcoma cells. To date, little is known about the function and underlying mechanism of CSE1L in osteosarcoma. In the present study, we show that knockdown of CSE1L inhibits osteosarcoma growth in vitro and in vivo. By co-immunoprecipitation and RNA-seq analysis, CSE1L was found to interact with mutS homolog 6 (MSH6) and function as a positive regulator of MSH6 protein in osteosarcoma cells. A rescue study showed that decreased growth of osteosarcoma cells by CSE1L knockdown was reversed by MSH6 overexpression, indicating that the activity of CSE1L was an MSH6-dependent function. In addition, depletion of MSH6 hindered cellular proliferation in vitro and in vivo. Notably, CSE1L expression was correlated with MSH6 expression in tumor samples and was associated with poor prognosis in patients with osteosarcoma. Taken together, our results demonstrate that the CSE1L-MSH6 axis has an important role in osteosarcoma progression. PMID:28387323

  1. NDRG1 overexpression promotes the progression of esophageal squamous cell carcinoma through modulating Wnt signaling pathway.

    PubMed

    Ai, Runna; Sun, Yulin; Guo, Zhimin; Wei, Wei; Zhou, Lanping; Liu, Fang; Hendricks, Denver T; Xu, Yang; Zhao, Xiaohang

    2016-09-01

    N-myc down-regulated gene 1 (NDRG1) has been shown to regulate tumor growth and metastasis in various malignant tumors and also to be dysregulated in esophageal squamous cell carcinoma (ESCC). Here, we show that NDRG1 overexpression (91.9%, 79/86) in ESCC tumor tissues is associated with poor overall survival of esophageal cancer patients. When placed in stable transfectants of the KYSE 30 ESCC cell line generated by lentiviral transduction with the ectopic overexpression of NDRG1, the expression of transducin-like enhancer of Split 2 (TLE2) was decreased sharply, however β-catenin was increased. Mechanistically, NDRG1 physically associates with TLE2 and β-catenin to affect the Wnt pathway. RNA interference and TLE2 overexpression studies demonstrate that NDRG1 fails to active Wnt pathway compared with isogenic wild-type controls. Strikingly, NDRG1 overexpression induces the epithelial mesenchymal transition (EMT) through activating the Wnt signaling pathway in ESCC cells, decreased the expression of E-cadherin and enhanced the expression of Snail. Our study elucidates a mechanism of NDRG1-regulated Wnt pathway activation and EMT via affecting TLE2 and  β-catenin expression in esophageal cancer cells. This indicates a pro-oncogenic role for NDRG1 in esophageal cancer cells whereby it modulates tumor progression.

  2. The Werner's Syndrome protein collaborates with REV1 to promote replication fork progression on damaged DNA

    PubMed Central

    Phillips, Lara G.; Sale, Julian E.

    2010-01-01

    DNA damage tolerance pathways facilitate the bypass of DNA lesions encountered during replication. These pathways can be mechanistically divided into recombinational damage avoidance and translesion synthesis, in which the lesion is directly bypassed by specialised DNA polymerases. We have recently shown distinct genetic dependencies for lesion bypass at and behind the replication fork in the avian cell line DT40, bypass at the fork requiring REV1 and bypass at post-replicative gaps requiring PCNA ubiquitination by RAD18. The WRN helicase/exonuclease, which is mutated in the progeroid and cancer predisposition disorder Werner's Syndrome, has previously been implicated in a RAD18-dependent DNA damage tolerance pathway. However, WRN has also been shown to be required to maintain normal replication fork progression on a damaged DNA template, a defect reminiscent of REV1-deficient cells. Here we use the avian cell line DT40 to demonstrate that WRN assists REV1-dependent translesion synthesis at the replication fork and that PCNA ubiquitination-dependent post-replicative lesion bypass provides an important backup mechanism for damage tolerance in the absence of WRN protein. PMID:20691646

  3. Development of a gas-promoted oil agglomeration process. Technical progress report, April 1, 1995--June 30, 1995

    SciTech Connect

    Wheelock, T.D.

    1995-12-01

    Several scale model mixing systems have been built and are being utilized to study the gas-promoted, oil agglomeration process for cleaning coal. Numerous batch agglomeration tests have been conducted with these systems. During an individual test the progress of agglomeration has been monitored by observing either changes in agitator torque in the case of concentrated particle suspensions or changes in turbidity in the case of dilute suspensions. A mathematical model has been developed for relating the rate of agglomeration of coal particles to the rate of change of turbidity of a dilute particle suspension undergoing agglomeration. The model has been utilized for analyzing and interpreting the results of a number of oil agglomeration tests in which several different system parameters were varied.

  4. The global burden of disease for skin, lung, and bladder cancer caused by arsenic in food.

    PubMed

    Oberoi, Shilpi; Barchowsky, Aaron; Wu, Felicia

    2014-07-01

    Arsenic is a ubiquitous, naturally occurring metalloid that poses a significant human cancer risk. While water consumption provides the majority of human exposure, millions of individuals worldwide are significantly exposed to arsenic through naturally occurring levels of arsenic in grains, vegetables, meats and fish, as well as through food processed with water containing arsenic. Thus, we estimated the global burdens of disease for bladder, lung, and skin cancers attributable to inorganic arsenic in food. To determine foodborne inorganic arsenic exposures worldwide, we used World Health Organization estimates of food consumption in thirteen country clusters, in conjunction with reported measurements of total and inorganic arsenic in different foods. We estimated slope factors for arsenic-related bladder and lung cancers, and used the U.S. Environmental Protection Agency skin cancer slope factor, to calculate the annual risk of the cancer incidence in males and females within each country cluster. We estimated that each year 9,129 to 119,176 additional cases of bladder cancer, 11,844 to 121,442 of lung cancer, and 10,729 to 110,015 of skin cancer worldwide are attributable to inorganic arsenic in food. These estimates indicate that foodborne arsenic exposure causes a significant global burden of human disease. Estimating the global cancer burden caused by arsenic exposure in food will support policies that reduce exposure to disease-promoting environmental hazards. ©2014 American Association for Cancer Research.

  5. Environmental biochemistry of arsenic.

    PubMed

    Tamaki, S; Frankenberger, W T

    1992-01-01

    Microorganisms are involved in the redistribution and global cycling of arsenic. Arsenic can accumulate and can be subject to various biotransformations including reduction, oxidation, and methylation. Bacterial methylation of inorganic arsenic is coupled to the methane biosynthetic pathway in methanogenic bacteria under anaerobic conditions and may be a mechanism for arsenic detoxification. The pathway proceeds by reduction of arsenate to arsenite followed by methylation to dimethylarsine. Fungi are also able to transform inorganic and organic arsenic compounds into volatile methylarsines. The pathway proceeds aerobically by arsenate reduction to arsenite followed by several methylation steps producing trimethylarsine. Volatile arsine gases are very toxic to mammals because they destroy red blood cells (LD50 in rats; 3.0 mg kg-1). Further studies are needed on dimethylarsine and trimethylarsine toxicity tests through inhalation of target animals. Marine algae transform arsenate into non-volatile methylated arsenic compounds (methanearsonic and dimethylarsinic acids) in seawater. This is considered to be a beneficial step not only to the primary producers, but also to the higher trophic levels, since non-volatile methylated arsenic is much less toxic to marine invertebrates. Freshwater algae like marine algae synthesize lipid-soluble arsenic compounds and do not produce volatile methylarsines. Aquatic plants also synthesize similar lipid-soluble arsenic compounds. In terrestrial plants, arsenate is preferentially taken up 3 to 4 times the rate of arsenite. In the presence of phosphate, arsenate uptake is inhibited while in the presence of arsenate, phosphate uptake is only slightly inhibited. There is a competitive interaction between arsenate and phosphate for the same uptake system in terrestrial plants. The mode of toxicity of arsenate is to partially block protein synthesis and interfere with protein phosphorylation but the presence of phosphate prevents this

  6. OTX1 promotes colorectal cancer progression through epithelial-mesenchymal transition

    SciTech Connect

    Yu, Kun; Cai, Xin-Yi; Li, Qiang; Yang, Zhi-Bin; Xiong, Wei; Shen, Tao; Wang, Wei-Ya; Li, Yun-Feng

    2014-01-31

    Highlights: • OTX1 is overexpression in colorectal cancer tissues. • Overexpression of OTX1 promotes colorectal cancer cell proliferation and invasion in vitro and tumor growth in vivo. • Depletion of OTX1 inhibits colorectal cancer cell proliferation and invasion in vitro. • Overexpression of OTX1 is linked to the EMT-like phenotype. - Abstract: Orthodenticle homeobox 1 (OTX1), a transcription factor containing a bicoid-like homeodomain, plays a role in brain and sensory organ development. In this study, we report that OTX1 is overexpressed in human colorectal cancer (CRC) and OTX1 overexpression is associated with higher stage. Functional analyses reveal that overexpression of OTX1 results in accumulation of CRC cell proliferation and invasion in vitro and tumor growth in vivo, whereas ablation of OTX1 expression significantly inhibits the proliferative and invasive capability of CRC cells in vitro. Together, our results indicate that OTX1 is involved in human colon carcinogenesis and may serve as a potential therapeutic target for human colorectal cancer.

  7. MiR-449a promotes breast cancer progression by targeting CRIP2.

    PubMed

    Shi, Wei; Bruce, Jeff; Lee, Matthew; Yue, Shijun; Rowe, Matthew; Pintilie, Melania; Kogo, Ryunosuke; Bissey, Pierre-Antoine; Fyles, Anthony; Yip, Kenneth W; Liu, Fei-Fei

    2016-04-05

    The identification of prognostic biomarkers and their underlying mechanisms of action remain of great interest in breast cancer biology. Using global miRNA profiling of 71 lymph node-negative invasive ductal breast cancers and 5 normal mammary epithelial tissues, we identified miR-449a to be highly overexpressed in the malignant breast tissue. Its expression was significantly associated with increased incidence of patient relapse, decreased overall survival, and decreased disease-free survival. In vitro, miR-449a promoted breast cancer cell proliferation, clonogenic survival, migration, and invasion. By utilizing a tri-modal in silico approach for target identification, Cysteine-Rich Protein 2 (CRIP2; a transcription factor) was identified as a direct target of miR-449a, corroborated using qRT-PCR, Western blot, and luciferase reporter assays. MDA-MB-231 cells stably transfected with CRIP2 demonstrated a significant reduction in cell viability, migration, and invasion, as well as decreased tumor growth and angiogenesis in mouse xenograft models. Our data revealed that overexpression of miR-449a suppresses CRIP2, which then affects the tumor vasculature, likely via NF-κB/p65 complex-mediated transcription of VEGF. These finding define an oncogenic function of miR-449a in human breast cancer, and highlight the importance of this pathway in driving aggressive behaviour.

  8. Prefoldin 1 promotes EMT and lung cancer progression by suppressing cyclin A expression

    PubMed Central

    Wang, D; Shi, W; Tang, Y; Liu, Y; He, K; Hu, Y; Li, J; Yang, Y; Song, J

    2017-01-01

    Prefoldin (PFDN) is a co-chaperone protein that is primarily known for its classic cytoplasmic functions in the folding of actin and tubulin monomers during cytoskeletal assembly. Here, we report a marked increase in prefoldin subunit 1 (PFDN1) levels during the transforming growth factor (TGF)-β1-mediated epithelial-mesenchymal transition (EMT) and in human lung tumor tissues. Interestingly, the nuclear localization of PFDN1 was also detected. These observations suggest that PFDN1 may be essential for important novel functions. Overexpression of PFDN1 induced EMT and cell invasion. In sharp contrast, knockdown of PFDN1 generated the opposite effects. Overexpression of PFDN1 was also found to induce lung tumor growth and metastasis. Further experiments showed that PFDN1 overexpression inhibits the expression of cyclin A. PFDN1 suppressed cyclin A expression by directly interacting with the cyclin A promoter at the transcriptional start site. Strikingly, cyclin A overexpression abolished the above PFDN1-mediated effects on the behavior of lung cancer cells, whereas cyclin A knockdown alone induced EMT and increased cell migration and invasion ability. This study reveals that the TGF-β1/PFDN1/cyclin A axis is essential for EMT induction and metastasis of lung cancer cells. PMID:27694898

  9. Inflammatory monocytes promote progression of Duchenne muscular dystrophy and can be therapeutically targeted via CCR2.

    PubMed

    Mojumdar, Kamalika; Liang, Feng; Giordano, Christian; Lemaire, Christian; Danialou, Gawiyou; Okazaki, Tatsuma; Bourdon, Johanne; Rafei, Moutih; Galipeau, Jacques; Divangahi, Maziar; Petrof, Basil J

    2014-11-01

    Myofiber necrosis and fibrosis are hallmarks of Duchenne muscular dystrophy (DMD), leading to lethal weakness of the diaphragm. Macrophages (MPs) are required for successful muscle regeneration, but the role of inflammatory monocyte (MO)-derived MPs in either promoting or mitigating DMD is unclear. We show that DMD (mdx) mouse diaphragms exhibit greatly increased expression of CCR2 and its chemokine ligands, along with inflammatory (Ly6C(high)) MO recruitment and accumulation of CD11b(high) MO-derived MPs. Loss-of-function of CCR2 preferentially reduced this CD11b(high) MP population by impeding the release of Ly6C(high) MOs from the bone marrow but not the splenic reservoir. CCR2 deficiency also helped restore the MP polarization balance by preventing excessive skewing of MPs toward a proinflammatory phenotype. These effects were linked to amelioration of histopathological features and increased muscle strength in the diaphragm. Chronic inhibition of CCR2 signaling by mutated CCL2 secreted from implanted mesenchymal stem cells resulted in similar improvements. These data uncover a previously unrecognized role of inflammatory MOs in DMD pathogenesis and indicate that CCR2 inhibition could offer a novel strategy for DMD management.

  10. Circadian Clock in a Mouse Colon Tumor Regulates Intracellular Iron Levels to Promote Tumor Progression*

    PubMed Central

    Okazaki, Fumiyasu; Matsunaga, Naoya; Okazaki, Hiroyuki; Azuma, Hiroki; Hamamura, Kengo; Tsuruta, Akito; Tsurudome, Yuya; Ogino, Takashi; Hara, Yukinori; Suzuki, Takuya; Hyodo, Kenji; Ishihara, Hiroshi; Kikuchi, Hiroshi; To, Hideto; Aramaki, Hironori; Koyanagi, Satoru; Ohdo, Shigehiro

    2016-01-01

    Iron is an important biological catalyst and is critical for DNA synthesis during cell proliferation. Cellular iron uptake is enhanced in tumor cells to support increased DNA synthesis. Circadian variations in DNA synthesis and proliferation have been identified in tumor cells, but their relationship with intracellular iron levels is unclear. In this study, we identified a 24-h rhythm in iron regulatory protein 2 (IRP2) levels in colon-26 tumors implanted in mice. Our findings suggest that IRP2 regulates the 24-h rhythm of transferrin receptor 1 (Tfr1) mRNA expression post-transcriptionally, by binding to RNA stem-loop structures known as iron-response elements. We also found that Irp2 mRNA transcription is promoted by circadian clock genes, including brain and muscle Arnt-like 1 (BMAL1) and the circadian locomotor output cycles kaput (CLOCK) heterodimer. Moreover, growth in colon-26(Δ19) tumors expressing the clock-mutant protein (CLOCKΔ19) was low compared with that in wild-type colon-26 tumor. The time-dependent variation of cellular iron levels, and the proliferation rate in wild-type colon-26 tumor was decreased by CLOCKΔ19 expression. Our findings suggest that circadian organization contributes to tumor cell proliferation by regulating iron metabolism in the tumor. PMID:26797126

  11. Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression.

    PubMed

    Miao, H Q; Lee, P; Lin, H; Soker, S; Klagsbrun, M

    2000-12-01

    Neuropilin-1 (NRP1) is a VEGF(165) and semaphorin receptor expressed by vascular endothelial cells (EC) and tumor cells. The function of NRP1 in tumor cells is unknown. NRP1 was overexpressed in Dunning rat prostate carcinoma AT2.1 cells using a tetracycline-inducible promoter. Concomitant with increased NRP1 expression in response to a tetracycline homologue, doxycycline (Dox), basal cell motility, and VEGF(165) binding were increased three- to fourfold in vitro. However, induction of NRP1 did not affect tumor cell proliferation. When rats injected with AT2.1/NRP1 tumor cells were fed Dox, NRP1 synthesis was induced in vivo and AT2.1 cell tumor size was increased 2.5- to 7-fold in a 3-4 wk period compared to controls. The larger tumors with induced NRP1 expression were characterized by markedly increased microvessel density, increased proliferating EC, dilated blood vessels, and notably less tumor cell apoptosis compared to noninduced controls. It was concluded that NRP1 expression results in enlarged tumors associated with substantially enhanced tumor angiogenesis.

  12. Structure and regulation of an archaebacterial promoter: An in vivo study. Progress report

    SciTech Connect

    Daniels, C.J.

    1993-12-31

    In the initial grant period the authors have devised an in vivo assay system for the analysis of gene expression in the halophilic archaea. This system has been used to analyzed the H. volcanii tRNALys promoter where it was found that the a 40 bp fragment carrying BoxA and BoxB sequences in sufficient for in vivo expression. Detailed analysis of the BoxA element indicates that the BoxA TA sequence is essential for efficient expression. Support for the hypothesis that all archaea share common transcriptional signals was obtained when a methanogen tRNAGln gene, with its associated BoxA sequence, was found to direct its own transcription in H. volcanii. In related experiments a eukaryotic RNA polymerase 3 terminator was found to act as a strong termination signal in H. volcanii. Sequence comparisons between this element and mapped RNA 3{prime} ends indicates that T-rich sequences may be important role in directing termination in vivo. Finally, in an attempt to establish a model system to study regulated gene expression, the authors have isolated a DNA fragment that encodes a heat shock inaudible transcript. This gene will not serve as a model for detailed studies of the mechanisms of gene expression in the archaea.

  13. MicroRNA-424 impairs ubiquitination to activate STAT3 and promote prostate tumor progression

    PubMed Central

    Dallavalle, Cecilia; Civenni, Gianluca; Merulla, Jessica; Ostano, Paola; Mello-Grand, Maurizia; Rossi, Simona; Losa, Marco; D’Ambrosio, Gioacchino; Sessa, Fausto; Thalmann, George N.; Zitella, Andrea; Chiorino, Giovanna; Catapano, Carlo V.

    2016-01-01

    Mutations and deletions in components of ubiquitin ligase complexes that lead to alterations in protein turnover are important mechanisms in driving tumorigenesis. Here we describe an alternative mechanism involving upregulation of the microRNA miR-424 that leads to impaired ubiquitination and degradation of oncogenic transcription factors in prostate cancers. We found that miR-424 targets the E3 ubiquitin ligase COP1 and identified STAT3 as a key substrate of COP1 in promoting tumorigenic and cancer stem-like properties in prostate epithelial cells. Altered protein turnover due to impaired COP1 function led to accumulation and enhanced basal and cytokine-induced activity of STAT3. We further determined that loss of the ETS factor ESE3/EHF is the initial event that triggers the deregulation of the miR-424/COP1/STAT3 axis. COP1 silencing and STAT3 activation were effectively reverted by blocking of miR-424, suggesting a possible strategy to attack this key node of tumorigenesis in ESE3/EHF–deficient tumors. These results establish miR-424 as an oncogenic effector linked to noncanonical activation of STAT3 and as a potential therapeutic target. PMID:27820701

  14. High expression of small GTPase Rab3D promotes cancer progression and metastasis

    PubMed Central

    Yang, Jian; Liu, Wei; Lu, Xin'an; Fu, Yan; Li, Lin; Luo, Yongzhang

    2015-01-01

    Rab GTPases control exocytic and endocytic membrane trafficking such as exosomes release. As a secretory small GTPase, Rab3D is a vital regulator for protein secretion. However, the role of Rab3D in cancer was never systematically studied. The aim of this study is to examine its function and mechanism in cancer, especially metastasis. We detected protein levels of Rab3D in nine cancer cell lines and twelve types of clinical cancer specimens. Subsequently, we established in vitro migration and in vivo orthotopic metastatic mouse models to study the role of Rab3D in tumor metastasis. Here, we reported that the expression levels of Rab3D were dysregulated in cancer cells and highly correlated with tumor malignancies in the clinical samples. Increased expressions of Rab3D led to tumor invasion in vitro and lung metastasis in vivo, whereas Rab3D knockdown suppressed the tumor cell motility. Mechanistic studies revealed that Rab3D activated intracellular the AKT/GSK3β signaling to induce the EMT process. In addition, it also regulated the extracellular secretion of Hsp90α to promote tumor cell migration and invasion. These results prove that Rab3D is a key molecule to regulate tumor metastasis, suggesting that blocking the Rab3D function can be a potential therapeutic approach for cancer metastasis. PMID:25823663

  15. Extracellular matrix protein Reelin promotes myeloma progression by facilitating tumor cell proliferation and glycolysis

    PubMed Central

    Qin, Xiaodan; Lin, Liang; Cao, Li; Zhang, Xinwei; Song, Xiao; Hao, Jie; Zhang, Yan; Wei, Risheng; Huang, Xiaojun; Lu, Jin; Ge, Qing

    2017-01-01

    Reelin is an extracellular matrix protein that is crucial for neuron migration, adhesion, and positioning. We examined the expression of Reelin in a large cohort of multiple myeloma patients recorded in Gene Expression Omnibus (GEO) database and used over-expression and siRNA knockdown of Reelin to investigate the role of Reelin in myeloma cell growth. We find that Reelin expression is negatively associated with myeloma prognosis. Reelin promotes myeloma cell proliferation in vitro as well as in vivo. The Warburg effect, evidenced by increased glucose uptake and lactate production, is also enhanced in Reelin-expressing cells. The activation of FAK/Syk/Akt/mTOR and STAT3 pathways contributes to Reelin-induced cancer cell growth and metabolic reprogramming. Our findings further reveal that activated Akt and STAT3 pathways induce the upregulation of HIF1α and its downstream targets (LDHA and PDK1), leading to increased glycolysis in myeloma cells. Together, our results demonstrate the critical contributions of Reelin to myeloma growth and metabolism. It presents an opportunity for myeloma therapeutic intervention by inhibiting Reelin and its signaling pathways. PMID:28345605

  16. The adhesion molecule NCAM promotes ovarian cancer progression via FGFR signalling

    PubMed Central

    Zecchini, Silvia; Bombardelli, Lorenzo; Decio, Alessandra; Bianchi, Marco; Mazzarol, Giovanni; Sanguineti, Fabio; Aletti, Giovanni; Maddaluno, Luigi; Berezin, Vladimir; Bock, Elisabeth; Casadio, Chiara; Viale, Giuseppe; Colombo, Nicoletta; Giavazzi, Raffaella; Cavallaro, Ugo

    2011-01-01

    Epithelial ovarian carcinoma (EOC) is an aggressive neoplasm, which mainly disseminates to organs of the peritoneal cavity, an event mediated by molecular mechanisms that remain elusive. Here, we investigated the expression and functional role of neural cell adhesion molecule (NCAM), a cell surface glycoprotein involved in brain development and plasticity, in EOC. NCAM is absent from normal ovarian epithelium but becomes highly expressed in a subset of human EOC, in which NCAM expression is associated with high tumour grade, suggesting a causal role in cancer aggressiveness. We demonstrate that NCAM stimulates EOC cell migration and invasion in vitro and promotes metastatic dissemination in mice. This pro-malignant function of NCAM is mediated by its interaction with fibroblast growth factor receptor (FGFR). Indeed, not only FGFR signalling is required for NCAM-induced EOC cell motility, but targeting the NCAM/FGFR interplay with a monoclonal antibody abolishes the metastatic dissemination of EOC in mice. Our results point to NCAM-mediated stimulation of FGFR as a novel mechanism underlying EOC malignancy and indicate that this interplay may represent a valuable therapeutic target. PMID:21739604

  17. MicroRNA-424 impairs ubiquitination to activate STAT3 and promote prostate tumor progression.

    PubMed

    Dallavalle, Cecilia; Albino, Domenico; Civenni, Gianluca; Merulla, Jessica; Ostano, Paola; Mello-Grand, Maurizia; Rossi, Simona; Losa, Marco; D'Ambrosio, Gioacchino; Sessa, Fausto; Thalmann, George N; Garcia-Escudero, Ramon; Zitella, Andrea; Chiorino, Giovanna; Catapano, Carlo V; Carbone, Giuseppina M

    2016-12-01

    Mutations and deletions in components of ubiquitin ligase complexes that lead to alterations in protein turnover are important mechanisms in driving tumorigenesis. Here we describe an alternative mechanism involving upregulation of the microRNA miR-424 that leads to impaired ubiquitination and degradation of oncogenic transcription factors in prostate cancers. We found that miR-424 targets the E3 ubiquitin ligase COP1 and identified STAT3 as a key substrate of COP1 in promoting tumorigenic and cancer stem-like properties in prostate epithelial cells. Altered protein turnover due to impaired COP1 function led to accumulation and enhanced basal and cytokine-induced activity of STAT3. We further determined that loss of the ETS factor ESE3/EHF is the initial event that triggers the deregulation of the miR-424/COP1/STAT3 axis. COP1 silencing and STAT3 activation were effectively reverted by blocking of miR-424, suggesting a possible strategy to attack this key node of tumorigenesis in ESE3/EHF-deficient tumors. These results establish miR-424 as an oncogenic effector linked to noncanonical activation of STAT3 and as a potential therapeutic target.

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

    PubMed

    Yang, Lei; Zhu, Jia; 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.

  19. Chemokines and chemokine receptors as promoters of prostate cancer growth and progression.

    PubMed

    Salazar, Nicole; Castellan, Miguel; Shirodkar, Samir S; Lokeshwar, Bal L

    2013-01-01

    Prostate cancer (CaP) is estimated to be first in incidence among cancers, with more than 240,000 new cases in 2012 in the United States. Chemokines and their receptors provide survival, proliferation, and invasion characteristics to CaP cells in both primary sites of cancer and metastatic locations. The emerging data demonstrate that many chemokines and their receptors are involved in the multistep process of CaP, leading to metastasis, and, further, that these factors act cooperatively to enhance other mechanisms of tumor cell survival, growth, and metastasis. Changes of chemokine receptor cohorts may be necessary to activate tumor-promoting signals. Chemokine receptors can activate downstream effectors, such as mitogen-activated protein kinases, by complex mechanisms of ligand-dependent activation of cryptic growth factors; guanosine triphosphate-binding, protein-coupled activation of survival kinases; or transactivation of other receptors such as ErbB family members. We describe vanguard research in which more than the classic view of chemokine receptor biology was clarified. Control of chemokines and inhibition of their receptor activation may add critical tools to reduce tumor growth, especially in chemo-hormonal refractory CaP that is both currently incurable and the most aggressive form of the disease, accounting for most of the more than 28,000 annual deaths.

  20. Binational Arsenic Exposure Survey: Methodology and Estimated Arsenic Intake from Drinking Water and Urinary Arsenic Concentrations

    PubMed Central

    Roberge, Jason; O’Rourke, Mary Kay; Meza-Montenegro, Maria Mercedes; Gutiérrez-Millán, Luis Enrique; Burgess, Jefferey L.; Harris, Robin B.

    2012-01-01

    The Binational Arsenic Exposure Survey (BAsES) was designed to evaluate probable arsenic exposures in selected areas of southern Arizona and northern Mexico, two regions with known elevated levels of arsenic in groundwater reserves. This paper describes the methodology of BAsES and the relationship between estimated arsenic intake from beverages and arsenic output in urine. Households from eight communities were selected for their varying groundwater arsenic concentrations in Arizona, USA and Sonora, Mexico. Adults responded to questionnaires and provided dietary information. A first morning urine void and water from all household drinking sources were collected. Associations between urinary arsenic concentration (total, organic, inorganic) and estimated level of arsenic consumed from water and other beverages were evaluated through crude associations and by random effects models. Median estimated total arsenic intake from beverages among participants from Arizona communities ranged from 1.7 to 14.1 µg/day compared to 0.6 to 3.4 µg/day among those from Mexico communities. In contrast, median urinary inorganic arsenic concentrations were greatest among participants from Hermosillo, Mexico (6.2 µg/L) whereas a high of 2.0 µg/L was found among participants from Ajo, Arizona. Estimated arsenic intake from drinking water was associated with urinary total arsenic concentration (p < 0.001), urinary inorganic arsenic concentration (p < 0.001), and urinary sum of species (p < 0.001). Urinary arsenic concentrations increased between 7% and 12% for each one percent increase in arsenic consumed from drinking water. Variability in arsenic intake from beverages and urinary arsenic output yielded counter intuitive results. Estimated intake of arsenic from all beverages was greatest among Arizonans yet participants in Mexico had higher urinary total and inorganic arsenic concentrations. Other contributors to urinary arsenic concentrations should be evaluated. PMID:22690182

  1. Binational arsenic exposure survey: methodology and estimated arsenic intake from drinking water and urinary arsenic concentrations.

    PubMed

    Roberge, Jason; O'Rourke, Mary Kay; Meza-Montenegro, Maria Mercedes; Gutiérrez-Millán, Luis Enrique; Burgess, Jefferey L; Harris, Robin B

    2012-04-01

    The Binational Arsenic Exposure Survey (BAsES) was designed to evaluate probable arsenic exposures in selected areas of southern Arizona and northern Mexico, two regions with known elevated levels of arsenic in groundwater reserves. This paper describes the methodology of BAsES and the relationship between estimated arsenic intake from beverages and arsenic output in urine. Households from eight communities were selected for their varying groundwater arsenic concentrations in Arizona, USA and Sonora, Mexico. Adults responded to questionnaires and provided dietary information. A first morning urine void and water from all household drinking sources were collected. Associations between urinary arsenic concentration (total, organic, inorganic) and estimated level of arsenic consumed from water and other beverages were evaluated through crude associations and by random effects models. Median estimated total arsenic intake from beverages among participants from Arizona communities ranged from 1.7 to 14.1 µg/day compared to 0.6 to 3.4 µg/day among those from Mexico communities. In contrast, median urinary inorganic arsenic concentrations were greatest among participants from Hermosillo, Mexico (6.2 µg/L) whereas a high of 2.0 µg/L was found among participants from Ajo, Arizona. Estimated arsenic intake from drinking water was associated with urinary total arsenic concentration (p < 0.001), urinary inorganic arsenic concentration (p < 0.001), and urinary sum of species (p < 0.001). Urinary arsenic concentrations increased between 7% and 12% for each one percent increase in arsenic consumed from drinking water. Variability in arsenic intake from beverages and urinary arsenic output yielded counter intuitive results. Estimated intake of arsenic from all beverages was greatest among Arizonans yet participants in Mexico had higher urinary total and inorganic arsenic concentrations. Other contributors to urinary arsenic concentrations should be evaluated.

  2. Cyclic AMP can promote APL progression and protect myeloid leukemia cells against anthracycline-induced apoptosis

    PubMed Central

    Gausdal, G; Wergeland, A; Skavland, J; Nguyen, E; Pendino, F; Rouhee, N; McCormack, E; Herfindal, L; Kleppe, R; Havemann, U; Schwede, F; Bruserud, Ø; Gjertsen, B T; Lanotte, M; Ségal-Bendirdjian, E; Døskeland, S O

    2013-01-01

    We show that cyclic AMP (cAMP) elevating agents protect blasts from patients with acute promyelocytic leukemia (APL) against death induced by first-line anti-leukemic anthracyclines like daunorubicin (DNR). The cAMP effect was reproduced in NB4 APL cells, and shown to depend on activation of the generally cytoplasmic cAMP-kinase type I (PKA-I) rather than the perinuclear PKA-II. The protection of both NB4 cells and APL blasts was associated with (inactivating) phosphorylation of PKA site Ser118 of pro-apoptotic Bad and (activating) phosphorylation of PKA site Ser133 of the AML oncogene CREB. Either event would be expected to protect broadly against cell death, and we found cAMP elevation to protect also against 2-deoxyglucose, rotenone, proteasome inhibitor and a BH3-only mimetic. The in vitro findings were mirrored by the findings in NSG mice with orthotopic NB4 cell leukemia. The mice showed more rapid disease progression when given cAMP-increasing agents (prostaglandin E2 analog and theophylline), both with and without DNR chemotherapy. The all-trans retinoic acid (ATRA)-induced terminal APL cell differentiation is a cornerstone in current APL treatment and is enhanced by cAMP. We show also that ATRA-resistant APL cells, believed to be responsible for treatment failure with current ATRA-based treatment protocols, were protected by cAMP against death. This suggests that the beneficial pro-differentiating and non-beneficial pro-survival APL cell effects of cAMP should be weighed against each other. The results suggest also general awareness toward drugs that can affect bone marrow cAMP levels in leukemia patients. PMID:23449452

  3. Cyclic AMP can promote APL progression and protect myeloid leukemia cells against anthracycline-induced apoptosis.

    PubMed

    Gausdal, G; Wergeland, A; Skavland, J; Nguyen, E; Pendino, F; Rouhee, N; McCormack, E; Herfindal, L; Kleppe, R; Havemann, U; Schwede, F; Bruserud, O; Gjertsen, B T; Lanotte, M; Ségal-Bendirdjian, E; Døskeland, S O

    2013-02-28

    We show that cyclic AMP (cAMP) elevating agents protect blasts from patients with acute promyelocytic leukemia (APL) against death induced by first-line anti-leukemic anthracyclines like daunorubicin (DNR). The cAMP effect was reproduced in NB4 APL cells, and shown to depend on activation of the generally cytoplasmic cAMP-kinase type I (PKA-I) rather than the perinuclear PKA-II. The protection of both NB4 cells and APL blasts was associated with (inactivating) phosphorylation of PKA site Ser118 of pro-apoptotic Bad and (activating) phosphorylation of PKA site Ser133 of the AML oncogene CREB. Either event would be expected to protect broadly against cell death, and we found cAMP elevation to protect also against 2-deoxyglucose, rotenone, proteasome inhibitor and a BH3-only mimetic. The in vitro findings were mirrored by the findings in NSG mice with orthotopic NB4 cell leukemia. The mice showed more rapid disease progression when given cAMP-increasing agents (prostaglandin E2 analog and theophylline), both with and without DNR chemotherapy. The all-trans retinoic acid (ATRA)-induced terminal APL cell differentiation is a cornerstone in current APL treatment and is enhanced by cAMP. We show also that ATRA-resistant APL cells, believed to be responsible for treatment failure with current ATRA-based treatment protocols, were protected by cAMP against death. This suggests that the beneficial pro-differentiating and non-beneficial pro-survival APL cell effects of cAMP should be weighed against each other. The results suggest also general awareness toward drugs that can affect bone marrow cAMP levels in leukemia patients.

  4. Fibroblast-derived MT1-MMP promotes tumor progression in vitro and in vivo.

    PubMed

    Zhang, Wenyue; Matrisian, Lynn M; Holmbeck, Kenn; Vick, Catherine C; Rosenthal, Eben L

    2006-03-06

    Identification of fibroblast derived factors in tumor progression has the potential to provide novel molecular targets for modulating tumor cell growth and metastasis. Multiple matrix metalloproteases (MMPs) are expressed by both mesenchymal and epithelial cells within head and neck squamous cell carcinomas (HNSCCs), but the relative importance of these enzymes and the cell source is the subject of controversy. The invasive potential of HNSCC tumor cells were assessed in vitro atop type I collagen gels in coculture with wild-type (WT), MMP-2 null, MMP-9 null or MT1-MMP null fibroblasts. A floor of mouth mouse model of HNSCC was used to assess in vivo growth after co-injection of FaDu tumor cells with MMP null fibroblasts. Here we report changes in tumor phenotype when FaDu HNSCCs cells are cocultured with WT, MMP-2 null, MMP-9 null or MT1-MMP null fibroblasts in vitro and in vivo. WT, MMP-2 null and MMP-9 null fibroblasts, but not MT1-MMP null fibroblasts, spontaneously invaded into type I collagen gels. WT fibroblasts stimulated FaDu tumor cell invasion in coculture. This invasive phenotype was unaffected by combination with MMP-9 null fibroblasts, reduced with MMP-2 null fibroblasts (50%) and abrogated in MT1-MMP null fibroblasts. Co-injection of FaDu tumor cells with fibroblasts in an orthotopic oral cavity SCID mouse model demonstrated a reduction of tumor volume using MMP-9 and MMP-2 null fibroblasts (48% and 49%, respectively) compared to WT fibroblasts. Consistent with in vitro studies, MT1-MMP null fibroblasts when co-injected with FaDu cells resulted in a 90% reduction in tumor volume compared to FaDu cells injected with WT fibroblasts. These data suggest a role for fibroblast-derived MMP-2 and MT1-MMP in HNSCC tumor invasion in vitro and tumor growth in vivo.

  5. The hyposensitive N187D P2X7 mutant promotes malignant progression in nude mice.

    PubMed

    Chong, Jing-Hui; Zheng, Guo-Guang; Ma, Yuan-Yuan; Zhang, Hai-Yan; Nie, Kun; Lin, Yong-Min; Wu, Ke-Fu

    2010-11-12

    Nucleotides are new players in the intercellular communication network. P2X7 is a member of the P2X family of receptors, which are ATP-gated plasma membrane ion channels with diverse biological functions. Abnormal expression and dysfunction of P2X7 have been reported in leukemias. Here, we report a new P2X7 mutant (an A(559)-to-G substitution causing N187D P2X7) cloned from J6-1 leukemia cells. The characteristics of N187D P2X7 were studied by establishing stably transfected K562 cell lines. Our results show that N187D P2X7 required a higher concentration of agonist for its activation, leading to Ca(2+) influx (EC(50) = 293.3 ± 6.6 μm for the mutant and 93.6 ± 2.2 μm for wild-type P2X7) and ERK phosphorylation, which were not caused by differential cell-surface expression or related to high ATPase activity on the cell surface and in the extracellular space. K562 cells expressing this N187D mutant showed a proliferative advantage and reduced pro-apoptosis effects in vitro and in vivo. Furthermore, elevated angiogenesis and CD206-positive macrophage infiltration were found in tumor tissues formed by K562-M cells. In addition, higher expression of VEGF and MCP1 could be detected in tumor tissues formed by K562-M cells. Our results suggest that N187D P2X7, representing mutants hyposensitive to agonist, might be a positive regulator in the progression of hematopoietic malignancies.

  6. FBXO11 promotes ubiquitination of the Snail family of transcription factors in cancer progression and epidermal development.

    PubMed

    Jin, Yue; Shenoy, Anitha K; Doernberg, Samuel; Chen, Hao; Luo, Huacheng; Shen, Huangxuan; Lin, Tong; Tarrash, Miriam; Cai, Qingsong; Hu, Xin; Fiske, Ryan; Chen, Ting; Wu, Lizi; Mohammed, Kamal A; Rottiers, Veerle; Lee, Siu Sylvia; Lu, Jianrong

    2015-06-28

    The Snail family of transcription factors are core inducers of epithelial-to-mesenchymal transition (EMT). Here we show that the F-box protein FBXO11 recognizes and promotes ubiquitin-mediated degradation of multiple Snail family members including Scratch. The association between FBXO11 and Snai1 in vitro is independent of Snai1 phosphorylation. Overexpression of FBXO11 in mesenchymal cells reduces Snail protein abundance and cellular invasiveness. Conversely, depletion of endogenous FBXO11 in epithelial cancer cells causes Snail protein accumulation, EMT, and tumor invasion, as well as loss of estrogen receptor expression in breast cancer cells. Expression of FBXO11 is downregulated by EMT-inducing signals TGFβ and nickel. In human cancer, high FBXO11 levels correlate with expression of epithelial markers and favorable prognosis. The results suggest that FBXO11 sustains the epithelial state and inhibits cancer progression. Inactivation of FBXO11 in mice leads to neonatal lethality, epidermal thickening, and increased Snail protein levels in epidermis, validating that FBXO11 is a physiological ubiquitin ligase of Snail. Moreover, in C. elegans, the FBXO11 mutant phenotype is attributed to the Snail factors as it is suppressed by inactivation/depletion of Snail homologs. Collectively, these findings suggest that the FBXO11-Snail regulatory axis is evolutionarily conserved and critically governs carcinoma progression and mammalian epidermal development. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Pleiotrophin and N-syndecan promote perineural invasion and tumor progression in an orthotopic mouse model of pancreatic cancer.

    PubMed

    Yao, Jun; Zhang, Lu-Lin; Huang, Xu-Mei; Li, Wen-Yao; Gao, She-Gan

    2017-06-07

    To detect the expression of pleiotrophin (PTN) and N-syndecan in pancreatic cancer and analyze their association with tumor progression and perineural invasion (PNI). An orthotopic mouse model of pancreatic cancer was created by injecting tumor cells subcapsularly in a root region of the pancreas beneath the spleen. Pancreatic cancer tissues were taken from 36 mice that survived for more than 90 d. PTN and N-syndecan proteins were detected by immunohistochemistry and analyzed for their correlation with pathological features, PNI, and prognosis. The expression rates of PTN and N-syndecan proteins were 66.7% and 61.1%, respectively, in cancer tissue. PTN and N-syndecan expression was associated with PNI (P = 0.019 and P = 0.032, respectively). High PTN expression was closely associated with large bloody ascites (P = 0.009), liver metastasis (P = 0.035), and decreased survival time (P = 0.022). N-syndecan expression was significantly associated with tumor size (P = 0.025), but not with survival time (P = 0.539). High PTN and N-syndecan expression was closely associated with metastasis and poor prognosis, suggesting that they may promote tumor progression and PNI in the orthotopic mouse model of pancreatic cancer.

  8. A DDB2 mutant protein unable to interact with PCNA promotes cell cycle progression of human transformed embryonic kidney cells.

    PubMed

    Perucca, Paola; Sommatis, Sabrina; Mocchi, Roberto; Prosperi, Ennio; Stivala, Lucia Anna; Cazzalini, Ornella

    2015-01-01

    DNA damage binding protein 2 (DDB2) is a protein involved in the early step of DNA damage recognition of the nucleotide excision repair (NER) process. Recently, it has been suggested that DDB2 may play a role in DNA replication, based on its ability to promote cell proliferation. We have previously shown that DDB2 binds PCNA during NER, but also in the absence of DNA damage; however, whether and how this interaction influences cell proliferation is not known. In this study, we have addressed this question by using HEK293 cell clones stably expressing DDB2(Wt) protein, or a mutant form (DDB2(Mut)) unable to interact with PCNA. We report that overexpression of the DDB2(Mut) protein provides a proliferative advantage over the wild type form, by influencing cell cycle progression. In particular, an increase in the number of S-phase cells, together with a reduction in p21(CDKN1A) protein level, and a shorter cell cycle length, has been observed in the DDB2(Mut) cells. These results suggest that DDB2 influences cell cycle progression thanks to its interaction with PCNA.

  9. Lysyl oxidase-like 2 represses Notch1 expression in the skin to promote squamous cell carcinoma progression

    PubMed Central

    Martin, Alberto; Salvador, Fernando; Moreno-Bueno, Gema; Floristán, Alfredo; Ruiz-Herguido, Cristina; Cuevas, Eva P; Morales, Saleta; Santos, Vanesa; Csiszar, Katalin; Dubus, Pierre; Haigh, Jody J; Bigas, Anna; Portillo, Francisco; Cano, Amparo

    2015-01-01

    Lysyl oxidase-like 2 (LOXL2) is involved in a wide range of physiological and pathological processes, including fibrosis and tumor progression, implicating intracellular and extracellular functions. To explore the specific in vivo role of LOXL2 in physiological and tumor contexts, we generated conditional gain- and loss-of-function mouse models. Germ-line deletion of Loxl2 promotes lethality in half of newborn mice mainly associated to congenital heart defects, while Loxl2 overexpression triggers male sterility due to epididymal dysfunction caused by epithelial disorganization, fibrosis and acute inflammation. Remarkably, when challenged to chemical skin carcinogenesis, Loxl2-overexpressing mice increased tumor burden and malignant progression, while Loxl2-deficient mice exhibit the opposite phenotypes. Loxl2 levels in premalignant tumors negatively correlate with expression of epidermal differentiation markers and components of the Notch1 pathway. We show that LOXL2 is a direct repressor of NOTCH1. Additionally, we identify an exclusive expression pattern between LOXL2 and members of the canonical NOTCH1 pathway in human HNSCC. Our data identify for the first time novel LOXL2 roles in tissue homeostasis and support it as a target for SCC therapy. PMID:25759215

  10. The C. elegans NR4A nuclear receptor gene nhr-6 promotes cell cycle progression in the spermatheca lineage.

    PubMed

    Praslicka, Brandon; Gissendanner, Chris R

    2015-03-01

    NR4A nuclear receptors are a conserved, functionally diverse group of nuclear receptors that regulate multiple cellular processes including proliferation and differentiation. The gene nhr-6 encodes the sole Caenorhabditis elegans NR4A nuclear receptor homolog with an essential role in reproduction by regulating morphogenesis of the spermatheca, a somatic gonad organ involved in ovulation and fertilization. Here, we identify the spermatheca cell lineage defects that occur in nhr-6 mutants. Utilizing cell marker analysis, we find that nhr-6 is required for cell cycle progression and that the cell proliferation phenotype is not due to premature cell cycle exit. We also show that loss of the negative cell cycle regulators fzr-1 and lin-35 suppresses the cell proliferation defects. We further demonstrate that NHR-6 activity intersects with Eph receptor signaling during spermatheca cell proliferation. NHR-6 has an essential function in promoting cell cycle progression during G1 phase in a specific spermatheca cell lineage. Genetic suppression of the proliferation phenotype does not affect the differentiation phenotypes observed in nhr-6 mutants, indicating a dualistic role for nhr-6 in regulating cell proliferation and cell differentiation during spermatheca organogenesis. © 2014 Wiley Periodicals, Inc.

  11. Fibroblast growth factor receptor 4 promotes progression and correlates to poor prognosis in cholangiocarcinoma

    SciTech Connect

    Xu, Yun-Fei; Yang, Xiao-Qing; Lu, Xiao-Fei; Guo, Sen; Liu, Yi; Iqbal, Mohammad; Ning, Shang-Lei; Yang, Hui; Suo, Ning; Chen, Yu-Xin

    2014-03-28

    Highlights: • FGFR4 is significantly related with N stage in IHCC, with T stage and TNM stage in PHCC. • FGFR4 is an independent prognostic factor in IHCC and PHCC. • FGFR4 promotes proliferation, invasion and EMT in cholangiocarinoma cell lines. • Inhibitor AP24354 can decrease proliferation, invasion and induce apoptosis of CCA. - Abstract: Fibroblast growth factor receptor 4 (FGFR4) is related to poor prognosis of several cancers, but the correlation between FGFR4 expression and cholangiocarcinoma (CCA) has not been well elucidated. We investigated the expression of FGFR4 in 83 intrahepatic cholangiocarcinomas (IHCCs), 75 perihilar cholangiocarcinomas (PHCCs) and 41 distal cholangiocarcinomas (DCCs) by immunohistochemistry (IHC), and subsequently evaluated association of FGFR4 with clinicopathologic parameters and survival rate. The rate of FGFR4 higher expression was 61.4% (51/83) in IHCCs, 53.3% (40/75) in PHCCs and 56.1% (23/41) in DCCs. FGFR4 expression was significantly related to poor prognosis of IHCC (P = 0.002) and PHCC (P = 0.019) with univariate analysis, and also identified as an independent prognostic factor in IHCC (P = 0.045) and PHCC (P = 0.049) with multivariate analysis. Additionally, with functional assays in vitro, we found FGFR4 can induce proliferation, invasion and epithelial–mesenchymal transition (EMT) of CCA cell lines with FGF19 stimulation. Moreover, FGFR4 inhibitor AP24354 can suppress proliferation, invasion and induce apoptosis of CCA cells. In conclusion, FGFR4 expression can be identified as a significant independent prognostic biomarker of IHCC and PHCC. FGFR4 played a pivotal role in proliferation, invasion and EMT of CCA. FGFR4 inhibitor can suppress proliferation, invasion and induce apoptosis of CCA, indicating that FGFR4 may act as a potential therapeutic target.

  12. Selection, de-selection and progression in German football talent promotion.

    PubMed

    Güllich, Arne

    2014-01-01

    This study explored to which extent the development of German professional football players is based on early talent identification (TID) and long-term nurture in talent promotion (TP) programmes or on their emergence in the course of repeated procedures of player selection and de-selection in these programmes through childhood and youth. The annual turnover of squad members in national junior teams (2001-2013) and youth elite academies was calculated; national U-team members were followed up with regard to nominations through subsequent seasons and to their success level eventually achieved at senior age; and all current Bundesliga players were analysed retrospectively regarding their earlier involvement in TID/TP programmes. Analyses revealed that the mean annual turnover of squad members was 24.5% (youth academies) and 41.0% (national U-teams), respectively. At any age, the probability of persisting in the programme three years later was <50%. Among current Bundesliga players, the age of recruitment into the TID/TP programme was widely evenly distributed across childhood and youth, respectively. Accordingly, the number of (future) Bundesliga players who were involved in TID/TP was built up continuously through all age categories. The observations suggest that the collective of professional players emerged from repeated procedures of selection and de-selection through childhood and youth rather than from early selection and long-term continuous nurture in TID/TP programmes. The findings are discussed with regard to the uncertainty of TID and of interventions applied to the selected players, and they are related to the individualistic and collectivistic approach in TP.

  13. Renal, hepatic, pulmonary and adrenal tumors induced by prenatal inorganic arsenic followed by dimethylarsinic acid in adulthood in CD1 mice

    PubMed Central

    Tokar, Erik J.; Diwan, Bhalchandra A.; Waalkes, Michael P.

    2012-01-01

    Inorganic arsenic, an early life carcinogen in humans and mice, can initiate lesions promotable by other agents in later life. The biomethylation product of arsenic, dimethylarsinic acid (DMA), is a multi-site tumor promoter. Thus, pregnant CD1 mice were given drinking water (0 or 85 ppm arsenic) from gestation day 8 to 18 and after weaning male offspring received DMA (0 or 200 ppm; drinking water) for up to 2 years. No renal tumors occurred in controls or DMA alone treated mice while gestational arsenic exposure plus later DMA induced a significant renal tumor incidence of 17% (primarily renal cell carcinoma). Arsenic plus DMA or arsenic alone also increased renal hyperplasia over control but DMA alone did not. Arsenic alone, DMA alone and arsenic plus DMA all induced urinary bladder hyperplasia (33–35%) versus control (2%). Compared to control (6%), arsenic alone tripled hepatocellular carcinoma (20%), and arsenic plus DMA doubled this rate again (43%), but DMA alone had no effect. DMA alone, arsenic alone, and arsenic plus DMA increased lung adenocarcinomas and adrenal adenomas versus control. Overall, DMA in adulthood promoted tumors/lesions initiated by prenatal arsenic in the kidney and liver, but acted independently in the urinary bladder, lung and adrenal. PMID:22230260

  14. Over-Expressed miR-224 Promotes the Progression of Cervical Cancer via Targeting RASSF8

    PubMed Central

    Wang, Fen F.; Lv, WeiGuo; Xie, Xing; Cheng, Xiaodong

    2016-01-01

    Cervical cancer is the most common cause of cancer-related deaths in women from developing countries. Identification of novel prognostic predictors or therapeutic targets may improve patient prognosis. In the current study, we demonstrated by real-time PCR that miR-224 expression was significantly upregulated (1.82-fold, P = 0.0025) in cervical cancer tissues (n = 126) compared with in normal cervical tissues (n = 64). Higher expression of miR-224 was significantly associated with poorer prognostic factors, including advanced FIGO stage, nodal metastasis, larger tumor size, vascular involvement and deep stromal invasion (all P < 0.05). Enforced expression of miR-224 promoted cell proliferation, migration and invasion in SiHa and CaSki cancer cell lines. Bioinformatic analysis indicated that RASSF8 (RAS-association domain family 8) was a potential target of miR-224. Western blot analysis and luciferase reporter assay showed that overexpressed miR-224 inhibited RASSF8 protein expression and decreased the activity of a luciferase reporter containing the 3′ untranslated region (UTR) of RASSF8, respectively. Further, RASSF8 knockdown by specific RNAi showed similar effects in cervical cancer cells transfected with miR-224 mimic. Our findings suggest that miR-224 directly targets RASSF8 and thereby acts as a tumor promoter in cervical cancer progression. PMID:27626930

  15. Chitosan promotes cancer progression and stem cell properties in association with Wnt signaling in colon and hepatocellular carcinoma cells

    PubMed Central

    Chang, Po-Hsiang; Sekine, Keisuke; Chao, Hsiao-Mei; Hsu, Shan-hui; Chern, Edward

    2017-01-01

    Cancer stem cells (CSCs), a small population of cancer cells, have been considered to be the origin of cancer initiation, recurrence, and metastasis. Tumor microenvironment provides crucial signals for CSCs to maintain stem cell properties and promotes tumorigenesis. Therefore, establishment of an appropriate cell culture system to mimic the microenvironment for CSC studies is an important issue. In this study, we grew colon and hepatocellular carcinoma (HCC) cells on chitosan membranes and evaluated the tumor progression and the CSC properties. Experimental results showed that culturing cancer cells on chitosan increased cell motility, drug resistance, quiescent population, self-renewal capacity, and the expression levels of stemness and CSC marker genes, such as OCT4, NANOG, CD133, CD44, and EpCAM. Furthermore, we demonstrated that chitosan might activate canonical Wnt/β-catenin-CD44 axis signaling in CD44positive colon cancer cells and noncanonical Wnt-STAT3 signaling in CD44negative HCC cells. In conclusion, chitosan as culture substrates activated the essential signaling of CSCs and promoted CSC properties. The chitosan culture system provides a convenient platform for the research of CSC biology and screening of anticancer drugs. PMID:28367998

  16. Hsp72 is targeted to the mitotic spindle by Nek6 to promote K-fiber assembly and mitotic progression.

    PubMed

    O'Regan, Laura; Sampson, Josephina; Richards, Mark W; Knebel, Axel; Roth, Daniel; Hood, Fiona E; Straube, Anne; Royle, Stephen J; Bayliss, Richard; Fry, Andrew M

    2015-05-11

    Hsp70 proteins represent a family of chaperones that regulate cellular homeostasis and are required for cancer cell survival. However, their function and regulation in mitosis remain unknown. In this paper, we show that the major inducible cytoplasmic Hsp70 isoform, Hsp72, is required for assembly of a robust bipolar spindle capable of efficient chromosome congression. Mechanistically, Hsp72 associates with the K-fiber-stabilizing proteins, ch-TOG and TACC3, and promotes their interaction with each other and recruitment to spindle microtubules (MTs). Targeting of Hsp72 to the mitotic spindle is dependent on phosphorylation at Thr-66 within its nucleotide-binding domain by the Nek6 kinase. Phosphorylated Hsp72 concentrates on spindle poles and sites of MT-kinetochore attachment. A phosphomimetic Hsp72 mutant rescued defects in K-fiber assembly, ch-TOG/TACC3 recruitment and mitotic progression that also resulted from Nek6 depletion. We therefore propose that Nek6 facilitates association of Hsp72 with the mitotic spindle, where it promotes stable K-fiber assembly through recruitment of the ch-TOG-TACC3 complex.

  17. Interleukin-22 promotes aerobic glycolysis associated with tumor progression via targeting hexokinase-2 in human colon cancer cells.

    PubMed

    Liu, Yulin; Xiang, Fan; Huang, Yongming; Shi, Liang; Hu, Chaojie; Yang, Yiming; Wang, Di; He, Nan; Tao, Kaixiong; Wu, Ke; Wang, Guobin

    2017-04-11

    Interleukin-22 has been explored extensively in human cancer, but its functions and underlying mechanisms are incompletely understood. Here, we show that aberrant interleukin-22 expression facilitates aerobic glycolysis in colon cancer cells. Elevated interleukin-22 mRNA expression was observed and positively correlated with hexokinase-2 in colon cancer tissues. In vitro, interleukin-22 enhanced glucose consumption and lactate production via targeting hexokinase-2 in colon cancer cells. Moreover, the transcriptional factor c-Myc and signal transducer and activator of transcription 3 were involved in interleukin-22-induced up-regulation of hexokinase-2. We further demonstrated that hexokinase-2 partly accounted for interleukin-22-mediated cellular proliferation in DLD-1 cells. In vivo, our data demonstrated that interleukin-22 significantly promoted tumor growth along with elevated expression of c-Myc and hexokinase-2 in mice. In summary, our findings provide a new perspective on the pro-inflammatory cytokine interleukin-22 in promoting aerobic glycolysis associated with tumor progression in human colon cancer cells.

  18. Adrenergic receptor β2 activation by stress promotes breast cancer progression through macrophages M2 polarization in tumor microenvironment

    PubMed Central

    Qin, Jun-fang; Jin, Feng-jiao; Li, Ning; Guan, Hai-tao; Lan, Lan; Ni, Hong; Wang, Yue

    2015-01-01

    Stress and its related hormones epinephrine (E) and norepinephrine (NE) play a crucial role in tumor progression. Macrophages in the tumor microenvironment (TME) polarized to M2 is also a vital pathway for tumor deterioration. Here, we explore the underlying role of macrophages in the effect of stress and E promoting breast cancer growth. It was found that the weight and volume of tumor in tumor bearing mice were increased, and dramatically accompanied with the rising E level after chronic stress using social isolation. What is most noteworthy, the number of M2 macrophages inside tumor was up-regulated with it. The effects of E treatment appear to be directly related to the change of M2 phenotype is reproduced in vitro. Moreover, E receptor ADRβ2 involved in E promoting M2 polarization was comprehended simultaneously. Our results imply psychological stress is influential on specific immune system, more essential for the comprehensive treatment against tumors. [BMB Reports 2015; 48(5): 295-300] PMID:25748171

  19. Environmental biochemistry of arsenic

    SciTech Connect

    Tamaki, S.; Frankenberger, W.T. Jr. )

    1992-01-01

    Microorganisms are involved in the redistribution and global cycling of arsenic. Arsenic can accumulate and can be subject to various biotransformations including reduction, oxidation, and methylation. Bacterial methylation of inorganic arsenic is coupled to the methane biosynthetic pathway in methanogenic bacteria under anaerobic conditions and may be a mechanism for arsenic detoxification. The pathway proceeds by reduction of arsenate to arsenite followed by methylation to dimethylarsine. Fungi are also able to transform inorganic and organic arsenic compounds into volatile methylarsines. The pathway proceeds aerobically by arsenate reduction to arsenite followed by several methylation steps producing trimethylarsine. Volatile arsine gases are very toxic to mammals because they destroy red blood cells (LD50 in rats; 3.0 mg kg-1). Further studies are needed on dimethylarsine and trimethylarsine toxicity tests through inhalation of target animals. Marine algae transform arsenate into non-volatile methylated arsenic compounds (methanearsonic and dimethylarsinic acids) in seawater. This is considered to be a beneficial step not only to the primary producers, but also to the higher trophic levels, since non-volatile methylated arsenic is much less toxic to marine invertebrates. Freshwater algae like marine algae synthesize lipid-soluble arsenic compounds and do not produce volatile methylarsines. Aquatic plants also synthesize similar lipid-soluble arsenic compounds. In terrestrial plants, arsenate is preferentially taken up 3 to 4 times the rate of arsenite. In the presence of phosphate, arsenate uptake is inhibited while in the presence of arsenate, phosphate uptake is only slightly inhibited. There is a competitive interaction between arsenate and phosphate for the same uptake system in terrestrial plants.

  20. The EP1 receptor for prostaglandin E2 promotes the development and progression of malignant murine skin tumors

    PubMed Central

    Surh, Inok; Rundhaug, Joyce E.; Pavone, Amy; Mikulec, Carol; Abel, Erika; Simper, Melissa; Fischer, Susan M.

    2011-01-01

    High levels of prostaglandin E2 (PGE2) synthesis resulting from the upregulation of COX-2 has been shown to be critical for the development of non-melanoma skin tumors. This effect of PGE2 is likely mediated by one or more of its 4 G-protein coupled membrane receptors, EP1–4. A previous study showed that BK5.EP1 transgenic mice produced more carcinomas than wild type (WT) mice using initiation/promotion protocols, although the tumor response was dependent on the type of tumor promoter used. In this study, a single topical application of either 7,12-dimethylbenz[a]anthracene (DMBA) or benzo[a]pyrene (B[a]P), alone, was found to elicit squamous cell carcinomas (SCC) in the BK5.EP1 transgenic mice, but not in WT mice. While the epidermis of both WT and transgenic mice was hyperplastic several days after DMBA, this effect regressed in the WT mice while proliferation continued in the transgenic mice. Several parameters associated with carcinogen initiation were measured and were found to be similar between genotypes, including CYP1B1 and aromatase expression, B[a]P adduct formation, Ras activity and keratinocyte stem cell numbers. However, EP1 transgene expression elevated COX-2 levels in the epidermis and SCC could be completely prevented in DMBA-treated BK5.EP1 mice either by feeding the selective COX-2 inhibitor celecoxib in their diet or by crossing them onto a COX-2 null background. These data suggest that the tumor promoting/progressing effects of EP1 require the PGE2 synthesized by COX-2. PMID:21739481

  1. Association of Promoter Methylation of VGF and PGP9.5 with Ovarian Cancer Progression

    PubMed Central

    Noordhuis, Maartje; Begum, Shahnaz; Loyo, Myriam; Poeta, Maria Luana; Barbosa, Alvaro; Fazio, Vito M.; Angioli, Roberto; Rabitti, Carla; Marchionni, Luigi; de Graeff, Pauline; J. van der Zee, Ate G.; Wisman, G. Bea A.; Sidransky, David; Hoque, Mohammad O.

    2013-01-01

    Purpose To elucidate the role of biological and clinical impact of aberrant promoter hypermethylation (PH) in ovarian cancer (OC). Experimental Design PH of PGP9.5, HIC1, AIM1, APC, PAK3, MGMT, KIF1A, CCNA1, ESR1, SSBP2, GSTP1, FKBP4 and VGF were assessed by quantitative methylation specific PCR (QMSP) in a training set. We selected two genes (VGF and PGP9.5) for further QMSP analysis in a larger independent validation (IV) set with available clinical data. Biologic relevance of VGF gene was also evaluated. Results PH frequency for PGP9.5 and VGF were 85% (316/372) and 43% (158/366) respectively in the IV set of samples while no PH was observed in controls. In 372 OC cases with available follow up, PGP9.5 and VGF PH were correlated with better patient survival [Hazard Ratios (HR) for overall survival (OS) were 0.59 (95% Confidence Intervals (CI)  = 0.42–0.84, p = 0.004), and 0.73 (95%CI = 0.55–0.97, p = 0.028) respectively, and for disease specific survival (DSS) were 0.57 (95%CI 0.39–0.82, p = 0.003) and 0.72 (95%CI 0.54–0.96, p = 0.027). In multivariate analysis, VGF PH remained an independent prognostic factor for OS (HR 0.61, 95%CI 0.43–0.86, p<0.005) and DSS (HR 0.58, 95%CI 0.41–0.83, p<0.003). Furthermore, PGP9.5 PH was significantly correlated with lower grade, early stage tumors, and with absence of residual disease. Forced expression of VGF in OC cell lines inhibited cell growth. Conclusions Our results indicate that VGF and PGP9.5 PH are potential biomarkers for ovarian carcinoma. Confirmatory cohorts with longitudinal follow-up are required in future studies to define the clinical impact of VGF and PGP9.5 PH before clinical application. PMID:24086249

  2. Association of promoter methylation of VGF and PGP9.5 with ovarian cancer progression.

    PubMed

    Brait, Mariana; Maldonado, Leonel; Noordhuis, Maartje G; Noordhuis, Maartje; Begum, Shahnaz; Loyo, Myriam; Poeta, Maria Luana; Barbosa, Alvaro; Fazio, Vito M; Angioli, Roberto; Rabitti, Carla; Marchionni, Luigi; de Graeff, Pauline; van der Zee, Ate G J; Wisman, G Bea A; Sidransky, David; Hoque, Mohammad O

    2013-01-01

    To elucidate the role of biological and clinical impact of aberrant promoter hypermethylation (PH) in ovarian cancer (OC). PH of PGP9.5, HIC1, AIM1, APC, PAK3, MGMT, KIF1A, CCNA1, ESR1, SSBP2, GSTP1, FKBP4 and VGF were assessed by quantitative methylation specific PCR (QMSP) in a training set. We selected two genes (VGF and PGP9.5) for further QMSP analysis in a larger independent validation (IV) set with available clinical data. Biologic relevance of VGF gene was also evaluated. PH frequency for PGP9.5 and VGF were 85% (316/372) and 43% (158/366) respectively in the IV set of samples while no PH was observed in controls. In 372 OC cases with available follow up, PGP9.5 and VGF PH were correlated with better patient survival [Hazard Ratios (HR) for overall survival (OS) were 0.59 (95% Confidence Intervals (CI)  = 0.42-0.84, p = 0.004), and 0.73 (95%CI = 0.55-0.97, p = 0.028) respectively, and for disease specific survival (DSS) were 0.57 (95%CI 0.39-0.82, p = 0.003) and 0.72 (95%CI 0.54-0.96, p = 0.027). In multivariate analysis, VGF PH remained an independent prognostic factor for OS (HR 0.61, 95%CI 0.43-0.86, p<0.005) and DSS (HR 0.58, 95%CI 0.41-0.83, p<0.003). Furthermore, PGP9.5 PH was significantly correlated with lower grade, early stage tumors, and with absence of residual disease. Forced expression of VGF in OC cell lines inhibited cell growth. Our results indicate that VGF and PGP9.5 PH are potential biomarkers for ovarian carcinoma. Confirmatory cohorts with longitudinal follow-up are required in future studies to define the clinical impact of VGF and PGP9.5 PH before clinical application.

  3. Chronic Arsenic poisoning.

    PubMed

    Ahsan, Tasnim; Zehra, Kaneez; Munshi, Alia; Ahsan, Samiah

    2009-02-01

    Chronic Arsenic Toxicity may have varied clinical presentations ranging from non-cancerous manifestations to malignancy of skin and different internal organs. Dermal lesions such as hyper pigmentation and hyperkeratosis, predominantly over palms and soles are diagnostic of Chronic Arsenicosis. We report two cases from a family living in Sukkur who presented with classical skin lesions described in Chronic Arsenicosis. The urine, nail and hair samples of these patients contained markedly elevated levels of arsenic. Also the water samples from their household and the neighbouring households were found to have alarming levels of inorganic Arsenic.

  4. Water hyacinth removes arsenic from arsenic-contaminated drinking water.

    PubMed

    Misbahuddin, Mir; Fariduddin, Atm

    2002-01-01

    Water hyacinth (Eichhornia crassipes) removes arsenic from arsenic-contaminated drinking water. This effect depends on several factors, such as the amount of water hyacinth, amount of arsenic present in the water, duration of exposure, and presence of sunlight and air. On the basis of the present study, the authors suggest that water hyacinth is useful for making arsenic-contaminated drinking water totally arsenic free. Water hyacinth provides a natural means of removing arsenic from drinking water at the household level without monetary cost.

  5. Arsenic removal during precipitative softening

    SciTech Connect

    McNeill, L.S.; Edwards, M.

    1997-05-01

    Because utilities with hard waters tend to have higher concentrations of arsenic, removal of arsenic via precipitative softening processes was investigated in the context of the more stringent proposed arsenic regulation. Arsenic removal can be facilitated by a variety of solids formed during softening including CaCO{sub 3}, Mg(OH){sub 2}, Mn(OH){sub 2}, and Fe(OH){sub 3}. The extent of As(V) removal is decreased in the presence of orthophosphate and carbonate. As(III) removal is much lower than As(V) removal. At typical solids concentrations, arsenic removal followed a linear isotherm for CaCO{sub 3}, Mg(OH){sub 2}, and Fe(OH){sub 3}, with constant percentage arsenic removal regardless of initial arsenic concentrations. However, for Mn(OH){sub 2} solids arsenic removal was sensitive to arsenic concentrations. A framework for predicting arsenate removal when multiple solids form during softening is presented.

  6. The die is cast - Arsenic exposure in early life and disease susceptibility

    EPA Science Inventory

    Abstract Early life exposure to arsenic in humans and mice produces similar patterns of disease in later life. Given the long interval between exposure and effect, epigenetic effects of early life exposure to arsenic may account for development and progression of disease in bo...

  7. The die is cast - Arsenic exposure in early life and disease susceptibility

    EPA Science Inventory

    Abstract Early life exposure to arsenic in humans and mice produces similar patterns of disease in later life. Given the long interval between exposure and effect, epigenetic effects of early life exposure to arsenic may account for development and progression of disease in bo...

  8. Arsenic-resistant and plant growth-promoting Firmicutes and γ-Proteobacteria species from industrially polluted irrigation water and corresponding cropland.

    PubMed

    Qamar, N; Rehman, Y; Hasnain, S

    2017-09-01

    The aim of the study was to explore irrigation water polluted with industrial waste and corresponding cropland to screen bacteria for As detoxification and plant growth promotion. Plant growth-promoting (PGP) As-resistant cropland bacteria were isolated from contaminated irrigation water and corresponding agricultural soil. Phylogenetic analysis revealed that the isolates belonged to two distinct bacterial lineages; Firmicutes and γ-Proteobacteria. Maximum As(V) resistance was exhibited by Klebsiella pneumoniae T22 and Klebsiella oxytoca N53 (550 mmol l(-1) ), whereas maximum resistance against As(III) was exhibited by K. oxytoca N53 (200 mmol l(-1) ). Maximum As(V) reduction was shown by K. pneumoniae T22 (6·7 mmol l(-1) ), whereas maximum As(III) oxidation was exhibited by Bacillus subtilis T23 (4·8 mmol l(-1) ). As resistance genes arsB and ACR3 were detected in many of the isolates through polymerase chain reaction. Many of these isolates exhibited PGP traits such as hydrogen cyanide and auxin production as well as phosphate solubilization. The bacterial strains were able to enhance Triticum aestivum growth both in the absence and presence of As, and statistically significant increase in shoot and root lengths was observed especially in case of Acinetobacter lwoffii T24 and Citrobacter freundii N52-treated plants. Cropland bacteria have the ability to support plant growth. Bacteria of croplands irrigated with industrially polluted water develop resistance against toxicants. These bacteria are helpful for the plant growth in such contaminated lands. The bacteria capable of both As detoxification and plant growth promotion, such as A. lwoffii T24 and C. freundii N52, are ideal for remediation and reclamation of polluted lands for agriculture purposes. © 2017 The Society for Applied Microbiology.

  9. Chromated Arsenicals (CCA)

    EPA Pesticide Factsheets

    Chromated copper arsenate (CCA) is a wood preservative pesticide containing chromium, copper, and arsenic that protects wood against termites, fungi, mites and other pests that can degrade or threaten the integrity of wood products.

  10. ARSENIC TREATMENT TECHNOLOGIES 1

    EPA Science Inventory

    A 75 minute presentation will be given at the State of Pennsylvania drinking water training session for state personnel. It will cover four topics: arsenic chemistry, best available technology, demonstration programs and technologies (adsorptive media and iron removal processes)....

  11. ENZYMOLOGY OF ARSENIC METHYLATION

    EPA Science Inventory

    Enzymology of Arsenic Methylation

    David J. Thomas, Pharmacokinetics Branch, Experimental Toxicology Division, National
    Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park...

  12. ENZYMOLOGY OF ARSENIC METHYLATION

    EPA Science Inventory

    Enzymology of Arsenic Methylation

    David J. Thomas, Pharmacokinetics Branch, Experimental Toxicology Division, National
    Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park...

  13. Arsenite-oxidizing bacteria exhibiting plant growth promoting traits isolated from the rhizosphere of Oryza sativa L.: Implications for mitigation of arsenic contamination in paddies.

    PubMed

    Das, Suvendu; Jean, Jiin-Shuh; Chou, Mon-Lin; Rathod, Jagat; Liu, Chia-Chuan

    2016-01-25

    Arsenite-oxidizing bacteria exhibiting plant growth promoting (PGP) traits can have the advantages of reducing As-uptake by rice and promoting plant growth in As-stressed soil. A gram-positive bacterium Bacillus flexus ASO-6 resistant to high levels of As (32 and 280 mM for arsenite and arsenate, respectively) and exhibiting elevated rates of As(III) oxidation (Vmax=1.34 μM min(-1) 10(-7) cell) was isolated from rhizosphere of rice. The presence of aoxB gene and exhibition of As(III)-oxidase enzyme activity of this strain was observed. The ability of the strain to produce siderophore, IAA, ACC-deaminase and to solubilize phosphate was verified. The rice seed treated with the strain exhibited significantly improved seed germination and seedling vigor compared with the un-inoculated seeds. The bacterial inoculation significantly increased root biomass, straw yield, grain yield, chlorophyll and carotenoid in the rice plant. Moreover, As uptake from root to shoot and As accumulation in straw and grain decreased significantly as a result of the bacterial inoculation. Noteworthy, the inoculation effect is more prominent in non-flooded soil than it is in flooded soil. Owing to its wide action spectrum, this As(III)-oxidizing PGPB could serve as a potential bio-inoculant for mitigation of As in paddies and sustainable rice production in As-contaminated areas. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. OXIDATIVE STRESS AS A POSSIBLE MODE OF ACTION FOR ARSENIC CARCINOGENESIS

    EPA Science Inventory

    Abstract

    Many modes of action for arsenic carcinogenesis have been proposed, but few theories have a substantial mass of supporting data. Three stronger theories of arsenic carcinogenesis are production of chromosomal abnormalities, promotion of carcinogenesis and oxidati...

  15. OXIDATIVE STRESS AS A POSSIBLE MODE OF ACTION FOR ARSENIC CARCINOGENESIS

    EPA Science Inventory

    Abstract

    Many modes of action for arsenic carcinogenesis have been proposed, but few theories have a substantial mass of supporting data. Three stronger theories of arsenic carcinogenesis are production of chromosomal abnormalities, promotion of carcinogenesis and oxidati...

  16. Oxidative stress indicated by elevated expression of Nrf2 and 8-OHdG promotes hepatocellular carcinoma progression.

    PubMed

    Ma-On, Chakriwong; Sanpavat, Anapat; Whongsiri, Patcharawalai; Suwannasin, Surasit; Hirankarn, Nattiya; Tangkijvanich, Pisit; Boonla, Chanchai

    2017-04-01

    Reactive oxygen species (ROS) is excessively generated in tumors creating an oxidative stress in tumor microenvironment. We investigated hepatic expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and 8-hydroxydeoxyguanosine (8-OHdG) in hepatocellular carcinoma (HCC) patients, and asked if ROS epigenetically upregulated Nrf2 and enhanced aggressiveness in HCC cells. Expression of Nrf2 (n = 100) and 8-OHdG (n = 53) was remarkably increased in HCC tissues compared with the noncancerous hepatic tissues. Elevated expression of 8-OHdG was associated with poor survival in HCC patients. H2O2, as ROS representative, provoked oxidative stress in HepG2 cells, indicated by increased protein carbonyl content and decreased total antioxidant capacity. Nrf2 expression and 8-OHdG formation were markedly increased in the H2O2-treated cells compared with the untreated control. Co-treatment with antioxidants, tocopheryl acetate (TA) and S-adenosylmethionine (SAM) effectively attenuated expression of Nrf2 and 8-OHdG in H2O2-treated cells. HepG2 cells treated with H2O2 had significantly higher migration and invasion capabilities than the untreated control cells, and this aggressiveness was significantly inhibited by TA and SAM. Bisulfite sequencing revealed that CpG dinucleotides in Nrf2 promoter were unmethylated in the H2O2-treated cells similar to the untreated control. In conclusion, robust histological evidence of increased antioxidative response and oxidative DNA damage in human HCC tissues was demonstrated. Elevated oxidative DNA lesion 8-OHdG was associated with shorter survival. Experimentally, ROS enhanced Nrf2 expression, 8-OHdG formation and tumor progression in HCC cells. These effects were inhibited by antioxidants. Therefore, oxidative stress-reducing regimens might be beneficial to diminish the ROS-induced HCC progression.

  17. Fibroblast growth factor 8 increases breast cancer cell growth by promoting cell cycle progression and by protecting against cell death

    SciTech Connect

    Nilsson, Emeli M.; Brokken, Leon J.S.; Haerkoenen, Pirkko L.

    2010-03-10

    Fibroblast growth factor 8 (FGF-8) is expressed in a large proportion of breast cancers, whereas its level in normal mammary gland epithelium is low. Previous studies have shown that FGF-8b stimulates breast cancer cell growth in vitro and in vivo. To explore the mechanisms by which FGF-8b promotes growth, we studied its effects on cell cycle regulatory proteins and signalling pathways in mouse S115 and human MCF-7 breast cancer cells. We also studied the effect of FGF-8b on cell survival. FGF-8b induced cell cycle progression and up-regulated particularly cyclin D1 mRNA and protein in S115 cells. Silencing cyclin D1 with siRNA inhibited most but not all FGF-8b-induced proliferation. Inhibition of the FGF-8b-activated ERK/MAPK pathway decreased FGF-8b-stimulated proliferation. Blocking the constitutively active PI3K/Akt and p38 MAPK pathways also lowered FGF-8b-induced cyclin D1 expression and proliferation. Corresponding results were obtained in MCF-7 cells. In S115 and MCF-7 mouse tumours, FGF-8b increased cyclin D1 and Ki67 levels. Moreover, FGF-8b opposed staurosporine-induced S115 cell death which effect was blocked by inhibiting the PI3K/Akt pathway but not the ERK/MAPK pathway. In conclusion, our results suggest that FGF-8b increases breast cancer cell growth both by stimulating cell cycle progression and by protecting against cell death.

  18. Promoting macrophage survival delays progression of pre-existing atherosclerotic lesions through macrophage-derived apoE.

    PubMed

    Bouchareychas, Laura; Pirault, John; Saint-Charles, Flora; Deswaerte, Virginie; Le Roy, Tiphaine; Jessup, Wendy; Giral, Philippe; Le Goff, Wilfried; Huby, Thierry; Gautier, Emmanuel L; Lesnik, Philippe

    2015-10-01

    Macrophage apoptosis is a prominent feature of atherosclerosis, yet whether cell death-protected macrophages would favour the resolution of already established atherosclerotic lesions, and thus hold therapeutic potential, remains unknown. We irradiated then transplanted into Apoe(-/-) or LDLr(-/-) recipient mice harbouring established atherosclerotic lesions, bone marrow cells from mice displaying enhanced macrophage survival through overexpression of the antiapoptotic gene hBcl-2 (Mø-hBcl2 Apoe(-/-) or Mø-hBcl2 Apoe(+/+) LDLr(-/-)). Both recipient mice exhibited decreased lesional apoptotic cell content and reduced necrotic areas when repopulated with Mø-hBcl2 mouse-derived bone marrow cells. In contrast, only LDLr(-/-) recipients showed a reduction in plasma cholesterol levels and in atherosclerotic lesions. The absence of significant reduction of plasma cholesterol levels in the context of apoE deficiency highlighted macrophage-derived apoE as key in both the regulation of plasma and tissue cholesterol levels and the progression of pre-existing lesion. Accordingly, hBcl2 expression in macrophages was associated with larger pools of Kupffer cells and Ly-6C(low) monocytes, both high producers of apoE. Additionally, increased Kupffer cells population was associated with improved clearance of apoptotic cells and modified lipoproteins. Collectively, these data show that promoting macrophage survival provides a supplemental source of apoE, which hinders pre-existing plaque progression. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

  19. AKAP95 promotes cell cycle progression via interactions with cyclin E and low molecular weight cyclin E.

    PubMed

    Kong, Xiang-Yu; Zhang, Deng-Cheng; Zhuang, Wen-Xin; Hua, Su-Hang; Dai, Yue; Yuan, Yang-Yang; Feng, Li-Li; Huang, Qian; Teng, Bo-Gang; Yu, Xiu-Yi; Liu, Wen-Zhi; Zhang, Yong-Xing

    2016-01-01

    AKAP95 in lung cancer tissues showed higher expression than in paracancerous tissues. AKAP95 can bind with cyclin D and cyclin E during G1/S cell cycle transition, but its molecular mechanisms remain unclear. To identify the mechanism of AKAP95 in cell cycle progression, we performed AKAP95 transfection and silencing in A549 cells, examined AKAP95, cyclin E1 and cyclin E2 expression, and the interactions of AKAP95 with cyclins E1 and E2. Results showed that over-expression of AKAP95 promoted cell growth and AKAP95 bound cyclin E1 and E2, low molecular weight cyclin E1 (LWM-E1) and LWM-E2. Additionally AKAP95 bound cyclin E1 and LMW-E2 in the nucleus during G1/S transition, bound LMW-E1 during G1, S and G2/M, and bound cyclin E2 mainly on the nuclear membrane during interphase. Cyclin E2 and LMW-E2 were also detected. AKAP95 over-expression increased cyclin E1 and LMW-E2 expression but decreased cyclin E2 levels. Unlike cyclin E1 and LMW-E2 that were nuclear located during the G1, S and G1/S phases, cyclin E2 and LMW-E1 were expressed in all cell cycle phases, with cyclin E2 present in the cytoplasm and nuclear membrane, with traces in the nucleus. LMW-E1 was present in both the cytoplasm and nucleus. The 20 kDa form of LMW-E1 showed only cytoplasmic expression, while the 40 kDa form was nuclear expressed. The expression of AKAP95, cyclin E1, LMW-E1 and -E2, might be regulated by cAMP. We conclude that AKAP95 might promote cell cycle progression by interacting with cyclin E1 and LMW-E2. LMW-E2, but not cyclin E2, might be involved in G1/S transition. The binding of AKAP95 and LMW-E1 was found throughout cell cycle.

  20. AKAP95 promotes cell cycle progression via interactions with cyclin E and low molecular weight cyclin E

    PubMed Central

    Kong, Xiang-Yu; Zhang, Deng-Cheng; Zhuang, Wen-Xin; Hua, Su-Hang; Dai, Yue; Yuan, Yang-Yang; Feng, Li-Li; Huang, Qian; Teng, Bo-Gang; Yu, Xiu-Yi; Liu, Wen-Zhi; Zhang, Yong-Xing

    2016-01-01

    AKAP95 in lung cancer tissues showed higher expression than in paracancerous tissues. AKAP95 can bind with cyclin D and cyclin E during G1/S cell cycle transition, but its molecular mechanisms remain unclear. To identify the mechanism of AKAP95 in cell cycle progression, we performed AKAP95 transfection and silencing in A549 cells, examined AKAP95, cyclin E1 and cyclin E2 expression, and the interactions of AKAP95 with cyclins E1 and E2. Results showed that over-expression of AKAP95 promoted cell growth and AKAP95 bound cyclin E1 and E2, low molecular weight cyclin E1 (LWM-E1) and LWM-E2. Additionally AKAP95 bound cyclin E1 and LMW-E2 in the nucleus during G1/S transition, bound LMW-E1 during G1, S and G2/M, and bound cyclin E2 mainly on the nuclear membrane during interphase. Cyclin E2 and LMW-E2 were also detected. AKAP95 over-expression increased cyclin E1 and LMW-E2 expression but decreased cyclin E2 levels. Unlike cyclin E1 and LMW-E2 that were nuclear located during the G1, S and G1/S phases, cyclin E2 and LMW-E1 were expressed in all cell cycle phases, with cyclin E2 present in the cytoplasm and nuclear membrane, with traces in the nucleus. LMW-E1 was present in both the cytoplasm and nucleus. The 20 kDa form of LMW-E1 showed only cytoplasmic expression, while the 40 kDa form was nuclear expressed. The expression of AKAP95, cyclin E1, LMW-E1 and -E2, might be regulated by cAMP. We conclude that AKAP95 might promote cell cycle progression by interacting with cyclin E1 and LMW-E2. LMW-E2, but not cyclin E2, might be involved in G1/S transition. The binding of AKAP95 and LMW-E1 was found throughout cell cycle. PMID:27158371

  1. Spectral reflectance as an indicator of foliar concentrations of arsenic in common sunflower (Helianthus annuus)

    NASA Astrophysics Data System (ADS)

    Gandy, Yuridia Patricia Peralta De

    Studies were conducted to investigate the use of spectral reflectance by foliage of common sunflower as a potential indicator of arsenic contamination of soil. Germination method was developed for sunflower seeds, and cohorts of sunflower seedlings in hydroponic tanks were established. The cohorts were exposed to 0 ppm, 5 ppm, 7.5 ppm, and 10 ppm treatments of As (V) and reflectance measurements of foliage were collected using a spectroradiometer during two experiments. Results demonstrated the feasibility of using spectral reflectance by foliage of common sunflower as a potential indicator of arsenic contamination. In both experiments, arsenic concentrations in leaf tissues were directly proportional to arsenic concentrations in hydroponic solutions in which such plants were grown. Although the effect(s) of arsenic accumulation had minimal impact on reflectance of visible wavelengths, the effects on NIR reflectance were substantial and resulted in a progressive decrease in reflectance as arsenic concentrations in foliage increased.

  2. Policy intervention for arsenic mitigation in drinking water in rural habitations in India: achievements and challenges.

    PubMed

    Shrivastava, Brajesh K

    2016-10-01

    This article provides updated status of the arsenic affected rural habitations in India, summarizes the policy initiatives of the Ministry of Drinking Water & Sanitation (Government of India), reviews the technologies for arsenic treatment and analyses the progress made by states in tackling arsenic problems in rural habitations. It also provides a list of constraints based on experiences and recommends suggested measures to tackle arsenic problems in an holistic manner. It is expected that the paper would be useful for policy formulators in states, non-government organizations, researchers of academic and scientific institutions and programme managers working in the area of arsenic mitigation in drinking water, especially in developing countries, as it provides better insights compared to other available information in India on mitigating arsenic problems in drinking water in rural areas.

  3. KLF4α Upregulation Promotes Cell Cycle Progression and Reduces Survival Time of Patients with Pancreatic Cancer

    PubMed Central

    WEI, DAOYAN; WANG, LIWEI; KANAI, MASASHI; JIA, ZHILIANG; LE, XIANGDONG; LI, QIANG; WANG, HUAMIN; XIE, KEPING

    2011-01-01

    Background & Aims Krüppel-like factor (KLF)4 is a transcription factor associated with tumor suppression and oncogenesis. KLF4 suppresses pancreatic tumorigenesis by unknown mechanisms; we investigated alterations that might affect KLF4 function and lead to tumor formation. Methods We identified different isoforms of KLF4 in pancreatic cancer cells by reverse transcriptase-PCR, cloning, and DNA sequence analyses. We constructed vectors to express the isoform KLF4α and characterize its function. Using real-time PCR, immunoprecipitation, and immunohistochemical analyses, we assessed expression of KLF4α in pancreatic cancer cell lines and tumor tissue samples; xenograft models were used to determine the effect of KLF4α on pancreatic tumorigenesis. Results We identified 4 KLF4 isoforms in human pancreatic cancer cells, designated KLF4α, KLF4β, KLF4γ, and KLF4δ. KLF4α localized primarily to the cytoplasm; its protein and mRNA were upregulated in pancreatic cancer cell lines with high metastatic potential and human pancreatic tumors, compared with normal pancreatic tissue. Transgenic expression of KLF4α reduced expression of p27Kip1 and p21CIP1, promoting cell cycle progression and in vivo tumor formation by pancreatic cancer cells. Increased expression of KLF4α in pancreatic tumor tissue was inversely correlated with overall time of survival in patients with stage II pancreatic ductal adenocarcinoma. Conclusions We identified a splice variant of KLF4 (KLF4α) that is upregulated in aggressive pancreatic cancer cells and human pancreatic tumor tissues. Increased expression promotes growth of pancreatic tumors in mice is associated with reduced survival times of patients. PMID:20727893

  4. Obesity, but not ethanol, promotes tumor incidence and progression in a mouse model of hepatocellular carcinoma in vivo.

    PubMed

    Thompson, Kyle J; Swan, Ryan Z; Walling, Tracy L; Iannitti, David A; McKillop, Iain H; Sindram, David

    2013-08-01

    Hepatocellular carcinoma (HCC) is a major global health burden. Although chronic, heavy alcohol abuse is an established risk factor for HCC, obesity is emerging as an increasingly important factor in HCC development. Given that other risk factors for HCC act synergistically to promote tumorigenesis, we investigated the effects of diet-induced obesity and chronic ethanol consumption on tumor progression. A diethylnitrosamine (DEN) mouse model of HCC was established and mice randomized to control (CD; 10 % kcal% fat) or high fat (HFD; 60 % kcal% fat diet) at 5 weeks of age. At 35 weeks, mice were randomized to 10/20 % ethanol (EtOH) in drinking water (alternate days), or drinking water (H2O) alone. Tumor incidence/size were measured and confirmed. Liver tissue was analyzed for oxidative stress and EtOH-metabolizing enzymes and serum analyzed for liver function and nutritional status. DEN treatment induced HCC formation in 60 % CD-H2O mice (6 of 10), an effect exacerbated by HFD (89 %). Tumors in HFD animals occupied significantly more of the liver than mice on CD. EtOH-feeding did not impact HCC incidence or tumor size. HFD resulted in increased liver injury and liver:body weight ratio regardless of EtOH consumption. Increased tumor incidence was associated with elevated hepatic oxidative stress in the absence of changes in intrinsic antioxidant (glutathione) levels. Obesity independently promoted HCC formation in the absence or presence of a known hepatocarcinogen (DEN), and enhanced both number and size of hepatic tumors independent of chronic EtOH consumption in mice.

  5. Circular RNA MYLK as a competing endogenous RNA promotes bladder cancer progression through modulating VEGFA/VEGFR2 signaling pathway.

    PubMed

    Zhong, Zhenyu; Huang, Mengge; Lv, Mengxin; He, Yunfeng; Duan, Changzhu; Zhang, Luyu; Chen, Junxia

    2017-09-10

    Accumulating evidences indicate that circular RNAs (circRNAs) play a vital role in modulating gene expression. However, the mechanisms underlying circRNAs remain largely elusive. Here, we screened circRNA and mRNA expression profiles of bladder carcinoma (BC) using microarray analysis. We found that circRNA-MYLK and VEGFA were significantly up-regulated and co-expressed in BC. Importantly, circRNA-MYLK levels were related to the progression of stage and grade of BC. Mechanistically, we demonstrated that circRNA-MYLK could directly bind to miR-29a and relieve suppression for target VEGFA, which activated VEGFA/VEGFR2 signaling pathway. Functionally, we found that ectopically expressing circRNA-MYLK accelerated cell proliferation, migration, tube formation of HUVEC and rearranged cytoskeleton. Moreover, up-regulating circRNA-MYLK promoted epithelial-mesenchymal transition (EMT). Whereas circRNA-MYLK knockdown decreased cell proliferation, motility, and induced apoptosis. Finally, up-regulating circRNA-MYLK promoted the growth, angiogenesis and metastasis of BC xenografts. Taken together, this study demonstrated for the first time that circRNA-MYLK might function as competing endogenous RNA (ceRNA) for miR-29a, which could contribute to EMT and the development of BC through activating VEGFA/VEGFR2 and downstream Ras/ERK signaling pathway. Our data suggest that circRNA-MYLK would be a promising target for BC diagnosis and therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Cancer/stroma interplay via cyclooxygenase-2 and indoleamine 2,3-dioxygenase promotes breast cancer progression.

    PubMed

    Chen, Jing-Yi; Li, Chien-Feng; Kuo, Cheng-Chin; Tsai, Kelvin K; Hou, Ming-Feng; Hung, Wen-Chun

    2014-07-25

    Expression of indoleamine 2,3-dioxygenase (IDO) in primary breast cancer increases tumor growth and metastasis. However, the clinical significance of stromal IDO and the regulation of stromal IDO are unclear. Metabolomics and enzyme-linked immunosorbent assay (ELISA) were used to study the effect of cyclooxygenase-2 (COX-2)-overexpressing breast cancer cells on IDO expression in co-cultured human breast fibroblasts. Biochemical inhibitors and short-hairpin RNA (shRNA) were used to clarify how prostaglandin E2 (PGE2) upregulates IDO expression. Associations of stromal IDO with clinicopathologic parameters were tested in tumor specimens. An orthotopic animal model was used to examine the effect of COX-2 and IDO inhibitors on tumor growth. Kynurenine, the metabolite generated by IDO, increases in the supernatant of fibroblasts co-cultured with COX-2-overexpressing breast cancer cells. PGE2 released by cancer cells upregulates IDO expression in fibroblasts through an EP4/signal transducer and activator of transcription 3 (STAT3)-dependent pathway. Conversely, fibroblast-secreted kynurenine promotes the formation of the E-cadherin/Aryl hydrocarbon receptor (AhR)/S-phase kinase-associated protein 2 (Skp2) complex, resulting in degradation of E-cadherin to increase breast cancer invasiveness. The enhancement of motility of breast cancer cells induced by co-culture with fibroblasts is suppressed by the IDO inhibitor 1-methyl-tryptophan. Pathological analysis demonstrates that upregulation of stromal IDO is a poor prognosis factor and is associated with of COX-2 overexpression. Co-expression of cancer COX-2 and stromal IDO predicts a worse disease-free and metastasis-free survival. Finally, COX-2 and IDO inhibitors inhibit tumor growth in vivo. Integration of metabolomics and molecular and pathological approaches reveals the interplay between cancer and stroma via COX-2, and IDO promotes tumor progression and predicts poor patient survival.

  7. Arsenic Hyperaccumulation Strategies: An Overview

    PubMed Central

    Souri, Zahra; Karimi, Naser; Sandalio, Luisa M.

    2017-01-01

    Arsenic (As) pollution, which is on the increase around the world, poses a growing threat to the environment. Phytoremediation, an important green technology, uses different strategies, including As uptake, transport, translocation, and detoxification, to remediate this metalloid. Arsenic hyperaccumulator plants have developed various strategies to accumulate and tolerate high concentrations of As. In these plants, the formation of AsIII complexes with GSH and phytochelatins and their transport into root and shoot vacuoles constitute important mechanisms for coping with As stress. The oxidative stress induced by reactive oxygen species (ROS) production is one of the principal toxic effects of As; moreover, the strong antioxidative defenses in hyperaccumulator plants could constitute an important As detoxification strategy. On the other hand, nitric oxide activates antioxidant enzyme and phytochelatins biosynthesis which enhances As stress tolerance in plants. Although several studies have focused on transcription, metabolomics, and proteomic changes in plants induced by As, the mechanisms involved in As transport, translocation, and detoxification in hyperaccumulator plants need to be studied in greater depth. This review updates recent progress made in the study of As uptake, translocation, chelation, and detoxification in As hyperaccumulator plants. PMID:28770198

  8. Arsenic Hyperaccumulation Strategies: An Overview.

    PubMed

    Souri, Zahra; Karimi, Naser; Sandalio, Luisa M

    2017-01-01

    Arsenic (As) pollution, which is on the increase around the world, poses a growing threat to the environment. Phytoremediation, an important green technology, uses different strategies, including As uptake, transport, translocation, and detoxification, to remediate this metalloid. Arsenic hyperaccumulator plants have developed various strategies to accumulate and tolerate high concentrations of As. In these plants, the formation of AsIII complexes with GSH and phytochelatins and their transport into root and shoot vacuoles constitute important mechanisms for coping with As stress. The oxidative stress induced by reactive oxygen species (ROS) production is one of the principal toxic effects of As; moreover, the strong antioxidative defenses in hyperaccumulator plants could constitute an important As detoxification strategy. On the other hand, nitric oxide activates antioxidant enzyme and phytochelatins biosynthesis which enhances As stress tolerance in plants. Although several studies have focused on transcription, metabolomics, and proteomic changes in plants induced by As, the mechanisms involved in As transport, translocation, and detoxification in hyperaccumulator plants need to be studied in greater depth. This review updates recent progress made in the study of As uptake, translocation, chelation, and detoxification in As hyperaccumulator plants.

  9. Arsenic exposure is associated with DNA hypermethylation of the tumor suppressor gene p16.

    PubMed

    Lu, Guangming; Xu, Huiwen; Chang, De; Wu, Zhenglai; Yao, Xiaoyuan; Zhang, Shiying; Li, Zhenlong; Bai, Jieben; Cai, Qing; Zhang, Wen

    2014-01-01

    Occupational and environmental exposure to inorganic arsenic leads to development of cancer and represents a significant health hazard in more than 70 countries. The underlying mechanism for arsenic-induced carcinogenesis remains unclear. Laboratory studies suggest that arsenic is a poor mutagen but may cause epigenetic silencing of key tumor suppressor genes such as p16 through DNA hypermethylation. However, the evidence for an association between human arsenic exposure and abnormal DNA methylation of tumor suppressor genes is lacking. Paired case-control studies were conducted involving 40 individuals with high arsenic exposure and arsenicosis, 40 individuals with similarly high exposure to arsenic but without arsenicosis, and 40 individuals with normal exposure to arsenic. DNA methylation status of p16 was determined using methylation-specific PCR. Conditional logistic regression analysis showed that DNA hypermethylation of p16 gene was significantly associated with high arsenic exposure (Odds Ratio = 10.0, P = 0.0019) independently of the development of arsenicosis (Odds Ratio = 2.0, P = 0.1343). High exposure of arsenic in human is positively linked to DNA hypermethylation of p16 gene, suggesting that epigenetic silencing of key tumor suppressor may be an important mechanism by which arsenic promotes cancer initiation.

  10. An Emerging Role for Epigenetic Dysregulation in Arsenic Toxicity and Carcinogenesis

    PubMed Central

    Ren, Xuefeng; McHale, Cliona M.; Skibola, Christine F.; Smith, Allan H.; Smith, Martyn T.; Zhang, Luoping

    2011-01-01

    Background Exposure to arsenic, an established human carcinogen, through consumption of highly contaminated drinking water is a worldwide public health concern. Several mechanisms by which arsenical compounds induce tumorigenesis have been proposed, including oxidative stress, genotoxic damage, and chromosomal abnormalities. Recent studies have suggested that epigenetic mechanisms may also mediate toxicity and carcinogenicity resulting from arsenic exposure. Objective We examined the evidence supporting the roles of the three major epigenetic mechanisms—DNA methylation, histone modification, and microRNA (miRNA) expression—in arsenic toxicity and, in particular, carcinogenicity. We also investigated future research directions necessary to clarify epigenetic and other mechanisms in humans. Data sources and synthesis We conducted a PubMed search of arsenic exposure and epigenetic modification through April 2010 and summarized the in vitro and in vivo research findings, from both our group and others, on arsenic-associated epigenetic alteration and its potential role in toxicity and carcinogenicity. Conclusions Arsenic exposure has been shown to alter methylation levels of both global DNA and gene promoters; histone acetylation, methylation, and phosphorylation; and miRNA expression, in studies analyzing mainly a limited number of epigenetic end points. Systematic epigenomic studies in human populations exposed to arsenic or in patients with arsenic-associated cancer have not yet been performed. Such studies would help to elucidate the relationship between arsenic exposure, epigenetic dysregulation, and carcinogenesis and are becoming feasible because of recent technological advancements. PMID:20682481

  11. Synergistic effects of the combination of oxalate and ascorbate on arsenic extraction from contaminated soils.

    PubMed

    Lee, Jae-Cheol; Kim, Eun Jung; Baek, Kitae

    2017-02-01

    Arsenic is often associated with iron oxides in soils due to its high affinity with iron oxides and the abundance of iron oxides in the environment. Dissolution of iron oxides can subsequently release arsenic associated with them into the environment, which results in the increase of arsenic mobility in the soil environment. In this study, arsenic extraction from soils via the dissolution of iron oxides was investigated using oxalate, ascorbate, and their combination in order to effectively remediate arsenic-contaminated soils. Oxalate mainly extracted iron from soils via a ligand-promoted reaction, while ascorbate extracted iron mainly via a reductive reaction. Arsenic extractions from soils by oxalate and ascorbate were shown to behave similarly to iron extractions, indicating the concurrent release of arsenic adsorbed on iron oxides upon the dissolution of iron oxides. The combination of oxalate and ascorbate greatly increased arsenic extraction, indicating the synergistic effects of the combination of oxalate and ascorbate on iron and arsenic extraction from soils. Oxalate and ascorbate are naturally-occurring organic reagents that have chelating and reducing capacity. Therefore, the use of oxalate and ascorbate is environmentally friendly and effective for the remediation of arsenic-contaminated soils. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Specific histone modification responds to arsenic-induced oxidative stress.

    PubMed

    Ma, Lu; Li, Jun; Zhan, Zhengbao; Chen, Liping; Li, Daochuan; Bai, Qing; Gao, Chen; Li, Jie; Zeng, Xiaowen; He, Zhini; Wang, Shan; Xiao, Yongmei; Chen, Wen; Zhang, Aihua

    2016-07-01

    To explore whether specific histone modifications are associated with arsenic-induced oxidative damage, we recruited 138 arsenic-exposed and arsenicosis subjects from Jiaole Village, Xinren County of Guizhou province, China where the residents were exposed to arsenic from indoor coal burning. 77 villagers from Shang Batian Village that were not exposed to high arsenic coal served as the control group. The concentrations of urine and hair arsenic in the arsenic-exposure group were 2.4-fold and 2.1-fold (all P<0.001) higher, respectively, than those of the control group. Global histone modifications in human peripheral lymphocytes (PBLCs) were examined by ELISA. The results showed that altered global levels of H3K18ac, H3K9me2, and H3K36me3 correlated with both urinary and hair-arsenic levels of the subjects. Notably, H3K36me3 and H3K18ac modifications were associated with urinary 8-OHdG (H3K36me3: β=0.16; P=0.042, H3K18ac: β=-0.24; P=0.001). We also found that the modifications of H3K18ac and H3K36me3 were enriched in the promoters of oxidative stress response (OSR) genes in human embryonic kidney (HEK) cells and HaCaT cells, providing evidence that H3K18ac and H3K36me3 modifications mediate transcriptional regulation of OSR genes in response to NaAsO2 treatment. Particularly, we found that reduced H3K18ac modification correlated with suppressed expression of OSR genes in HEK cells with long term arsenic treatment and in PBLCs of all the subjects. Taken together, we reveal a critical role for specific histone modification in response to arsenic-induced oxidative damage. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Influence of Sulfur on the Arsenic Phytoremediation Using Vallisneria natans (Lour.) Hara.

    PubMed

    Chen, Guoliang; Feng, Tao; Li, Zhixian; Chen, Zhang; Chen, Yuanqi; Wang, Haihua; Xiang, Yanci

    2017-07-04

    Influences of sulfur (S) on the accumulation and detoxification of arsenic (As) in Vallisneria natans (Lour.) Hara, an arsenic hyperaccumulating submerged aquatic plant, were investigated. At low sulfur levels (<20 mg/L), the thiols and As concentrations in the plant increased significantly with increasing sulfate nutrient supply. If sulfur levels were above 20 mg/L, the thiols and As concentrations in the plant did not increase further. There was a significant positive correlation between thiols and As in the plant. As(III) is the main form (>75%) present in the plant after exposure to As(V). Sulfur plays an important role in the arsenic translocation and detoxification, possibly through stimulating the synthesis of thiols and complexation of arsenite-phytochelatins. This suggests that addition of sulfur to the arsenic-contaminated water may provide a way to promote arsenic bioaccumulation in plants for phytoremediation of arsenic pollution.

  14. EZH2 promotes progression of small cell lung cancer by suppressing the TGF-β-Smad-ASCL1 pathway

    PubMed Central

    Murai, Fumihiko; Koinuma, Daizo; Shinozaki-Ushiku, Aya; Fukayama, Masashi; Miyaozono, Kohei; Ehata, Shogo

    2015-01-01

    Transforming growth factor-β (TGF-β) induces apoptosis in many types of cancer cells and acts as a tumor suppressor. We performed a functional analysis of TGF-β signaling to identify a molecular mechanism that regulated survival in small cell lung cancer cells. Here, we found low expression of TGF-β type II receptor (TβRII) in most small cell lung cancer cells and tissues compared to normal lung epithelial cells and normal lung tissues, respectively. When wild-type TβRII was overexpressed in small cell lung cancer cells, TGF-β suppressed cell growth in vitro and tumor formation in vivo through induction of apoptosis. Components of polycomb repressive complex 2, including enhancer of zeste 2 (EZH2), were highly expressed in small cell lung cancer cells; this led to epigenetic silencing of TβRII expression and suppression of TGF-β-mediated apoptosis. Achaete-scute family bHLH transcription factor 1 (ASCL1; also known as ASH1), a Smad-dependent target of TGF-β, was found to induce survival in small cell lung cancer cells. Thus, EZH2 promoted small cell lung cancer progression by suppressing the TGF-β-Smad-ASCL1 pathway. PMID:27462425

  15. Effectiveness of progressive muscle relaxation therapy as a worksite health promotion program in the automobile assembly line

    PubMed Central

    SUNDRAM, Bala Murali; DAHLUI, Maznah; CHINNA, Karuthan

    2015-01-01

    The aim of this study was to examine the effectiveness of Progressive Muscle Relaxation (PMR) as part of a Worksite Health Promotion Program on self-perceived stress, anxiety and depression among male automotive assembly-line workers through a quasi-experimental trial. Two assembly plants were chosen with one receiving PMR therapy and the other Pamphlets. Intention-to-treat analysis was conducted to test the effectiveness of the relaxation therapy. Stress, Depression and Anxiety levels were measured using the shortened DASS-21 questionnaire. Data were analyzed using Chi-square, Independent sample t test and Repeated-measures analysis of variance to test the significance of the effects of intervention (time * group) for the measures of Stress, Depression and Anxiety. Significant favourable intervention effects on stress were found in the PMR group (Effect size=0.6) as compared to the Pamphlet group (Effect size=0.2). There was a significant group *time interaction effect (p<0.001) on Stress levels. Depression and Anxiety levels were minimal at baseline in both the groups with mild or no reduction in levels. The improvement in stress levels showed the potential of PMR therapy as a coping strategy at the workplace. Further research in this field is necessary to examine the beneficial effects of coping strategies in the workplace. PMID:26726829

  16. Effectiveness of progressive muscle relaxation therapy as a worksite health promotion program in the automobile assembly line.

    PubMed

    Sundram, Bala Murali; Dahlui, Maznah; Chinna, Karuthan

    2016-06-10

    The aim of this study was to examine the effectiveness of Progressive Muscle Relaxation (PMR) as part of a Worksite Health Promotion Program on self-perceived stress, anxiety and depression among male automotive assembly-line workers through a quasi-experimental trial. Two assembly plants were chosen with one receiving PMR therapy and the other Pamphlets. Intention-to-treat analysis was conducted to test the effectiveness of the relaxation therapy. Stress, Depression and Anxiety levels were measured using the shortened DASS-21 questionnaire. Data were analyzed using Chi-square, Independent sample t test and Repeated-measures analysis of variance to test the significance of the effects of intervention (time * group) for the measures of Stress, Depression and Anxiety. Significant favourable intervention effects on stress were found in the PMR group (Effect size=0.6) as compared to the Pamphlet group (Effect size=0.2). There was a significant group *time interaction effect (p<0.001) on Stress levels. Depression and Anxiety levels were minimal at baseline in both the groups with mild or no reduction in levels. The improvement in stress levels showed the potential of PMR therapy as a coping strategy at the workplace. Further research in this field is necessary to examine the beneficial effects of coping strategies in the workplace.

  17. Aberrant overexpression of ADAR1 promotes gastric cancer progression by activating mTOR/p70S6K signaling

    PubMed Central

    Dou, Ning; Yu, Shijun; Ye, Xiaojuan; Yang, Dong; Li, Yandong; Gao, Yong

    2016-01-01

    ADAR1, one of adenosine deaminases acting on RNA, modulates RNA transcripts through converting adenosine (A) to inosine (I) by deamination. Emerging evidence has implicated that ADAR1 plays an important role in a few of human cancers, however, its expression and physiological significance in gastric cancer remain undefined. In the present study, we demonstrated that ADAR1 was frequently overexpressed in gastric cancer samples by quantitative real-time PCR analysis. In a gastric cancer tissue microarray, ADAR1 staining was closely correlated with tumor stage (P < 0.001) and N classification (P < 0.001). Functional analysis indicated that ADAR1 overexpression promoted cell proliferation and migration in vitro, whereas ADAR1 knockdown resulted in an opposite phenotypes. Furthermore, ADAR1 knockdown also inhibited tumorigenicity and lung metastasis potential of gastric cancer cells in nude mice models. Mechanistically, ADAR1 expression had a significant effect on phosphorylation level of mTOR, p70S kinase, and S6 ribosomal protein, implying its involvement in the regulation of mTOR signaling pathway. We conclude that ADAR1 contributes to gastric cancer development and progression via activating mTOR/p70S6K/S6 ribosomal protein signaling axis. Our findings suggest that ADAR1 may be a valuable biomarker for GC diagnosis and prognosis and may represent a new novel therapeutic opportunities. PMID:27863387

  18. Gr-1+CD11b+ cells are responsible for tumor promoting effect of TGF-β in breast cancer progression.

    PubMed

    Li, Zhaoyang; Pang, Yanli; Gara, Sudheer Kumar; Achyut, B R; Heger, Christopher; Goldsmith, Paul K; Lonning, Scott; Yang, Li

    2012-12-01

    One great challenge in our understanding of TGF-β cancer biology and the successful application of TGF-β-targeted therapy is that TGF-β works as both a tumor suppressor and a tumor promoter. The underlying mechanisms for its functional change remain to be elucidated. Using 4T1 mammary tumor model that shares many characteristics with human breast cancer, particularly its ability to spontaneously metastasize to the lungs, we demonstrate that Gr-1+CD11b+ cells or myeloid derived suppressor cells are important mediators in TGF-β regulation of mammary tumor progression. Depletion of Gr-1+CD11b+ cells diminished the antitumor effect of TGF-β neutralization. Two mechanisms were involved: first, treatment with TGF-β neutralization antibody (1D11) significantly decreased the number of Gr-1+CD11b+ cells in tumor tissues and premetastatic lung. This is mediated through increased Gr-1+CD11b+ cell apoptosis. In addition, 1D11 treatment significantly decreased the expression of Th2 cytokines and Arginase 1. Interestingly, the number and property of Gr-1+CD11b+ cells in peripheral blood/draining lymph nodes correlated with tumor size and metastases in response to 1D11 treatment. Our data suggest that the efficacy of TGF-β neutralization depends on the presence of Gr-1+CD11b+ cells, and these cells could be good biomarkers for TGF-β-targeted therapy.

  19. Development of a gas-promoted oil agglomeration process. Technical progress report, December 1, 1993--February 28, 1994

    SciTech Connect

    Wheelock, T.D.; Drzymala, J.; Zhang, F.

    1994-05-01

    The overall purpose of this research project is to carry out the preliminary laboratory-scale development of a gas-promoted, oil agglomeration process for cleaning coal using model mixing systems. A model mixing system has been previously designed and constructed for conducting oil agglomeration tests in such a way that agitator speed and torque can be measured as well as agglomeration performance. Equipment is also provided for monitoring the progress of agglomeration during a batch test. This equipment includes a photometric dispersion analyzer for measuring the turbidity of the particle suspension. In order to measure the turbidity a small stream of material is withdrawn from the mixing tank and conducted through an optical cell associated with the photometric dispersion analyzer. The material is then returned to the mixing tank. A peristaltic pump located between the optical cell and the mixing tank is used for circulating the material. During the past quarter a series of shakedown test were carried out to calibrate the equipment and to determine some of its operating characteristics. The accuracy of the agitator speed and torque measuring instrument was checked. Also the gas dispersing effectiveness of the mixing system was investigated. In addition, the effects of agitator speed and solids concentration on agitator torque and power requirements were studied.

  20. EGFRvIII/integrin β3 interaction in hypoxic and vitronectinenriching microenvironment promote GBM progression and metastasis.

    PubMed

    Liu, Zhaoyu; Han, Lei; Dong, Yucui; Tan, Yanli; Li, Yongsheng; Zhao, Manli; Xie, Hui; Ju, Huanyu; Wang, He; Zhao, Yu; Zheng, Qifan; Wang, Qixue; Su, Jun; Fang, Chuan; Fu, Songbin; Jiang, Tao; Liu, Jiaren; Li, Xia; Kang, Chunsheng; Ren, Huan

    2016-01-26

    Glioblastoma (GBM) is one of the most lethal brain tumors with a short survival time. EGFR amplification and mutation is the most significant genetic signature in GBM. About half of the GBMs with EGFR amplification express a constitutively autophosphorylated variant of EGFR, known as EGFRvIII. Our in vitro data demonstrated further enhanced EGFRvIII activity and tumor cell invasion in the tumor microenvironment of hypoxia plus extracellular matrix (ECM) vitronectin, in which EGFRvIII and integrin β3 tended to form complexes. The treatment with ITGB3 siRNA or the integrin antagonist cilengetide preferentially interrupted the EGFRvIII/integrin β3 complex, effectively reduced tumor cell invasion and activation of downstream signaling effectors. Cilengitide is recently failed in Phase III CENTRIC trial in unselected patients with GBM. However, we found that cilengitide demonstrated efficacious tumor regression via inhibition of tumor growth and angiogenesis in EGFRvIII orthotopic xenografts. Bioinformatics analysis emphasized key roles of integrin β3, hypoxia and vitronectin and their strong correlations with EGFRvIII expression in malignant glioma patient samples in vivo. In conclusion, we demonstrate that EGFRvIII/integrin β3 complexes promote GBM progression and metastasis in the environment of hypoxia and vitronectin-enrichment, and cilengitide may serve as a promising therapeutics for EGFRvIII-positive GBMs.

  1. Glycoprotein nonmetastatic melanoma protein B (GPNMB) promotes the progression of brain glioblastoma via Na(+)/K(+)-ATPase.

    PubMed

    Ono, Yoko; Chiba, Shinsuke; Yano, Hirohito; Nakayama, Noriyuki; Saio, Masanao; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Iwama, Toru; Hara, Hideaki

    2016-12-02

    Glycoprotein nonmetastatic melanoma protein B (GPNMB), which is involved in invasion and metastasis, was found to be overexpressed in various cancers. High levels of GPNMB and Na(+)/K(+)-ATPase α subunits are associated with a poor prognosis in glioblastoma patients. We showed that GPNMB interacts with Na(+)/K(+)-ATPase α subunits to activate PI3K/Akt and MEK/ERK pathways. However, it remains unclear whether the interaction of GPNMB and Na(+)/K(+)-ATPase α subunits is involves in progression of glioma. The tumor size induced by the injection of glioma GL261 cells was larger in transgenic mice overexpressing GPNMB when compared with wild-type mice. Additionally, the interaction of GPNMB and Na(+)/K(+)-ATPase α subunits was identified in the murine glioma model and in the tumors of glioblastoma patients. Ouabain, a Na(+)/K(+)-ATPase inhibitor, suppressed the glioma growth induced by the injection of glioma cells in the transgenic mice overexpressing GPNMB and blocked the GPNMB-induced migration of glioma cells. These findings indicate that GPNMB promotes glioma growth via Na(+)/K(+)-ATPase α subunits. Thus, the interaction between GPNMB and Na(+), K(+)-ATPase α subunits represents a novel therapeutic target for the treatment of brain glioblastomas. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Highly expressed long non-coding RNA FOXD2-AS1 promotes non-small cell lung cancer progression via Wnt/β-catenin signaling.

    PubMed

    Rong, Lin; Zhao, Ruixing; Lu, Jinxiu

    2017-03-11

    Non-small cell lung cancer (NSCLC) is one of the most common and aggressive tumors around the world. Long-noncoding RNAs (lncRNAs) have been recently shown to play important roles in regulating numerous biological processes including tumor progression. However, the role of lncRNA FOXD2-AS1 in NSCLC remains unclear. In this study, we found that lncRNA FOXD2-AS1 is significantly up-regulated in NSCLC tissues. Loss- and gain-function assays revealed that FOXD2-AS1 promotes NSCLC cell growth and NSCLC tumor progression. Furthermore, we also revealed that FOXD2-AS1 modulates Wnt/β-catenin signaling in NSCLC cells. Taken together, we conclude that lncRNA FOXD2-AS1 promotes NSCLC progression though Wnt/β-catenin signaling. These results suggest that lncRNA FOXD2-AS1 might act as a novel therapeutic target for NSCLC treatment.

  3. PATHWAY OF INORGANIC ARSENIC METABOLISM

    EPA Science Inventory

    A remarkable aspect of the metabolism of inorganic arsenic in humans is its conversion to methylated metabolites. These metabolites account for most of the arsenic found in urine after exposure to inorganic arsenic. At least some of the adverse health effects attributed to inor...

  4. PROPOSED CARCINOGENIC MECHANISMS FOR ARSENIC

    EPA Science Inventory

    PROPOSED CARCINOGENIC MECHANISMS FOR ARSENIC.

    Arsenic is a human carcinogen in skin, lung, liver, urinary bladder and kidney. In contrast,
    there is no accepted experimental animal model of inorganic arsenic carcinogenesis.
    Proposed mechanisms/modes of action for a...

  5. ARSENIC REMOVAL COST ESTIMATING PROGRAM

    EPA Science Inventory

    The Arsenic Removal Cost Estimating program (Excel) calculates the costs for using adsorptive media and anion exchange treatment systems to remove arsenic from drinking water. The program is an easy-to-use tool to estimate capital and operating costs for three types of arsenic re...

  6. ARSENIC REMOVAL COST ESTIMATING PROGRAM

    EPA Science Inventory

    The Arsenic Removal Cost Estimating program (Excel) calculates the costs for using adsorptive media and anion exchange treatment systems to remove arsenic from drinking water. The program is an easy-to-use tool to estimate capital and operating costs for three types of arsenic re...

  7. PROPOSED CARCINOGENIC MECHANISMS FOR ARSENIC

    EPA Science Inventory

    PROPOSED CARCINOGENIC MECHANISMS FOR ARSENIC.

    Arsenic is a human carcinogen in skin, lung, liver, urinary bladder and kidney. In contrast,
    there is no accepted experimental animal model of inorganic arsenic carcinogenesis.
    Proposed mechanisms/modes of action for a...

  8. Atherosclerosis induced by arsenic in drinking water in rats through altering lipid metabolism

    SciTech Connect

    Cheng, Tain-Junn; Chuu, Jiunn-Jye; Chang, Chia-Yu; Tsai, Wan-Chen; Chen, Kuan-Jung; Guo, How-Ran

    2011-10-15

    Arsenic in drinking water is a global environmental health problem, and the exposure may increase cardiovascular and cerebrovascular diseases mortalities, most likely through causing atherosclerosis. However, the mechanism of atherosclerosis formation after arsenic exposure is still unclear. To study the mechanism of atherosclerosis formation after arsenic exposure and explore the role of high cholesterol diet (HCD) in this process, we fed spontaneous hypertensive rats and Wistar Kyoto rats with basal diet or HCD and provided with them drinking water containing arsenic at different ages and orders for 20 consecutive weeks. We measured high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, heat shock protein 70 (HSP 70), and high sensitive C-reactive protein (hs-CRP) at predetermined intervals and determined expressions of cholesteryl ester transfer protein-1 (CETP-1) and liver X receptor {beta} (LXR{beta}) in the liver. Atherosclerosis was determined by examining the aorta with hematoxylin and eosin stain. After 20 weeks, we found arsenic, alone or combined with HCD, may promote atherosclerosis formation with transient increases in HSP 70 and hs-CRP. Early combination exposure decreased the HDL-C/LDL-C ratio without changing the levels of total cholesterol and triglyceride until 30 weeks old. Both CETP-1 and LXR{beta} activities were suppressed, most significantly in early combination exposure. In conclusion, arsenic exposure may induce atherosclerosis through modifying reverse cholesterol transport in cholesterol metabolism and suppressing LXR{beta} and CEPT-1 expressions. For decreasing atherosclerosis related mortality associated with arsenic, preventing exposure from environmental sources in early life is an important element. - Highlights: > Arsenic causes cardiovascular and cerebrovascular diseases through atherosclerosis. > Arsenic may promote atherosclerosis with transient increase in HSP

  9. Effects of glutathione on the in vivo metabolism and oxidative stress of arsenic in mice.

    PubMed

    Wang, Da; Lin, Lin; Li, Xin; Sun, Gui-Fan

    2015-01-01

    In this study, we investigated the in vivo effects of exogenous glutathione and buthionine sulfoximine on arsenic methylation and antioxidant capacity in mice exposed to arsenic via drinking water. Thirty-six female albino mice were randomly divided into six groups. All groups were given free access to drinking water that contained arsenic continuously except the control group. After ten days, mice were treated with different levels of glutathione or buthionine sulfoximine. The levels of the metabolites of arsenic were determined in the liver and urine. The levels of glutathione and total antioxidant capacity were determined in the whole blood and liver. Our results showed that the increase of arsenic species in the liver as well as the decrease of blood and hepatic glutathione and total antioxidant capacity, were all relieved by exogenous glutathione consistently. We also observed the involvement of glutathione in promoting arsenic methylation and urinary elimination in vivo. Increase of total arsenic in the urine was mainly due to the increase of dimethylated arsenic. Furthermore, administration of glutathione increased the first methylation ratio and secondary methylation ratio in the liver and urine, which resulted in the consequent increase of dimethylated arsenic percent and decrease of inorganic arsenic percent in the urine. Opposite effects appeared with the administration of buthionine sulfoximine, a scavenger of glutathione. Our study indicated that exogenous glutathione not only accelerated the methylation and the excretion of arsenic, but also relieve the arsenic-induced oxidative stress. This provides a potential useful chemopreventive dietary component for human populations being at risk of arsenic exposure.

  10. Arsenic (+3 oxidation state) methyltransferase and the methylation of arsenicals in the invertebrate chordate Ciona intestinalis

    EPA Science Inventory

    Biotransformation of inorganic arsenic (iAs) involves methylation catalyzed by arsenic (+3 oxidation state) methyltransferase (As3mt), yielding mono- , di- , and trimethylated arsenicals. To investigate the evolution of molecular mechanisms that mediate arsenic biotransformation,...

  11. Arsenic (+3 oxidation state) methyltransferase and the methylation of arsenicals in the invertebrate chordate Ciona intestinalis

    EPA Science Inventory

    Biotransformation of inorganic arsenic (iAs) involves methylation catalyzed by arsenic (+3 oxidation state) methyltransferase (As3mt), yielding mono- , di- , and trimethylated arsenicals. To investigate the evolution of molecular mechanisms that mediate arsenic biotransformation,...

  12. Arsenic, Anaerobes, and Astrobiology

    NASA Astrophysics Data System (ADS)

    Stolz, J. F.; Oremland, R. S.; Switzer Blum, J.; Hoeft, S. E.; Baesman, S. M.; Bennett, S.; Miller, L. G.; Kulp, T. R.; Saltikov, C.

    2013-12-01

    Arsenic is an element best known for its highly poisonous nature, so it is not something one would associate with being a well-spring for life. Yet discoveries made over the past two decades have delineated that not only are some microbes resistant to arsenic, but that this element's primary redox states can be exploited to conserve energy and support prokaryotic growth ('arsenotrophy') in the absence of oxygen. Hence, arsenite [As(III)] can serve as an electron donor for chemo- or photo-autotrophy while arsenate [As(V)] will serve as an electron acceptor for chemo-heterotrophs and chemo-autotrophs. The phylogenetic diversity of these microbes is broad, encompassing many individual species from diverse taxonomic groups in the Domain Bacteria, with fewer representatives in the Domain Archaea. Speculation with regard to the evolutionary origins of the key functional genes in anaerobic arsenic transformations (arrA and arxA) and aerobic oxidation (aioB) has led to a disputation as to which gene and function is the most ancient and whether arsenic metabolism extended back into the Archaean. Regardless of its origin, robust arsenic metabolism has been documented in extreme environments that are rich in their arsenic content, such as hot springs and especially hypersaline soda lakes associated with volcanic regions. Searles Lake, CA is an extreme, salt-saturated end member where vigorous arsenic metabolism occurs, but there is no detectable sulfate-reduction or methanogenesis. The latter processes are too weak bio-energetically to survive as compared with arsenotrophy, and are also highly sensitive to the abundance of borate ions present in these locales. These observations have implications with respect to the search for microbial life elsewhere in the Solar System where volcanic-like processes have been operative. Hence, because of the likelihood of encountering dense brines in the regolith of Mars (formed by evapo-concentration) or beneath the ice layers of Europa

  13. Cardiac conduction block at multiple levels caused by arsenic trioxide therapy.

    PubMed

    Kathirgamanathan, Kala; Angaran, Paul; Lazo-Langner, Alejandro; Gula, Lorne J

    2013-01-01

    We present a rare case of a woman aged 62 years with refractory acute promyelocytic leukemia treated with arsenic trioxide leading to progressive, multilevel cardiac conduction block. After chelation treatment with dimercaprol, there was normalization of conduction.

  14. Arsenic: The Silent Killer

    SciTech Connect

    Foster, Andrea

    2006-02-28

    Andrea Foster uses x-rays to determine the forms of potentially toxic elements in environmentally-important matrices such as water, sediments, plants, and microorganisms. In this free public lecture, Foster will discuss her research on arsenic, which is called the silent killer because dissolved in water, it is colorless, odorless, and tasteless, yet consumption of relatively small doses of this element in its most toxic forms can cause rapid and violent death. Arsenic is a well-known poison, and has been used as such since ancient times. Less well known is the fact that much lower doses of the element, consumed over years, can lead to a variety of skin and internal cancers that can also be fatal. Currently, what has been called the largest mass poisoning in history is occurring in Bangladesh, where most people are by necessity drinking ground water that is contaminated with arsenic far in excess of the maximum amounts determined to be safe by the World Health Organization. This presentation will review the long and complicated history with arsenic, describe how x-rays have helped explain the high yet spatially variable arsenic concentrations in Bangladesh, discuss the ways in which land use in Bangladesh may be exacerbating the problem, and summarize the impact of this silent killer on drinking water systems worldwide.

  15. [Arsenic - Poison or medicine?].

    PubMed

    Kulik-Kupka, Karolina; Koszowska, Aneta; Brończyk-Puzoń, Anna; Nowak, Justyna; Gwizdek, Katarzyna; Zubelewicz-Szkodzińska, Barbara

    2016-01-01

    Arsenic (As) is commonly known as a poison. Only a few people know that As has also been widely used in medicine. In the past years As and its compounds were used as a medicine for the treatment of such diseases as diabetes, psoriasis, syphilis, skin ulcers and joint diseases. Nowadays As is also used especially in the treatment of patients with acute promyelocytic leukemia. The International Agency for Research on Cancer (IARC) has recognized arsenic as an element with carcinogenic effect evidenced by epidemiological studies, but as previously mentioned it is also used in the treatment of neoplastic diseases. This underlines the specificity of the arsenic effects. Arsenic occurs widely in the natural environment, for example, it is present in soil and water, which contributes to its migration to food products. Long exposure to this element may lead to liver damages and also to changes in myocardium. Bearing in mind that such serious health problems can occur, monitoring of the As presence in the environmental media plays a very important role. In addition, the occupational risk of As exposure in the workplace should be identified and checked. Also the standards for As presence in food should be established. This paper presents a review of the 2015 publications based on the Medical database like PubMed and Polish Medical Bibliography. It includes the most important information about arsenic in both forms, poison and medicine. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.

  16. Promoting universal financial protection: evidence from seven low- and middle-income countries on factors facilitating or hindering progress.

    PubMed

    McIntyre, Di; Ranson, Michael K; Aulakh, Bhupinder K; Honda, Ayako

    2013-09-24

    problem in LMICs. The case studies also highlighted the critical role of high-level political leadership in pursuing UHC policies and citizen support in sustaining these policies.This series demonstrates the value of promoting greater sharing of experiences on UHC reforms across LMICs. It also identifies key areas of future research on health care financing in LMICs that would support progress towards UHC.

  17. Promoting universal financial protection: evidence from seven low- and middle-income countries on factors facilitating or hindering progress

    PubMed Central

    2013-01-01

    pervasive problem in LMICs. The case studies also highlighted the critical role of high-level political leadership in pursuing UHC policies and citizen support in sustaining these policies. This series demonstrates the value of promoting greater sharing of experiences on UHC reforms across LMICs. It also identifies key areas of future research on health care financing in LMICs that would support progress towards UHC. PMID:24228762

  18. Metabolism and toxicity of arsenicals in mammals.

    PubMed

    Sattar, Adeel; Xie, Shuyu; Hafeez, Mian Abdul; Wang, Xu; Hussain, Hafiz Iftikhar; Iqbal, Zahid; Pan, Yuanhu; Iqbal, Mujahid; Shabbir, Muhammad Abubakr; Yuan, Zonghui

    2016-12-01

    Arsenic (As) is a metalloid usually found in organic and inorganic forms with different oxidation states, while inorganic form (arsenite As-III and arsenate As-v) is considered to be more hazardous as compared to organic form (methylarsonate and dimethylarsinate), with mild or no toxicity in mammals. Due to an increasing trend to using arsenicals as growth promoters or for treatment purposes, the understanding of metabolism and toxicity of As gets vital importance. Its toxicity is mainly depends on oxi-reduction states (As-III or As-v) and the level of methylation during the metabolism process. Currently, the exact metabolic pathways of As have yet to be confirmed in humans and food producing animals. Oxidative methylation and glutathione conjugation is believed to be major pathways of As metabolism. Oxidative methylation is based on conversion of Arsenite in to mono-methylarsonic acid and di-methylarsenic acid in mammals. It has been confirmed that As is only methylated in the presence of glutathione or thiol compounds, suggesting that As is being methylated in trivalent states. Subsequently, non-conjugated trivalent arsenicals are highly reactive with thiol which converts the trivalent arsenicals in to less toxic pentavalent forms. The glutathione conjugate stability of As is the most important factor for determining the toxicity. It can lead to DNA damage by alerting enzyme profile and production of reactive oxygen and nitrogen species which causes the oxidative stress. Moreover, As causes immune-dysfunction by hindering cellular and humeral immune response. The present review discussed different metabolic pathways and toxic outcomes of arsenicals in mammals which will be helpful in health risk assessment and its impact on biological world.

  19. Interplay between Cellular Methyl Metabolism and Adaptive Efflux during Oncogenic Transformation from Chronic Arsenic Exposure in Human Cells*S⃞

    PubMed Central

    Coppin, Jean-François; Qu, Wei; Waalkes, Michael P.

    2008-01-01

    After protracted low level arsenic exposure, the normal human prostate epithelial cell line RWPE-1 acquires a malignant phenotype with DNA hypomethylation, indicative of disrupted methyl metabolism, and shows arsenic adaptation involving glutathione overproduction and enhanced arsenic efflux. Thus, the interplay between methyl and glutathione metabolism during this progressive arsenic adaptation was studied. Arsenic-treated cells showed a time-dependent increase in LC50 and a marked increase in homocysteine (Hcy) levels. A marked suppression of S-adenosylmethionine (SAM) levels occurred with decreased methionine adenosyltransferase 2A (converts methionine to SAM) expression and increased negative regulator methionine adenosyltransferase B, suggesting reduced conversion of Hcy to SAM. Consistent with Hcy overproduction, activity and expression of S-adenosylhomocysteine hydrolase (converts S-adenosylhomocysteine to Hcy) were both increased. Expression of cystathionine β-synthase, a key gene in the transsulfuration pathway, and various glutathione production genes were increased, resulting in a 5-fold increase in glutathione. Arsenic efflux increased along with expression of ATP-binding cassette protein C1, which effluxes arsenic as a glutathione conjugate. Evidence of genomic DNA hypomethylation was observed during early arsenic exposure, indicating that the disruption in methyl metabolism had a potential impact related to oncogenesis. Thus, cellular arsenic adaptation is a dynamic, progressive process that involves decreased SAM recycling and concurrent accumulation of Hcy, which is channeled via transsulfuration to increase glutathione and enhance arsenic efflux but may also impact the carcinogenic process. PMID:18487201

  20. Myeloid-derived suppressor cells expand during breast cancer progression and promote tumor-induced bone destruction

    PubMed Central

    Danilin, Sabrina; Merkel, Alyssa R.; Johnson, Joshua R.; Johnson, Rachelle W.; Edwards, James R.; Sterling, Julie A.

    2012-01-01

    Myeloid-derived suppressor cells (MDSCs), identified as Gr1+CD11b+ cells in mice, expand during cancer and promote tumor growth, recurrence and burden. However, little is known about their role in bone metastases. We hypothesized that MDSCs may contribute to tumor-induced bone disease, and inoculated breast cancer cells into the left cardiac ventricle of nude mice. Disease progression was monitored weekly by X-ray and fluorescence imaging and MDSCs expansion by fluorescence-activated cell sorting. To explore the contribution of MDSCs to bone metastasis, we co-injected mice with tumor cells or PBS into the left cardiac ventricle and Gr1+CD11b+ cells isolated from healthy or tumor-bearing mice into the left tibia. MDSCs didn’t induce bone resorption in normal mice, but increased resorption and tumor burden significantly in tumor-bearing mice. In vitro experiments showed that Gr1+CD11b+ cells isolated from normal and tumor-bearing mice differentiate into osteoclasts when cultured with RANK ligand and macrophage colony-stimulating factor, and that MDSCs from tumor-bearing mice upregulate parathyroid hormone-related protein (PTHrP) mRNA levels in cancer cells. PTHrP upregulation is likely due to the 2-fold increase in transforming growth factor β expression that we observed in MDSCs isolated from tumor-bearing mice. Importantly, using MDSCs isolated from GFP-expressing animals, we found that MDSCs differentiate into osteoclast-like cells in tumor-bearing mice as evidenced by the presence of GFP+TRAP+ cells. These results demonstrate that MDSCs expand in breast cancer bone metastases and induce bone destruction. Furthermore, our data strongly suggest that MDSCs are able to differentiate into osteoclasts in vivo and that this is stimulated in the presence of tumors. PMID:23264895

  1. Sphingosine-1-phosphate produced by sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesis

    PubMed Central

    Nagahashi, Masayuki; Ramachandran, Subramaniam; Kim, Eugene Y.; Allegood, Jeremy C.; Rashid, Omar M.; Yamada, Akimitsu; Zhao, Renping; Milstien, Sheldon; Zhou, Huiping; Spiegel, Sarah; Takabe, Kazuaki

    2011-01-01

    Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid mediator that promotes breast cancer progression by diverse mechanisms that remain somewhat unclear. Here we report pharmacological evidence of a critical role for sphingosine kinase 1 (SphK1) in producing S1P and mediating tumor-induced hemangiogenesis and lymphangiogenesis in a murine model of breast cancer metastasis. S1P levels increased both in the tumor and the circulation. In agreement, serum S1P levels were significantly elevated in stage IIIA human breast cancer patients, compared to age/ethnicity-matched healthy volunteers. However, treatment with the specific SphK1 inhibitor SK1-I suppressed S1P levels, reduced metastases to lymph nodes and lungs and decreased overall tumor burden of our murine model. Both S1P and angiopoietin 2 (Ang2) stimulated hemangiogenesis and lymphangiogenesis in vitro whereas SK1-I inhibited each process. We quantified both processes in vivo from the same specimen by combining Directed In Vivo Angiogenesis Assays (DIVAA) with Fluorescence Activated Cell Sorting (DIVAA/FACS), thereby confirming the results obtained in vitro. Notably, SK1-I decreased both processes not only at the primary tumor but also in lymph nodes, with peritumoral lymphatic vessel density reduced in SK1-I-treated animals. Taken together, our findings demonstrate that SphK1-produced S1P is a crucial mediator of breast cancer-induced hemangiogenesis and lymphangiogenesis. Our results implicate SphK1 along with S1P as therapeutic targets in breast cancer. PMID:22298596

  2. HLA-DRB1 and HLA-DQB1 methylation changes promote the occurrence and progression of Kazakh ESCC.

    PubMed

    Hu, Jian Ming; Li, Ling; Chen, Yun Zhao; Liu, Chunxia; Cui, Xiaobin; Yin, Liang; Yang, Lan; Zou, Hong; Pang, Lijuan; Zhao, Jin; Qi, Yan; Cao, Yuwen; Jiang, Jinfang; Liang, Weihua; Li, Feng

    2014-10-01

    Human leukocyte antigen II (HLA-II) plays an important role in host immune responses to cancer cells. Changes in gene methylation may result in aberrant expression of HLA-II, serving a key role in the pathogenesis of Kazakh esophageal squamous cell carcinoma (ESCC). We analyzed the expression level of HLA-II (HLA-DP, -DQ, and -DR) by immunohistochemistry, as well as the methylation status of HLA-DRB1 and HLA-DQB1 by MassARRAY spectrometry in Xinjiang Kazakh ESCC. Expression of HLA-II in ESCC was significantly higher than that in cancer adjacent normal (ACN) samples (P < 0.05). Decreased HLA-II expression was closely associated with later clinical stages of ESCC (P < 0.05). Hypomethylation of HLA-DRB1 and hypermethylation of HLA-DQB1 was significantly correlated with occurrence of Kazakh ESCC (P < 0.01), and mainly manifested as hypomethylation of CpG9, CpG10-11, and CpG16 in HLA-DRB1 and hypermethylation of CpG6-7 and CpG16-17 in HLA-DQB1 (P < 0.01). Moreover, hypomethylation of HLA-DQB1 CpG6-7 correlated with poor differentiation in ESCCs, whereas hypermethylation of HLA-DRB1 CpG16 and hypomethylation of HLA-DQB1 CpG16-17 were significantly associated with later stages of ESCC (P < 0.05). A significant inverse association between HLA-DRB1 CpG9 methylation and HLA-II expression was found in ESCC (P < 0.05). These findings suggest aberrant HLA-DRB1 and HLA-DQB1 methylation contributes to the aberrant expression of HLA-II. These molecular changes may influence the immune response to specific tumor epitopes, promoting the occurrence and progression of Kazakh ESCC.

  3. Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment.

    PubMed

    Ségaliny, Aude I; Mohamadi, Amel; Dizier, Blandine; Lokajczyk, Anna; Brion, Régis; Lanel, Rachel; Amiaud, Jérôme; Charrier, Céline; Boisson-Vidal, Catherine; Heymann, Dominique

    2015-07-01

    Interleukin-34 (IL-34) was recently characterized as the M-CSF "twin" cytokine, regulating the proliferation/differentiation/survival of myeloid cells. The implication of M-CSF in oncology was initially suspected by the reduced metastatic dissemination in knock-out mice, due to angiogenesis impairment. Based on this observation, our work studied the involvement of IL-34 in the pathogenesis of osteosarcoma. The in vivo effects of IL-34 were assessed on tissue vasculature and macrophage infiltration in a murine preclinical model based on a paratibial inoculation of human osteosarcoma cells overexpressing or not IL-34 or M-CSF. In vitro investigations using endothelial cell precursors and mature HUVEC cells were performed to analyse the involvement of IL-34 in angiogenesis and myeloid cell adhesion. The data revealed that IL-34 overexpression was associated with the progression of osteosarcoma (tumor growth, lung metastases) and an increase of neo-angiogenesis. In vitro analyses demonstrated that IL-34 stimulated endothelial cell proliferation and vascular cord formation. Pre-treatment of endothelial cells by chondroitinases/heparinases reduced the formation of vascular tubes and abolished the associated cell signalling. In addition, IL-34 increased the in vivo recruitment of M2 tumor-associated macrophages into the tumor tissue. IL-34 increased in vitro monocyte/CD34(+) cell adhesion to activated HUVEC monolayers under physiological shear stress conditions. This work also demonstrates that IL-34 is expressed by osteosarcoma cells, is regulated by TNF-α, IL-1β, and contributes to osteosarcoma growth by increasing the neo-angiogenesis and the recruitment of M2 macrophages. By promoting new vessel formation and extravasation of immune cells, IL-34 may play a key role in tumor development and inflammatory diseases.

  4. HCMV-encoded miR-UL112-3p promotes glioblastoma progression via tumour suppressor candidate 3

    PubMed Central

    Liang, Qing; Wang, Kejia; Wang, Bin; Cai, Qiliang

    2017-01-01

    Glioblastoma (GBM) is the most prevalent and lethal type of primary malignant brain tumour. Recent studies suggest that the discovery of human cytomegalovirus (HCMV)-encoded microRNAs (miRNAs) might play a role in the pathogenesis of diseases, including GBM. In this study, we aimed to analyse the expression and function of HCMV-encoded miRNAs in GBM. We found that miR-UL112-3p expression was significantly elevated in GBM, and its expression levels were highly associated with glioma size, differentiation, WHO stage and the overall and disease-free survival of patients. The overexpression of miR-UL112-3p in the GBM cells promoted cell proliferation, clone formation, migration and invasion. In contrast, the down-regulation of miR-UL112-3p exerted an inverse effects. Tumour suppressor candidate 3 (TUSC3), a potential target gene of miR-UL112-3p, was inversely correlated with miR-UL112-3p expression in GBM tissues and cell lines. Furthermore, we demonstrated that TUSC3 was directly regulated by miR-UL112-3p, and the ectopic expression of TUSC3 reversed the effects of miR-UL112-3p on GBM progression via the AKT signalling pathway. Taken together, these findings collectively demonstrate that miR-UL112-3p exerts its oncogene function by directly targeting TUSC3 in GBM, indicating a potential novel therapeutic target for GBM. PMID:28303930

  5. Tumor-promoting/progressing role of additional chromosome instability in hepatic carcinogenesis in Sgo1 (Shugoshin 1) haploinsufficient mice

    PubMed Central

    Yamada, Hiroshi Y.; Zhang, Yuting; Reddy, Arun; Mohammed, Altaf; Lightfoot, Stan; Dai, Wei

    2015-01-01

    A major etiological risk factor for hepatocellular carcinoma (HCC) is infection by Hepatitis viruses, especially hepatitis B virus and hepatitis C virus. Hepatitis B virus and hepatitis C virus do not cause aggressive activation of an oncogenic pathway, but they transactivate a broad array of genes, cause chronic inflammation, and, through interference with mitotic processes, lead to mitotic error-induced chromosome instability (ME-CIN). However, how ME-CIN is involved in the development of HCC remains unclear. Delineating the effect of ME-CIN on HCC development should help in identifying measures to combat HCC. In this study, we used ME-CIN model mice haploinsufficient in Shugoshin 1 (Sgo1−/+) to assess the role of ME-CIN in HCC development. Treatment with the carcinogen azoxymethane caused Sgo1−/+ ME-CIN model mice to develop HCCs within 6 months, whereas control mice developed no HCC (P < 0.003). The HCC development was associated with expression of early HCC markers (glutamine synthetase, glypican 3, heat shock protein 70, and the serum marker alpha fetoprotein), although without fibrosis. ME-CIN preceded the expression of HCC markers, suggesting that ME-CIN is an important early event in HCC development. In 12-month-old untreated Sgo1 mice, persistent DNA damage, altered gene expression, and spontaneous HCCs were observed. Sgo1 protein accumulated in response to DNA damage in vitro. Overall, Sgo1−/+-mediated ME-CIN strongly promoted/progressed development of HCC in the presence of an initiator carcinogen, and it had a mild initiator effect by itself. Use of the ME-CIN model mice should help in identifying drugs to counteract the effects of ME-CIN and should accelerate anti-HCC drug development. PMID:25740822

  6. Development of a gas-promoted oil agglomeration process. Technical progress report, October 1, 1993--September 30, 1994

    SciTech Connect

    Wheelock, T.D.

    1994-10-01

    During the first year of the project two model mixing systems, which differed in size but were similar in design, were constructed and tested. The systems were equipped for measuring agitator speed and torque and for measuring the turbidity of coal particle suspensions undergoing agglomeration. Preliminary measurements of aqueous suspensions of coal particles showed that the Beer-Lambert law applies to such suspensions at least for low concentrations. Therefore, the measured turbidity can be used as an indicator of particle concentration and a means for monitoring the progress of oil agglomeration. However, the method is not applicable for large particle concentrations so a different technique was tested for monitoring the agglomeration of large concentrations. This technique involves measuring agitator torque and observing changes in torque while agitator speed is held constant. The results of preliminary tests of the technique were encouraging. In these tests significant changes in agitator torque were observed when particle agglomeration took place as long as solids concentration of 25 w/v % or more were utilized. A number of agglomeration tests were conducted using either one or the other of the two monitoring techniques. Both methods showed that even very small amounts of air can promote the oil agglomeration of coal particles suspended in water. Even the amount of air dissolved in water at room temperature and pressure can affect the process providing the air is displaced from the solution by a slightly soluble agglomerant such as heptane. The apparent rate of agglomeration was observed to increase as more air was introduced and also as agitator speed was increased.

  7. Arsenic Speciation of Terrestrial Invertebrates

    SciTech Connect

    Moriarty, M.M.; Koch, I.; Gordon, R.A.; Reimer, K.J. ); )

    2009-07-01

    The distribution and chemical form (speciation) of arsenic in terrestrial food chains determines both the amount of arsenic available to higher organisms, and the toxicity of this metalloid in affected ecosystems. Invertebrates are part of complex terrestrial food webs. This paper provides arsenic concentrations and arsenic speciation profiles for eight orders of terrestrial invertebrates collected at three historical gold mine sites and one background site in Nova Scotia, Canada. Total arsenic concentrations, determined by inductively coupled plasma mass spectrometry (ICP-MS), were dependent upon the classification of invertebrate. Arsenic species were determined by high-performance liquid chromatography (HPLC) ICP-MS and X-ray absorption spectroscopy (XAS). Invertebrates were found by HPLC ICP-MS to contain predominantly arsenite and arsenate in methanol/water extracts, while XAS revealed that most arsenic is bound to sulfur in vivo. Examination of the spatial distribution of arsenic within an ant tissue highlighted the differences between exogenous and endogenous arsenic, as well as the extent to which arsenic is transformed upon ingestion. Similar arsenic speciation patterns for invertebrate groups were observed across sites. Trace amounts of arsenobetaine and arsenocholine were identified in slugs, ants, and spiders.

  8. Environmental Source of Arsenic Exposure

    PubMed Central

    Chung, Jin-Yong; Yu, Seung-Do; Hong, Young-Seoub

    2014-01-01

    Arsenic is a ubiquitous, naturally occurring metalloid that may be a significant risk factor for cancer after exposure to contaminated drinking water, cigarettes, foods, industry, occupational environment, and air. Among the various routes of arsenic exposure, drinking water is the largest source of arsenic poisoning worldwide. Arsenic exposure from ingested foods usually comes from food crops grown in arsenic-contaminated soil and/or irrigated with arsenic-contaminated water. According to a recent World Health Organization report, arsenic from contaminated water can be quickly and easily absorbed and depending on its metabolic form, may adversely affect human health. Recently, the US Food and Drug Administration regulations for metals found in cosmetics to protect consumers against contaminations deemed deleterious to health; some cosmetics were found to contain a variety of chemicals including heavy metals, which are sometimes used as preservatives. Moreover, developing countries tend to have a growing number of industrial factories that unfortunately, harm the environment, especially in cities where industrial and vehicle emissions, as well as household activities, cause serious air pollution. Air is also an important source of arsenic exposure in areas with industrial activity. The presence of arsenic in airborne particulate matter is considered a risk for certain diseases. Taken together, various potential pathways of arsenic exposure seem to affect humans adversely, and future efforts to reduce arsenic exposure caused by environmental factors should be made. PMID:25284196

  9. Environmental source of arsenic exposure.

    PubMed

    Chung, Jin-Yong; Yu, Seung-Do; Hong, Young-Seoub

    2014-09-01

    Arsenic is a ubiquitous, naturally occurring metalloid that may be a significant risk factor for cancer after exposure to contaminated drinking water, cigarettes, foods, industry, occupational environment, and air. Among the various routes of arsenic exposure, drinking water is the largest source of arsenic poisoning worldwide. Arsenic exposure from ingested foods usually comes from food crops grown in arsenic-contaminated soil and/or irrigated with arsenic-contaminated water. According to a recent World Health Organization report, arsenic from contaminated water can be quickly and easily absorbed and depending on its metabolic form, may adversely affect human health. Recently, the US Food and Drug Administration regulations for metals found in cosmetics to protect consumers against contaminations deemed deleterious to health; some cosmetics were found to contain a variety of chemicals including heavy metals, which are sometimes used as preservatives. Moreover, developing countries tend to have a growing number of industrial factories that unfortunately, harm the environment, especially in cities where industrial and vehicle emissions, as well as household activities, cause serious air pollution. Air is also an important source of arsenic exposure in areas with industrial activity. The presence of arsenic in airborne particulate matter is considered a risk for certain diseases. Taken together, various potential pathways of arsenic exposure seem to affect humans adversely, and future efforts to reduce arsenic exposure caused by environmental factors should be made.

  10. ELUCIDATING THE PATHWAY FOR ARSENIC METHYLATION

    EPA Science Inventory

    Enzymatically-catalyzed methylation of arsenic is part of a metabolic pathway that converts inorganic arsenic into methylated products. Hence, in humans chronically exposed to inorganic arsenic, methyl and dimethyl arsenic account for most of the arsenic that is excreted in the ...

  11. ARSENIC SPECIATION ANALYSIS IN HUMAN SALIVA

    EPA Science Inventory

    Background: Determination of arsenic species in human saliva is potentially useful for biomonitoring of human exposure to arsenic and for studying arsenic metabolism. However, there is no report on the speciation analysis of arsenic in saliva. Methods: Arsenic species in saliva ...

  12. Activation of mutant TERT promoter by RAS-ERK signaling is a key step in malignant progression of BRAF-mutant human melanomas

    PubMed Central

    Li, Yinghui; Cheng, Hui Shan; Chng, Wee Joo; Tergaonkar, Vinay

    2016-01-01

    Although activating BRAF/NRAS mutations are frequently seen in melanomas, they are not sufficient to drive malignant transformation and require additional events. Frequent co-occurrence of mutations in the promoter for telomerase reverse transcriptase (TERT), along with BRAF alterations, has recently been noted and correlated with poorer prognosis, implicating a functional link between BRAF signaling and telomerase reactivation in melanomas. Here, we report that RAS-ERK signaling in BRAF mutant melanomas is critical for regulating active chromatin state and recruitment of RNA polymerase II at mutant TERT promoters. Our study provides evidence that the mutant TERT promoter is a key substrate downstream of the RAS-ERK pathway. Reactivating TERT and hence reconstituting telomerase is an important step in melanoma progression from nonmalignant nevi with BRAF mutations. Hence, combined targeting of RAS-ERK and TERT promoter remodeling is a promising avenue to limit long-term survival of a majority of melanomas that harbor these two mutations. PMID:27911794

  13. Activation of mutant TERT promoter by RAS-ERK signaling is a key step in malignant progression of BRAF-mutant human melanomas.

    PubMed

    Li, Yinghui; Cheng, Hui Shan; Chng, Wee Joo; Tergaonkar, Vinay

    2016-12-13

    Although activating BRAF/NRAS mutations are frequently seen in melanomas, they are not sufficient to drive malignant transformation and require additional events. Frequent co-occurrence of mutations in the promoter for telomerase reverse transcriptase (TERT), along with BRAF alterations, has recently been noted and correlated with poorer prognosis, implicating a functional link between BRAF signaling and telomerase reactivation in melanomas. Here, we report that RAS-ERK signaling in BRAF mutant melanomas is critical for regulating active chromatin state and recruitment of RNA polymerase II at mutant TERT promoters. Our study provides evidence that the mutant TERT promoter is a key substrate downstream of the RAS-ERK pathway. Reactivating TERT and hence reconstituting telomerase is an important step in melanoma progression from nonmalignant nevi with BRAF mutations. Hence, combined targeting of RAS-ERK and TERT promoter remodeling is a promising avenue to limit long-term survival of a majority of melanomas that harbor these two mutations.

  14. Children's intellectual function in relation to arsenic exposure.

    PubMed

    von Ehrenstein, Ondine S; Poddar, Shalini; Yuan, Yan; Mazumder, Debendra Guha; Eskenazi, Brenda; Basu, Arin; Hira-Smith, Meera; Ghosh, Nalima; Lahiri, Sabari; Haque, Reina; Ghosh, Alakendu; Kalman, Dave; Das, Subankar; Smith, Allan H

    2007-01-01

    Very little evidence exists concerning the possible impairment of children's intellectual function in relation to arsenic exposure in utero and during childhood. We conducted a cross-sectional study among 351 children age 5 to 15 years who were selected from a source population of 7683 people in West Bengal, India, in 2001-2003. Intellectual function was assessed with 6 subtests from the Wechsler Intelligence Scale for Children as well as with the Total Sentence Recall test, the Colored Progressive Matrices test, and a pegboard test. Arsenic in urine and lifetime water sources (including during the pregnancy period) were assessed using measurements of samples from 409 wells. The test scores were analyzed with linear regression analyses based on the method of generalized estimating equations incorporating relevant covariates. Stratifying urinary arsenic concentrations into tertiles, we found associations between arsenic and reductions in the adjusted scores of the vocabulary test (0, -0.14, -0.28; P for trend = 0.02), the object assembly test (0, -0.16, -0.24; P for trend = 0.03), and the picture completion test (0, -0.15, -0.26; P for trend = 0.02). These findings correspond to relative declines of 12% (95% confidence interval =0.4% to 24%) in the vocabulary test, 21% (-0.8% to 42%) in the object assembly test, and of 13% (0.3% to 24%) in the picture completion test in the upper urinary arsenic tertile. However, we did not find evidence of an association between test results and arsenic water concentrations during pregnancy or childhood. Current arsenic concentrations in urine, which reflect all sources of recent exposure, including water and food, were associated with small decrements in intellectual testing in school-aged children in West Bengal. We did not see associations between long-term water arsenic concentrations and intellectual function.

  15. Government and school progress to promote a healthful diet to American children and adolescents: a comprehensive review of the available evidence.

    PubMed

    Kraak, Vivica I; Story, Mary; Wartella, Ellen A

    2012-03-01

    The IOM released an expert committee report in 2005 that assessed the nature, extent, and influence of food and beverage marketing practices on American children's and adolescents' diets and health. The report concluded that prevailing marketing practices did not support a healthful diet and offered recommendations for diverse stakeholders to promote a healthful diet. The investigators evaluated progress for government and schools to achieve the IOM report recommendations over 5 years. A literature review was conducted of evidence available between December 1, 2005, and January 31, 2011. Evidence selection was guided by the IOM LEAD principles (i.e., locate, evaluate, and assemble evidence to inform decisions) and five qualitative research criteria and validated by triangulation. The analysis was conducted between February and June 2011. The investigators categorized 80 data sources into three evidence tables to evaluate public-sector progress (i.e., none, limited, moderate, and extensive). Schools made moderate progress. Government made limited progress to strengthen the nation's research capacity to understand how marketing influences diets; and no progress either to create a national "healthy eating" social marketing campaign, or to designate a responsible agency to monitor and report on progress for all actions. Public-sector stakeholders have missed opportunities to promote healthy eating environments for young people. Government could optimally use all policy tools--incentives and disincentives, education, legislation, regulation, and legal actions. Schools could more effectively engage parents, promote national nutrition standards and available guidelines, provide technical assistance, require mandatory reporting of wellness policies, and evaluate collective efforts. Copyright © 2012 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

  16. Arsenic removal by coagulation

    SciTech Connect

    Scott, K.N.; Green, J.F.; Do, H.D.; McLean, S.J.

    1995-04-01

    This study evaluated the removal of naturally occurring arsenic in a full-scale (106-mgd) conventional treatment plant. When the source water was treated with 3--10 mg/L of ferric chloride or 6, 10, or 20 mg/L of alum, arsenic removal was 81--96% (ferric chloride) and 23--71% (alum). Metal concentrations in the sludge produced during this study were below the state`s current hazardous waste levels at all coagulant dosages. No operational difficulties were encountere