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Sample records for gprc5a tumor suppressor

  1. Lung Tumor Suppressor GPRC5A Binds EGFR and Restrains Its Effector Signaling.

    PubMed

    Zhong, Shuangshuang; Yin, Huijing; Liao, Yueling; Yao, Feng; Li, Qi; Zhang, Jie; Jiao, Huike; Zhao, Yongxu; Xu, Dongliang; Liu, Shuli; Song, Hongyong; Gao, Yong; Liu, Jingyi; Ma, Lina; Pang, Zhi; Yang, Ruixu; Ding, Chengyi; Sun, Beibei; Lin, Xiaofeng; Ye, Xiaofeng; Guo, Wenzheng; Han, Baohui; Zhou, Binhua P; Chin, Y Eugene; Deng, Jiong

    2015-05-01

    GPRC5A is a G-protein-coupled receptor expressed in lung tissue but repressed in most human lung cancers. Studies in Gprc5a(-/-) mice have established its role as a tumor-suppressor function in this setting, but the basis for its role has been obscure. Here, we report that GPRC5A functions as a negative modulator of EGFR signaling. Mouse tracheal epithelial cells (MTEC) from Gprc5a(-/-) mice exhibited a relative increase in EGFR and downstream STAT3 signaling, whereas GPRC5A expression inhibited EGFR and STAT3 signaling. GPRC5A physically interacted with EGFR through its transmembrane domain, which was required for its EGFR inhibitory activity. Gprc5a(-/-) MTEC were much more susceptible to EGFR inhibitors than wild-type MTEC, suggesting their dependence on EGFR signaling for proliferation and survival. Dysregulated EGFR and STAT3 were identified in the normal epithelia of small and terminal bronchioles as well as tumors of Gprc5a(-/-) mouse lungs. Moreover, in these lungs EGFR inhibitor treatment inhibited EGFR and STAT3 activation along with cell proliferation. Finally, overexpression of ectopic GPRC5A in human non-small cell lung carcinoma cells inhibited both EGF-induced and constitutively activated EGFR signaling. Taken together, our results show how GPRC5A deficiency leads to dysregulated EGFR and STAT3 signaling and lung tumorigenesis. Cancer Res; 75(9); 1801-14. ©2015 AACR. ©2015 American Association for Cancer Research.

  2. GPRC5A is a potential oncogene in pancreatic ductal adenocarcinoma cells that is upregulated by gemcitabine with help from HuR

    PubMed Central

    Zhou, H; Telonis, A G; Jing, Y; Xia, N L; Biederman, L; Jimbo, M; Blanco, F; Londin, E; Brody, J R; Rigoutsos, I

    2016-01-01

    GPRC5A is an orphan G-protein coupled receptor with an intriguing dual behavior, acting as an oncogene in some cancers and as a tumor suppressor in other cancers. In the pancreatic cancer context, very little is known about GPRC5A. By analyzing messenger RNA (mRNA) expression data from 675 human cancer cell lines and 10 609 samples from The Cancer Genome Atlas (TCGA) we found that GPRC5A's abundance in pancreatic cancer is highest (cell lines) or second highest (TCGA) among all tissues and cancer types. Further analyses of an independent set of 252 pancreatic normal and cancer samples showed GPRC5A mRNA to be more than twofold upregulated in primary tumor samples compared with normal pancreas (P-value<10−5), and even further upregulated in pancreatic cancer metastases to various organs (P-value=0.0021). Immunostaining of 208 cores (103 samples) of a tissue microarray showed generally low expression of GPRC5A protein in normal pancreatic ductal cells; on the other hand, in primary and metastatic samples, GPRC5A protein levels were dramatically increased in pancreatic ductal cells. In vitro studies of multiple pancreatic cancer cell lines showed that an increase in GPRC5A protein levels promoted pancreatic cancer cell growth and migration. Unexpectedly, when we treated pancreatic cancer cell lines with gemcitabine (2′,2′-difluorodeoxycytidine), we observed an increase in GPRC5A protein abundance. On the other hand, when we knocked down GPRC5A we sensitized pancreatic cancer cells to gemcitabine. Through further experimentation we showed that the monotonic increase in GPRC5A protein levels that we observe for the first 18 h following gemcitabine treatment results from interactions between GPRC5A's mRNA and the RNA-binding protein HuR, which is an established key mediator of gemcitabine's efficacy in cancer cells. As we discovered, the interaction between GPRC5A and HuR is mediated by at least one HuR-binding site in GPRC5A's mRNA. Our findings indicate that

  3. High prevalence of GPRC5A germline mutations in BRCA1-mutant breast cancer patients.

    PubMed

    Sokolenko, Anna P; Bulanova, Daria R; Iyevleva, Aglaya G; Aleksakhina, Svetlana N; Preobrazhenskaya, Elena V; Ivantsov, Alexandr O; Kuligina, Ekatherina Sh; Mitiushkina, Natalia V; Suspitsin, Evgeny N; Yanus, Grigoriy A; Zaitseva, Olga A; Yatsuk, Olga S; Togo, Alexandr V; Kota, Poojitha; Dixon, J Michael; Larionov, Alexey A; Kuznetsov, Sergey G; Imyanitov, Evgeny N

    2014-05-15

    In a search for new breast cancer (BC) predisposing genes, we performed a whole exome sequencing analysis using six patient samples of familial BC and identified a germline inactivating mutation c.183delG [p. Arg61fs] in an orphan G protein-coupled receptor GPRC5A. An extended case-control study revealed a tenfold enrichment for this mutation in BC patients carrying the 5382insC allele of BRCA1, the major founder mutation in the Russian population, compared to wild-type BRCA1 BC cases [6/117 (5.1%) vs. 8/1578 (0.5%), p = 0.0002]. In mammary tumors (n = 60), the mRNA expression of GPRC5A significantly correlated with that of BRCA1 (p = 0.00018). In addition, the amount of GPRC5A transcript was significantly lower in BC obtained from BRCA1 mutation carriers (n = 17) compared to noncarriers (n = 93) (p = 0.026). Accordingly, a siRNA-mediated knockdown of either BRCA1 or GPRC5A in the MDA-MB-231 human BC cell line reduced expression of GPRC5A or BRCA1, respectively. Knockdown of GPRC5A also attenuated radiation-induced BRCA1- and RAD51-containing nuclear DNA repair foci. Taken together, these data suggest that GPRC5A is a modifier of BC risk in BRCA1 mutation carriers and reveals a functional interaction of these genes.

  4. GPRC5A suppresses protein synthesis at the endoplasmic reticulum to prevent radiation-induced lung tumorigenesis

    PubMed Central

    Wang, Jian; Farris, Alton B.; Xu, Kaiming; Wang, Ping; Zhang, Xiangming; Duong, Duc M.; Yi, Hong; Shu, Hui-Kuo; Sun, Shi-Yong; Wang, Ya

    2016-01-01

    GPRC5A functions as a lung tumour suppressor to prevent spontaneous and environmentally induced lung carcinogenesis; however, the underlying mechanism remains unclear. Here we reveal that GPRC5A at the endoplasmic reticulum (ER) membrane suppresses synthesis of the secreted or membrane-bound proteins including a number of oncogenes, the most important one being Egfr. The ER-located GPRC5A disturbs the assembly of the eIF4F-mediated translation initiation complex on the mRNA cap through directly binding to the eIF4F complex with its two middle extracellular loops. Particularly, suppression of EGFR by GPRC5A contributes significantly to preventing ionizing radiation (IR)-induced lung tumorigenesis. Thus, GPRC5A deletion enhances IR-promoted EGFR expression through an increased translation rate, thereby significantly increasing lung tumour incidence in Gprc5a−/− mice. Our findings indicate that under-expressed GPRC5A during lung tumorigenesis enhances any transcriptional stimulation through an active translational status, which can be used to control oncogene expression and potentially the resulting related disease. PMID:27273304

  5. Tumor suppressors: enhancers or suppressors of regeneration?

    PubMed Central

    Pomerantz, Jason H.; Blau, Helen M.

    2013-01-01

    Tumor suppressors are so named because cancers occur in their absence, but these genes also have important functions in development, metabolism and tissue homeostasis. Here, we discuss known and potential functions of tumor suppressor genes during tissue regeneration, focusing on the evolutionarily conserved tumor suppressors pRb1, p53, Pten and Hippo. We propose that their activity is essential for tissue regeneration. This is in contrast to suggestions that tumor suppression is a trade-off for regenerative capacity. We also hypothesize that certain aspects of tumor suppressor pathways inhibit regenerative processes in mammals, and that transient targeted modification of these pathways could be fruitfully exploited to enhance processes that are important to regenerative medicine. PMID:23715544

  6. Orphan G protein-coupled receptor GPRC5A modulates integrin β1-mediated epithelial cell adhesion.

    PubMed

    Bulanova, Daria R; Akimov, Yevhen A; Rokka, Anne; Laajala, Teemu D; Aittokallio, Tero; Kouvonen, Petri; Pellinen, Teijo; Kuznetsov, Sergey G

    2016-10-07

    G-Protein Coupled Receptor (GPCR), Class C, Group 5, Member A (GPRC5A) has been implicated in several malignancies. The underlying mechanisms, however, remain poorly understood. Using a panel of human cell lines, we demonstrate that CRISPR/Cas9-mediated knockout and RNAi-mediated depletion of GPRC5A impairs cell adhesion to integrin substrates: collagens I and IV, fibronectin, as well as to extracellular matrix proteins derived from the Engelbreth-Holm-Swarm (EHS) mouse sarcoma (Matrigel). Consistent with the phenotype, knock-out of GPRC5A correlated with a reduced integrin β1 (ITGB1) protein expression, impaired phosphorylation of the focal adhesion kinase (FAK), and lower activity of small GTPases RhoA and Rac1. Furthermore, we provide the first evidence for a direct interaction between GPRC5A and a receptor tyrosine kinase EphA2, an upstream regulator of FAK, although its contribution to the observed adhesion phenotype is unclear. Our findings reveal an unprecedented role for GPRC5A in regulation of the ITGB1-mediated cell adhesion and it's downstream signaling, thus indicating a potential novel role for GPRC5A in human epithelial cancers.

  7. Neurons and tumor suppressors.

    PubMed

    Zochodne, Douglas W

    2014-08-20

    Neurons choose growth pathways with half hearted reluctance, behavior that may be appropriate to maintain fixed long lasting connections but not to regenerate them. We now recognize that intrinsic brakes on regrowth are widely expressed in these hesitant neurons and include classical tumor suppressor molecules. Here, we review how two brakes, PTEN (phosphatase and tensin homolog deleted on chromosome 10) and retinoblastoma emerge as new and exciting knockdown targets to enhance neuron plasticity and improve outcome from damage or disease.

  8. Single-cell Sequencing Reveals Variants in ARID1A, GPRC5A and MLL2 Driving Self-renewal of Human Bladder Cancer Stem Cells.

    PubMed

    Yang, Zhao; Li, Chong; Fan, Zusen; Liu, Hongjie; Zhang, Xiaolong; Cai, Zhiming; Xu, Liqin; Luo, Jian; Huang, Yi; He, Luyun; Liu, Chunxiao; Wu, Song

    2017-01-01

    Cancer stem cells are considered responsible for many important aspects of tumors such as their self-renewal, tumor-initiating, drug-resistance and metastasis. However, the genetic basis and origination of human bladder cancer stem cells (BCSCs) remains unknown. Here, we conducted single-cell sequencing on 59 cells including BCSCs, bladder cancer non-stem cells (BCNSCs), bladder epithelial stem cells (BESCs) and bladder epithelial non-stem cells (BENSCs) from three bladder cancer (BC) specimens. Specifically, BCSCs demonstrate clonal homogeneity and suggest their origin from BESCs or BCNSCs through phylogenetic analysis. Moreover, 21 key altered genes were identified in BCSCs including six genes not previously described in BC (ETS1, GPRC5A, MKL1, PAWR, PITX2 and RGS9BP). Co-mutations of ARID1A, GPRC5A and MLL2 introduced by CRISPR/Cas9 significantly enhance the capabilities of self-renewal and tumor-initiating of BCNSCs. To our knowledge, our study first provides an overview of the genetic basis of human BCSCs with single-cell sequencing and demonstrates the biclonal origin of human BCSCs via evolution analysis.

  9. Novel reciprocal regulation of cAMP signaling and apoptosis by orphan G-protein-coupled receptor GPRC5A gene expression

    SciTech Connect

    Hirano, Minoru; Zang, Liqing; Oka, Takehiko; Ito, Yoshiyuki; Shimada, Yasuhito; Nishimura, Yuhei; Tanaka, Toshio . E-mail: tanaka@doc.medic.mie-u.ac.jp

    2006-12-08

    GPRC5A is a member of G-protein-coupled receptors, which was originally identified as an all-trans-retinoic acid-induced gene. Although recent studies reported that this gene was highly expressed in the cancer cell lines and that GPRC5A might positively regulate cell proliferation, its mechanism remains unknown. We investigated the upstream and downstream signaling of GPRC5A and its biological function, and found that cAMP signaling is the novel GPRC5A induction pathway. When GPRC5A gene was overexpressed, intracellular cAMP concentration was decreased, and Gs{alpha} gene expression was downregulated. On the other hand, RNA interference of GPRC5A increased mRNA levels of Gs{alpha} and intracellular cAMP, reduced cell number, and induced apoptosis. Conversely, cell number was increased by GPRC5A overexpression. We first report the novel negative feedback model of cAMP signaling through GPRC5A gene expression. This evidence explains one of the mechanisms of the GPRC5A-regulated cell growth in some cancer cell lines.

  10. Is PML a Tumor Suppressor?

    PubMed Central

    Mazza, Massimiliano; Pelicci, Pier Giuseppe

    2013-01-01

    The role of the promyelocytic leukemia (PML) protein has been widely tested in many different contexts, as attested by the hundreds of papers present in the literature. In most of these studies, PML is regarded as a tumor suppressor, a notion on the whole accepted by the scientific community. In this review, we examine how the concept of tumor-suppressor gene has evolved until now and then systematically assess whether this assumption for PML is supported by unambiguous experimental evidence. PMID:23847764

  11. Tumor suppressor molecules and methods of use

    DOEpatents

    Welch, Peter J.; Barber, Jack R.

    2004-09-07

    The invention provides substantially pure tumor suppressor nucleic acid molecules and tumor suppressor polypeptides. The invention also provides hairpin ribozymes and antibodies selective for these tumor suppressor molecules. Also provided are methods of detecting a neoplastic cell in a sample using detectable agents specific for the tumor suppressor nucleic acids and polypeptides.

  12. WWOX: A fragile tumor suppressor

    PubMed Central

    Schrock, Morgan S

    2015-01-01

    WWOX, the WW domain-containing oxidoreductase gene at chromosome region 16q23.3–q24.1, spanning chromosomal fragile site FRA16D, encodes the 46 kDa Wwox protein, a tumor suppressor that is lost or reduced in expression in a wide variety of cancers, including breast, prostate, ovarian, and lung. The function of Wwox as a tumor suppressor implies that it serves a function in the prevention of carcinogenesis. Indeed, in vitro studies show that Wwox protein interacts with many binding partners to regulate cellular apoptosis, proliferation, and/or maturation. It has been reported that newborn Wwox knockout mice exhibit nascent osteosarcomas while Wwox+/− mice exhibit increased incidence of spontaneous and induced tumors. Furthermore, absence or reduction of Wwox expression in mouse xenograft models results in increased tumorigenesis, which can be rescued by Wwox re-expression, though there is not universal agreement among investigators regarding the role of Wwox loss in these experimental models. Despite this proposed tumor suppressor function, the overlap of the human WWOX locus with FRA16D sensitizes the gene to protein-inactivating deletions caused by replication stress. The high frequency of deletions within the WWOX locus in cancers of various types, without the hallmark protein inactivation-associated mutations of “classical” tumor suppressors, has led to the proposal that WWOX deletions in cancers are passenger events that occur in early cancer progenitor cells due to fragility of the genetic locus, rather than driver events which provide the cancer cell a selective advantage. Recently, a proposed epigenetic cause of chromosomal fragility has suggested a novel mechanism for early fragile site instability and has implications regarding the involvement of tumor suppressor genes at chromosomal fragile sites in cancer. In this review, we provide an overview of the evidence for WWOX as a tumor suppressor gene and put this into the context of fragility

  13. Tumor suppressor ARF

    PubMed Central

    Través, Paqui G.; Luque, Alfonso; Hortelano, Sonsoles

    2012-01-01

    ARF (alternative reading frame) is one of the most important tumor regulator playing critical roles in controlling tumor initiation and progression. Recently, we have demonstrated a novel and unexpected role for ARF as modulator of inflammatory responses. PMID:23162766

  14. Therapeutic targeting of tumor suppressor genes.

    PubMed

    Morris, Luc G T; Chan, Timothy A

    2015-05-01

    Carcinogenesis is a multistep process attributable to both gain-of-function mutations in oncogenes and loss-of-function mutations in tumor suppressor genes. Currently, most molecular targeted therapies are inhibitors of oncogenes, because inactivated tumor suppressor genes have proven harder to "drug." Nevertheless, in cancers, tumor suppressor genes undergo alteration more frequently than do oncogenes. In recent years, several promising strategies directed at tumor suppressor genes, or the pathways controlled by these genes, have emerged. Here, we describe advances in a number of different methodologies aimed at therapeutically targeting tumors driven by inactivated tumor suppressor genes.

  15. Epithelial neoplasia coincides with exacerbated injury and fibrotic response in the lungs of Gprc5a-knockout mice following silica exposure.

    PubMed

    Wang, Xiaofei; Xu, Dongliang; Liao, Yueling; Zhong, Shuangshuang; Song, Hongyong; Sun, Beibei; Zhou, Binhua P; Deng, Jiong; Han, Baohui

    2015-11-24

    Exposure to crystalline silica is suggested to increase the risk for a variety of lung diseases, including fibrosis and lung cancer. However, epidemiological evidences for the exposure-risk relationship are ambiguous and conflicting, and experimental study from a reliable animal model to explore the relationship is lacking. We reasoned that a mouse model that is sensitive to both lung injury and tumorigenesis would be appropriate to evaluate the exposure-risk relationship. Previously, we showed that, Gprc5a-/- mice are susceptible to both lung tumorigenesis and endotoxin-induced acute lung injury. In this study, we investigated the biological consequences in Gprc5a-/- mouse model following silica exposure. Intra-tracheal administration of fine silica particles in Gprc5a-/- mice resulted in more severe lung injury and pulmonary inflammation than in wild-type mice. Moreover, an enhanced fibrogenic response, including EMT-like characteristics, was induced in the lungs of Gprc5a-/- mice compared to those from wild-type ones. Importantly, increased hyperplasia or neoplasia coincided with silica-induced tissue injury and fibrogenic response in lungs from Gprc5a-/- mice. Consistently, expression of MMP9, TGFβ1 and EGFR was significantly increased in lungs from silica-treated Gprc5a-/- mice compared to those untreated or wild-type ones. These results suggest that, the process of tissue repair coincides with tissue damages; whereas persistent tissue damages leads to abnormal repair or neoplasia. Thus, silica-induced pulmonary inflammation and injury contribute to increased neoplasia development in lungs from Gprc5a-/- mouse model.

  16. Discovery of Tumor Suppressor Gene Function.

    ERIC Educational Resources Information Center

    Oppenheimer, Steven B.

    1995-01-01

    This is an update of a 1991 review on tumor suppressor genes written at a time when understanding of how the genes work was limited. A recent major breakthrough in the understanding of the function of tumor suppressor genes is discussed. (LZ)

  17. Discovery of Tumor Suppressor Gene Function.

    ERIC Educational Resources Information Center

    Oppenheimer, Steven B.

    1995-01-01

    This is an update of a 1991 review on tumor suppressor genes written at a time when understanding of how the genes work was limited. A recent major breakthrough in the understanding of the function of tumor suppressor genes is discussed. (LZ)

  18. Targeting tumor suppressor networks for cancer therapeutics.

    PubMed

    Guo, Xuning Emily; Ngo, Bryan; Modrek, Aram Sandaldjian; Lee, Wen-Hwa

    2014-01-01

    Cancer is a consequence of mutations in genes that control cell proliferation, differentiation and cellular homeostasis. These genes are classified into two categories: oncogenes and tumor suppressor genes. Together, overexpression of oncogenes and loss of tumor suppressors are the dominant driving forces for tumorigenesis. Hence, targeting oncogenes and tumor suppressors hold tremendous therapeutic potential for cancer treatment. In the last decade, the predominant cancer drug discovery strategy has relied on a traditional reductionist approach of dissecting molecular signaling pathways and designing inhibitors for the selected oncogenic targets. Remarkable therapies have been developed using this approach; however, targeting oncogenes is only part of the picture. Our understanding of the importance of tumor suppressors in preventing tumorigenesis has also advanced significantly and provides a new therapeutic window of opportunity. Given that tumor suppressors are frequently mutated, deleted, or silenced with loss-of-function, restoring their normal functions to treat cancer holds tremendous therapeutic potential. With the rapid expansion in our knowledge of cancer over the last several decades, developing effective anticancer regimens against tumor suppressor pathways has never been more promising. In this article, we will review the concept of tumor suppression, and outline the major therapeutic strategies and challenges of targeting tumor suppressor networks for cancer therapeutics.

  19. Metastasis Suppressors and the Tumor Microenvironment

    PubMed Central

    Cook, Leah M.; Hurst, Douglas R.; Welch, Danny R.

    2011-01-01

    The most lethal and debilitating attribute of cancer cells is their ability to metastasize. Throughout the process of metastasis, tumor cells interact with other tumor cells, host cells and a variety of molecules. Tumor cells are also faced with a number of insults, such as hemodynamic sheer pressure and immune selection. This brief review explores how metastasis suppressor proteins regulate interactions between tumor cells and the microenvironments in which tumor cells find themselves. PMID:21168504

  20. Global gene expression and functional network analysis of gastric cancer identify extended pathway maps and GPRC5A as a potential biomarker.

    PubMed

    Cheng, Lei; Yang, Sheng; Yang, Yanqing; Zhang, Wen; Xiao, Huasheng; Gao, Hengjun; Deng, Xiaxing; Zhang, Qinghua

    2012-12-29

    To get more understanding of the molecular mechanisms underlying gastric cancer, 25 paired samples were applied to gene expression microarray analysis. Here, expression microarray, quantitative reverse transcription-PCR (qRT-PCR) and immunohistochemical analysis indicated that GPRC5A was significantly elevated in gastric cancer tissues. The integrative network analysis of deregulated genes generated eight subnetworks. We also mapped copy number variations (CNVs) and associated mRNA expression changes into pathways and identified WNT, RTK-Ras-PI3K-AKT, NF-κB, and PLAU-JAK-STAT pathways involved in proliferation, evading apoptosis and sustained angiogenesis, respectively. Taken together, our results reveal several interesting genes including GPRC5A as potential biomarkers for gastric cancer, and highlight more systematical insight of deregulated genes in genetic pathways of gastric carcinogenesis. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  1. Antiviral action of the tumor suppressor ARF

    PubMed Central

    García, María A; Collado, Manuel; Muñoz-Fontela, César; Matheu, Ander; Marcos-Villar, Laura; Arroyo, Javier; Esteban, Mariano; Serrano, Manuel; Rivas, Carmen

    2006-01-01

    Oncogenic viruses frequently target the pathways controlled by tumor suppressor genes, suggesting an extra function for these proteins as antiviral factors. The control exerted by the tumor suppressor Arf on cellular proliferation is crucial to restrict tumor development; however, a potential contribution of Arf to prevent viral infectivity has remained unexplored. In the present study, we investigated the consequences of loss or increased expression of Arf on viral infection. Our results reveal that ARF expression is induced by interferon and after viral infection. Furthermore, we show that ARF protects against viral infection in a gene dosage-dependent manner, and that this antiviral action is mediated in part by PKR through a mechanism that involves ARF-induced release of PKR from nucleophosmin complexes. Finally, Arf-null mice were hypersensitive to viral infection compared to wild-type mice. Together, our results reveal a novel and unexpected role for the tumor suppressor ARF in viral infection surveillance. PMID:16957780

  2. PTEN: History of a Tumor Suppressor.

    PubMed

    Salmena, Leonardo

    2016-01-01

    Starting from the discovery of "inhibitory chromosomes" by Theodor Boveri to the finding by Henry Harris that fusing a normal cell to a cancer cell reduced tumorigenic potential, the notion of tumor suppression was recognized well before any tumor-suppressor genes were discovered. Although not the first to be revealed, PTEN has been demonstrated to be one of the most frequently altered tumor suppressors in cancer. This introductory chapter provides a historical perspective on our current understanding of PTEN including some of the seminal discoveries in the tumor suppressor field, the events leading to PTEN's discovery, and an introduction to some of the most important researchers and their studies which have shed light on PTEN biology and function as we know it today.

  3. Tumor suppressor identified as inhibitor of inflammation

    Cancer.gov

    Scientists at NCI have found that a protein, FBXW7, which acts as a tumor suppressor, is also important for the reduction in strength of inflammatory pathways. It has long been recognized that a complex interaction exists between cancer causing mechanisms

  4. Oncogenes and tumor-suppressor genes.

    PubMed Central

    Lehman, T A; Reddel, R; Peiifer, A M; Spillare, E; Kaighn, M E; Weston, A; Gerwin, B I; Harris, C C

    1991-01-01

    The functional role of oncogenes in human lung carcinogenesis has been investigated by transfer of activated oncogenes into normal cells or an immortalized bronchial epithelial cell line, BEAS-2B. Transfection of v-Ha-ras, Ki-ras, or the combination of myc and raf into BEAS-2B cells produced tumorigenic cell lines, while transfection of raf or myc alone produced nontumorigenic cell lines. In addition to studying the pathogenic role of oncogenes, we are attempting to define negative growth-regulating genes that have tumor-suppressive effects for human lung carcinomas. Our strategy to identify tumor-suppressor genes involves loss of heterozygosity studies, monochromosome-cell fusion, and cell-cell fusion studies. Loss of heterozygosity studies have revealed consistent allelic DNA sequence deletions on chromosome 17p in squamous cell carcinomas, while large cell carcinomas and adenocarcinomas retained this locus. Mutations in p53, a tumor-suppressor gene located on chromosome 17p, have been observed. Cell-cell hybrid clones produced from fusion of nontumorigenic BEAS-2B cells with tumorigenic HuT292DM cells generally are nontumorigenic. The mechanistic role of the known tumor-suppressor genes Rb-1 and p53 in the development of human lung carcinomas is being investigated in this epithelial cell model of human bronchogenic carcinogenesis. PMID:1685442

  5. Targeting tumor suppressor genes for cancer therapy.

    PubMed

    Liu, Yunhua; Hu, Xiaoxiao; Han, Cecil; Wang, Liana; Zhang, Xinna; He, Xiaoming; Lu, Xiongbin

    2015-12-01

    Cancer drugs are broadly classified into two categories: cytotoxic chemotherapies and targeted therapies that specifically modulate the activity of one or more proteins involved in cancer. Major advances have been achieved in targeted cancer therapies in the past few decades, which is ascribed to the increasing understanding of molecular mechanisms for cancer initiation and progression. Consequently, monoclonal antibodies and small molecules have been developed to interfere with a specific molecular oncogenic target. Targeting gain-of-function mutations, in general, has been productive. However, it has been a major challenge to use standard pharmacologic approaches to target loss-of-function mutations of tumor suppressor genes. Novel approaches, including synthetic lethality and collateral vulnerability screens, are now being developed to target gene defects in p53, PTEN, and BRCA1/2. Here, we review and summarize the recent findings in cancer genomics, drug development, and molecular cancer biology, which show promise in targeting tumor suppressors in cancer therapeutics.

  6. Targeting the LKB1 Tumor Suppressor

    PubMed Central

    Zhao, Rui-Xun; Xu, Zhi-Xiang

    2014-01-01

    LKB1 (also known as serine-threonine kinase 11, STK11) is a tumor suppressor, which is mutated or deleted in Peutz-Jeghers syndrome (PJS) and in a variety of cancers. Physiologically, LKB1 possesses multiple cellular functions in the regulation of cell bioenergetics metabolism, cell cycle arrest, embryo development, cell polarity, and apoptosis. New studies demonstrated that LKB1 may also play a role in the maintenance of function and dynamics of hematopoietic stem cells. Over the past years, personalized therapy targeting specific genetic aberrations has attracted intense interests. Within this review, several agents with potential activity against aberrant LKB1 signaling have been discussed. Potential strategies and challenges in targeting LKB1 inactivation are also considered. PMID:24387336

  7. Tumor suppressor genes in familial adenomatous polyposis.

    PubMed

    Eshghifar, Nahal; Farrokhi, Naser; Naji, Tahereh; Zali, Mohammadreza

    2017-01-01

    Colorectal cancer (CRC) is mostly due to a series of genetic alterations that are being greatly under the influence of the environmental factors. These changes, mutational or epigenetic modifications at transcriptional forefront and/or post-transcriptional effects via miRNAs, include inactivation and the conversion of proto-oncogene to oncogenes, and/or inactivation of tumor suppressor genes (TSG). Here, a thorough review was carried out on the role of TSGs with the focus on the APC as the master regulator, mutated genes and mal-/dysfunctional pathways that lead to one type of hereditary form of the CRC; namely familial adenomatous polyposis (FAP). This review provides a venue towards defining candidate genes that can be used as new PCR-based markers for early diagnosis of FAP. In addition to diagnosis, defining the modes of genetic alterations will open door towards genome editing to either suppress the disease or reduce its progression during the course of action.

  8. The tumor suppressor CDKN3 controls mitosis.

    PubMed

    Nalepa, Grzegorz; Barnholtz-Sloan, Jill; Enzor, Rikki; Dey, Dilip; He, Ying; Gehlhausen, Jeff R; Lehmann, Amalia S; Park, Su-Jung; Yang, Yanzhu; Yang, Xianlin; Chen, Shi; Guan, Xiaowei; Chen, Yanwen; Renbarger, Jamie; Yang, Feng-Chun; Parada, Luis F; Clapp, Wade

    2013-06-24

    Mitosis is controlled by a network of kinases and phosphatases. We screened a library of small interfering RNAs against a genome-wide set of phosphatases to comprehensively evaluate the role of human phosphatases in mitosis. We found four candidate spindle checkpoint phosphatases, including the tumor suppressor CDKN3. We show that CDKN3 is essential for normal mitosis and G1/S transition. We demonstrate that subcellular localization of CDKN3 changes throughout the cell cycle. We show that CDKN3 dephosphorylates threonine-161 of CDC2 during mitotic exit and we visualize CDC2(pThr-161) at kinetochores and centrosomes in early mitosis. We performed a phosphokinome-wide mass spectrometry screen to find effectors of the CDKN3-CDC2 signaling axis. We found that one of the identified downstream phosphotargets, CKβ phosphorylated at serine 209, localizes to mitotic centrosomes and controls the spindle checkpoint. Finally, we show that CDKN3 protein is down-regulated in brain tumors. Our findings indicate that CDKN3 controls mitosis through the CDC2 signaling axis. These results have implications for targeted anticancer therapeutics.

  9. Protein kinase C as a tumor suppressor.

    PubMed

    Newton, Alexandra C

    2017-05-02

    Protein kinase C (PKC) has historically been considered an oncoprotein. This stems in large part from the discovery in the early 1980s that PKC is directly activated by tumor-promoting phorbol esters. Yet three decades of clinical trials using PKC inhibitors in cancer therapies not only failed, but in some cases worsened patient outcome. Why has targeting PKC in cancer eluded successful therapies? Recent studies looking at the disease for insight provide an explanation: cancer-associated mutations in PKC are generally loss-of-function (LOF), supporting an unexpected function as tumor suppressors. And, contrasting with LOF mutations in cancer, germline mutations that enhance the activity of some PKC isozymes are associated with degenerative diseases such as Alzheimer's disease. This review provides a background on the diverse mechanisms that ensure PKC is only active when, where, and for the appropriate duration needed and summarizes recent findings converging on a paradigm reversal: PKC family members generally function by suppressing, rather than promoting, survival signaling. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Studies of Tumor Suppressor Genes via Chromosome Engineering.

    PubMed

    Kugoh, Hiroyuki; Ohira, Takahito; Oshimura, Mitsuo

    2015-12-30

    The development and progression of malignant tumors likely result from consecutive accumulation of genetic alterations, including dysfunctional tumor suppressor genes. However, the signaling mechanisms that underlie the development of tumors have not yet been completely elucidated. Discovery of novel tumor-related genes plays a crucial role in our understanding of the development and progression of malignant tumors. Chromosome engineering technology based on microcell-mediated chromosome transfer (MMCT) is an effective approach for identification of tumor suppressor genes. The studies have revealed at least five tumor suppression effects. The discovery of novel tumor suppressor genes provide greater understanding of the complex signaling pathways that underlie the development and progression of malignant tumors. These advances are being exploited to develop targeted drugs and new biological therapies for cancer.

  11. Tumor suppressor genes in familial adenomatous polyposis

    PubMed Central

    Eshghifar, Nahal; Farrokhi, Naser; Naji, Tahereh; Zali, Mohammadreza

    2017-01-01

    Colorectal cancer (CRC) is mostly due to a series of genetic alterations that are being greatly under the influence of the environmental factors. These changes, mutational or epigenetic modifications at transcriptional forefront and/or post-transcriptional effects via miRNAs, include inactivation and the conversion of proto-oncogene to oncogenes, and/or inactivation of tumor suppressor genes (TSG). Here, a thorough review was carried out on the role of TSGs with the focus on the APC as the master regulator, mutated genes and mal-/dysfunctional pathways that lead to one type of hereditary form of the CRC; namely familial adenomatous polyposis (FAP). This review provides a venue towards defining candidate genes that can be used as new PCR-based markers for early diagnosis of FAP. In addition to diagnosis, defining the modes of genetic alterations will open door towards genome editing to either suppress the disease or reduce its progression during the course of action. PMID:28331559

  12. Tumor suppressor activity of RIG-I

    PubMed Central

    Li, Xian-Yang; Guo, He-Zhou; Zhu, Jiang

    2014-01-01

    Retinoic acid inducible gene-I (RIG-I), named for the observation that its mRNA expression is highly upregulated in the progression of all-trans retinoic acid (ATRA)-induced maturation of acute promyelocytic leukemia (APL) cells, has been well documented as a pivotal virus-associated molecular pattern recognition receptor (PRR) responsible for triggering innate immunity. Upon recognizing viral RNA ligands, RIG-I experiences a series of programmed conformational changes and modifications that unleash its activity through the formation of complexes with various binding partners. Such partners include the mitochondria membrane-anchored protein IPS-1 (also named MAVS/VISA/Cardif) that activates both the IRF3/7 and NF-κB pathways. These partnerships and resulting pathway activations underlie the synthesis of type I interferon and other inflammatory factors. Recent studies have demonstrated that RIG-I is also involved in the regulation of basic cellular processes outside of innate immunity against viral infections, such as hematopoietic proliferation and differentiation, maintenance of leukemic stemness, and tumorigenesis of hepatocellular carcinoma. In this review, we will highlight recent studies leading up to the recognition that RIG-I performs an essential function as a tumor suppressor and try to reconcile this activity of RIG-I with its well-known role in protecting cells against viral infection. PMID:27308362

  13. Tumor Suppressors Status in Cancer Cell Line Encyclopedia

    PubMed Central

    Sonkin, Dmitriy; Hassan, Mehedi; Murphy, Denis J.; Tatarinova, Tatiana V.

    2013-01-01

    Tumor suppressors play a major role in the etiology of human cancer, and typically achieve a tumor promoting effect upon complete functional inactivation. Bi-allelic inactivation of tumor suppressors may occur through genetic mechanisms (such as loss-of-function mutation, copy number (CN) loss, or loss-of-heterozygosity (LOH)), epigenetic mechanisms (such as promoter methylation or histone modification), or a combination of the two. We report systematically derived status of 69 known or putative tumor suppressors, across 799 samples of the Cancer Cell Line Encyclopedia. In order to generate such resource we constructed a novel comprehensive computational framework for the assessment of tumor suppressor functional “status”. This approach utilizes several orthogonal genomic data types, including mutation data, copy number, LOH and expression. Through correlation with additional data types (compound sensitivity and gene set activity) we show that this integrative method provides a more accurate assessment of tumor suppressor status than can be inferred by expression, copy number, or mutation alone. This approach has the potential for a more realistic assessment of tumor suppressor genes for both basic and translational oncology research. PMID:23639312

  14. Tumor suppressors status in cancer cell line Encyclopedia.

    PubMed

    Sonkin, Dmitriy; Hassan, Mehedi; Murphy, Denis J; Tatarinova, Tatiana V

    2013-08-01

    Tumor suppressors play a major role in the etiology of human cancer, and typically achieve a tumor-promoting effect upon complete functional inactivation. Bi-allelic inactivation of tumor suppressors may occur through genetic mechanisms (such as loss of function mutation, copy number (CN) loss, or loss of heterozygosity (LOH)), epigenetic mechanisms (such as promoter methylation or histone modification), or a combination of the two. We report systematically derived status of 69 known or putative tumor suppressors, across 799 samples of the Cancer Cell Line Encyclopedia. In order to generate such resource we constructed a novel comprehensive computational framework for the assessment of tumor suppressor functional "status". This approach utilizes several orthogonal genomic data types, including mutation data, copy number, LOH and expression. Through correlation with additional data types (compound sensitivity and gene set activity) we show that this integrative method provides a more accurate assessment of tumor suppressor status than can be inferred by expression, copy number, or mutation alone. This approach has the potential for a more realistic assessment of tumor suppressor genes for both basic and translational oncology research.

  15. Structure of the Wilms Tumor Suppressor

    SciTech Connect

    Stoll, R.; Lee, B.M.; Debler, E.W.; Laity, J.H.; Wilson, I.A.; Dyson, H.J.; Wright, P.E.

    2009-06-04

    The zinc finger domain of the Wilms tumor suppressor protein (WT1) contains four canonical Cys{sub 2}His{sub 2} zinc fingers. WT1 binds preferentially to DNA sequences that are closely related to the EGR-1 consensus site. We report the structure determination by both X-ray crystallography and NMR spectroscopy of the WT1 zinc finger domain in complex with DNA. The X-ray structure was determined for the complex with a cognate 14 base-pair oligonucleotide, and composite X-ray/NMR structures were determined for complexes with both the 14 base-pair and an extended 17 base-pair DNA. This combined approach allowed unambiguous determination of the position of the first zinc finger, which is influenced by lattice contacts in the crystal structure. The crystal structure shows the second, third and fourth zinc finger domains inserted deep into the major groove of the DNA where they make base-specific interactions. The DNA duplex is distorted in the vicinity of the first zinc finger, with a cytidine twisted and tilted out of the base stack to pack against finger 1 and the tip of finger 2. By contrast, the composite X-ray/NMR structures show that finger 1 continues to follow the major groove in the solution complexes. However, the orientation of the helix is non-canonical, and the fingertip and the N terminus of the helix project out of the major groove; as a consequence, the zinc finger side-chains that are commonly involved in base recognition make no contact with the DNA. We conclude that finger 1 helps to anchor WT1 to the DNA by amplifying the binding affinity although it does not contribute significantly to binding specificity. The structures provide molecular level insights into the potential consequences of mutations in zinc fingers 2 and 3 that are associated with Denys-Drash syndrome and nephritic syndrome. The mutations are of two types, and either destabilize the zinc finger structure or replace key base contact residues.

  16. Oncogenes and tumor suppressor genes as paradigms in oncogenesis.

    PubMed

    Spandidos, Demetrios A

    2007-09-01

    Cancer is the result of genetic and epigenetic changes that occur mainly in stem (precursor) cells of various cell types. Two main categories of genes are involved in the process of carcinogenesis. Oncogenes are activated proto-oncogenes and tumor suppressor genes are inactivated by mutation in the global sense, that is point mutation, deletion, rearrangement, and duplication. Both types of genes are required for normal cell proliferation and differentiation and aberrant expression leads to abnormal cell proliferation. Ras and p53 genes are the paradigms for oncogenes and tumor suppressor genes, respectively, whereas the oncogenes carried by the human papillomaviruses (HPV) comprise the best example of tumor viruses involvement in human cancer.

  17. [Interaction of two tumor suppressors: Phosphatase CTDSPL and Rb protein].

    PubMed

    Beniaminov, A D; Krasnov, G S; Dmitriev, A A; Puzanov, G A; Snopok, B A; Senchenko, V N; Kashuba, V I

    2016-01-01

    Earlier we established that CTDSPL gene encoding small carboxy-terminal domain serine phosphatase can be considered a classical tumor suppressor gene. Besides, transfection of tumor cell line MCF-7 with CTDSPL led to the content decrease of inactive phosphorylated form of another tumor suppressor, retinoblastoma protein (Rb), and subsequently to cell cycle arrest at the G1/S boundary. This result implied that small phosphatase CTDSPL is able to specifically dephosphorylate and activate Rb protein. In order to add some fuel to this hypothesis, in the present work we studied the interaction of two tumor suppressors CTDSPL and Rb in vitro. GST pool-down assay revealed that CTDSPL is able to precipitate Rb protein from MCF-7 cell extracts, while surface plasmon resonance technique showed that interaction of the two proteins is direct. Results of this study reassert that phosphatase CTDSPL and Rb could be involved in the common mechanism of cell cycle regulation.

  18. RET is a potential tumor suppressor gene in colorectal cancer

    PubMed Central

    Luo, Yanxin; Tsuchiya, Karen D.; Park, Dong Il; Fausel, Rebecca; Kanngurn, Samornmas; Welcsh, Piri; Dzieciatkowski, Slavomir; Wang, Jianping; Grady, William M.

    2012-01-01

    Cancer arises as the consequence of mutations and epigenetic alterations that activate oncogenes and inactivate tumor suppressor genes. Through a genome-wide screen for methylated genes in colon neoplasms, we identified aberrantly methylated RET in colorectal cancer. RET, a transmembrane receptor tyrosine kinase and a receptor for the GDNF-family ligands, was one of the first oncogenes to be identified and has been shown to be an oncogene in thyroid cancer and pheochromocytoma. However, unexpectedly, we found RET is methylated in 27% of colon adenomas and in 63% of colorectal cancers, and now provide evidence that RET has tumor suppressor activity in colon cancer. The aberrant methylation of RET correlates with decreased RET expression, whereas the restoration of RET in colorectal cancer cell lines results in apoptosis. Furthermore, in support of a tumor suppressor function of RET, mutant RET has also been found in primary colorectal cancer. We now show that these mutations inactivate RET, which is consistent with RET being a tumor suppressor gene in the colon. These findings suggest that the aberrant methylation of RET and the mutational inactivation of RET promote colorectal cancer formation and that RET can serve as a tumor suppressor gene in the colon. Moreover, the increased frequency of methylated RET in colon cancers compared to adenomas suggests RET inactivation is involved in the progression of colon adenomas to cancer. PMID:22751117

  19. Multiplexed Methylation Profiles of Tumor Suppressor Genes in Bladder Cancer

    PubMed Central

    Cabello, Maria José; Grau, Laura; Franco, Noreli; Orenes, Esteban; Alvarez, Miguel; Blanca, Ana; Heredero, Oscar; Palacios, Alberto; Urrutia, Manuel; Fernández, Jesus María; López-Beltrán, Antonio; Sánchez-Carbayo, Marta

    2011-01-01

    Changes in DNA methylation of tumor suppressors can occur early in carcinogenesis and are potentially important early indicators of cancer. The objective of this study was to assess the methylation of 25 tumor suppressor genes in bladder cancer using a methylation-specific (MS) multiplex ligation-dependent probe amplification assay (MLPA). Initial analyses in bladder cancer cell lines (n = 14) and fresh-frozen primary bladder tumor specimens (n = 31) supported the panel of genes selected being altered in bladder cancer. The process of MS-MLPA was optimized for its application in body fluids using two independent training and validation sets of urinary specimens (n = 146), including patients with bladder cancer (n = 96) and controls (n = 50). BRCA1 (71.0%), WT1 (38.7%), and RARB (38.7%) were the most frequently methylated genes in bladder tumors, with WT1 methylation being significantly associated with tumor stage (P = 0.011). WT1 and PAX5A were identified as methylated tumor suppressors. In addition, BRCA1, WT1, and RARB were the most frequently methylated genes in urinary specimens. Receiver operating characteristic curve analyses revealed significant diagnostic accuracies in both urinary sets for BRCA1, RARB, and WT1. The novelty of this report relates to applying MS-MLPA, a multiplexed methylation technique, for tumor suppressors in bladder cancer and body fluids. Methylation profiles of tumor suppressor genes were clinically relevant for histopathological stratification of bladder tumors and offered a noninvasive diagnostic strategy for the clinical management of patients affected with uroepithelial neoplasias. PMID:21227392

  20. Targeted deletion of Wwox reveals a tumor suppressor function.

    PubMed

    Aqeilan, Rami I; Trapasso, Francesco; Hussain, Sadiq; Costinean, Stefan; Marshall, Dean; Pekarsky, Yuri; Hagan, John P; Zanesi, Nicola; Kaou, Mohamed; Stein, Gary S; Lian, Jane B; Croce, Carlo M

    2007-03-06

    The WW domain-containing oxidoreductase (WWOX) spans the second most common fragile site of the human genome, FRA16D, located at 16q23, and its expression is altered in several types of human cancer. We have previously shown that restoration of WWOX expression in cancer cells suppresses tumorigenicity. To investigate WWOX tumor suppressor function in vivo, we generated mice carrying a targeted deletion of the Wwox gene and monitored incidence of tumor formation. Osteosarcomas in juvenile Wwox(-/-) and lung papillary carcinoma in adult Wwox(+/-) mice occurred spontaneously. In addition, Wwox(+/-) mice develop significantly more ethyl nitrosourea-induced lung tumors and lymphomas in comparison to wild-type littermate mice. Intriguingly, these tumors still express Wwox protein, suggesting haploinsuffiency of WWOX itself is cancer predisposing. These results indicate that WWOX is a bona fide tumor suppressor.

  1. Tumor-Induced Myeloid-Derived Suppressor Cells.

    PubMed

    De Sanctis, Francesco; Bronte, Vincenzo; Ugel, Stefano

    2016-06-01

    Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous, immune-suppressive leukocyte population that develops systemically and infiltrates tumors. MDSCs can restrain the immune response through different mechanisms including essential metabolite consumption, reactive oxygen and nitrogen species production, as well as display of inhibitory surface molecules that alter T-cell trafficking and viability. Moreover, MDSCs play a role in tumor progression, acting directly on tumor cells and promoting cancer stemness, angiogenesis, stroma deposition, epithelial-to-mesenchymal transition, and metastasis formation. Many biological and pharmaceutical drugs affect MDSC expansion and functions in preclinical tumor models and patients, often reversing host immune dysfunctions and allowing a more effective tumor immunotherapy.

  2. Tumor Suppressor Genes: A Key to the Cancer Puzzle?

    ERIC Educational Resources Information Center

    Oppenheimer, Steven B.

    1991-01-01

    Author describes developments in understanding of tumor suppressor genes or antioncogenes that he feels is most important breakthrough in solving cancer problem. Describes 1969 starting work of Harris with mouse fibroblast genes and later work of Knudson with retinoblastoma cells. Provides evidence that deletion of chromosome that results in the…

  3. Tumor Suppressor Genes: A Key to the Cancer Puzzle?

    ERIC Educational Resources Information Center

    Oppenheimer, Steven B.

    1991-01-01

    Author describes developments in understanding of tumor suppressor genes or antioncogenes that he feels is most important breakthrough in solving cancer problem. Describes 1969 starting work of Harris with mouse fibroblast genes and later work of Knudson with retinoblastoma cells. Provides evidence that deletion of chromosome that results in the…

  4. "Ring-fencing" BRCA1 tumor suppressor activity.

    PubMed

    Patel, Ketan J; Crossan, Gerry P; Hodskinson, Michael R G

    2011-12-13

    BRCA1 is a crucial human breast and ovarian cancer tumor suppressor gene. The article by Drost et al. in this issue of Cancer Cell together with a recent paper in Science now provide a clearer picture of how this large and complex protein suppresses tumorigenesis.

  5. Enhanced transfection of brain tumor suppressor genes by photochemical internalization

    NASA Astrophysics Data System (ADS)

    Chou, Chih H.; Sun, Chung-Ho; Zhou, Yi-Hong; Madsen, Steen J.; Hirschberg, Henry

    2011-03-01

    One of many limitations for cancer gene therapy is the inability of the therapeutic gene to transfect a sufficient number of tumor cells. Photochemical internalization (PCI) is a photodynamic therapy-based approach for improving the delivery of macromolecules and genes into the cell cytosol. The utility of PCI for the delivery of a tumor suppressor gene (PAX-6) was investigated in monolayers and spheroids consisting of F98 rat glioma cells.

  6. Tumor-induced immune dysfunctions caused by myeloid suppressor cells.

    PubMed

    Bronte, V; Serafini, P; Apolloni, E; Zanovello, P

    2001-01-01

    In the late 1970s, several findings suggested that accessory cells distinct from lymphocytes might suppress immune reactivity in tumor-bearing hosts. Studies in animal models and patients later confirmed that cells driven to act as dominant immune suppressors by growing cancers could subvert the immune system. These cells have also been termed natural suppressors, a functional definition connoting their ability to hamper various T- and B-lymphocyte responses without prior activation and independently from antigen and MHC restriction. These properties were attributed to distinct cell populations. The phenotypic discrepancies, together with the lack of antigen specificity, have generated serious restraints to research on tumor-induced suppression. Recent evidence indicates that suppressor cells are closely related to immature myeloid precursors and can be found in several situations that can exert adverse effects on the immunotherapy of cancer. The present review is an attempt to address the nature and properties of immature myeloid suppressors and their relationship to dendritic cells and macrophages, with the aim of clarifying the complex network of tumor-induced, negative regulators of the immune system.

  7. Caffeine activates tumor suppressor PTEN in sarcoma cells.

    PubMed

    Miwa, Shinji; Sugimoto, Naotoshi; Shirai, Toshiharu; Hayashi, Katsuhiro; Nishida, Hideji; Ohnari, Issei; Takeuchi, Akihiko; Yachie, Akihiro; Tsuchiya, Hiroyuki

    2011-08-01

    The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Akt activation exerts a strong anti-apoptotic effect and inhibits key pro-apoptotic proteins. We investigated the effect of caffeine in the prevention of tumor cell proliferation and induction of cell death. We found that caffeine induced increased intracellular cAMP levels, PTEN activation and Akt inactivation, which together prevented proliferation of human osteosarcoma cells (MG63) and fibrosarcoma cells (HT1080). PTEN knockdown by siRNA reduced the effects of caffeine on Akt inactivation in osteosarcoma cells. These results indicate that the tumor suppressor PTEN signaling pathway contributes to the growth-inhibitory effect of caffeine on sarcoma cells. Our data suggest that caffeine and other drugs that act on this pathway could have promising therapeutic effects in the treatment of sarcoma patients.

  8. The tumor suppressor protein Fhit. A novel interaction with tubulin.

    PubMed

    Chaudhuri, A R; Khan, I A; Prasad, V; Robinson, A K; Ludueña, R F; Barnes, L D

    1999-08-20

    FHIT (fragile histidine triad) is a candidate human tumor suppressor gene located at chromosome 3p14.2, a location that encompasses the FRA3B chromosomal fragile site. Aberrant transcripts have been detected in a variety of primary tumors, and homozygous deletions in the FHIT locus have been detected in different tumor cell lines. The gene product Fhit in vitro possesses the ability to hydrolyze diadenosine 5',5"'-P(1),P(3)-triphosphate (Ap(3)A). The mechanism of action of Fhit as a tumor suppressor is unknown. Because the tubulin-microtubule system plays an important role in cell division and cell proliferation, we investigated the interaction between wild-type Fhit or mutant Fhit (H96N) and tubulin in vitro. The mutant form of Fhit (H96N) lacks Ap(3)A hydrolase activity but retains tumor suppressor activity. We found that both wild-type and mutated forms of Fhit bind to tubulin strongly and specifically with K(d) values of 1.4 and 2.1 microM, respectively. Neither wild-type nor mutant Fhit cause nucleation or formation of microtubules, but in the presence of microtubule-associated proteins, both wild-type and mutant Fhit promote assembly to a greater extent than do microtubule-associated proteins alone, and the microtubules formed appear normal by electron microscopy. Our results suggest the possibility that Fhit may exert its tumor suppressor activity by interacting with microtubules and also indicate that the interaction between Fhit and tubulin is not related to the Ap(3)A hydrolase activity of Fhit.

  9. Control of autophagy by oncogenes and tumor suppressor genes.

    PubMed

    Maiuri, M C; Tasdemir, E; Criollo, A; Morselli, E; Vicencio, J M; Carnuccio, R; Kroemer, G

    2009-01-01

    Multiple oncogenes (in particular phosphatidylinositol 3-kinase, PI3K; activated Akt1; antiapoptotic proteins from the Bcl-2 family) inhibit autophagy. Similarly, several tumor suppressor proteins (such as BH3-only proteins; death-associated protein kinase-1, DAPK1; the phosphatase that antagonizes PI3K, PTEN; tuberous sclerosic complex 1 and 2, TSC1 and TSC2; as well as LKB1/STK11) induce autophagy, meaning that their loss reduces autophagy. Beclin-1, which is required for autophagy induction acts as a haploinsufficient tumor suppressor protein, and other essential autophagy mediators (such as Atg4c, UVRAG and Bif-1) are bona fide oncosuppressors. One of the central tumor suppressor proteins, p53 exerts an ambiguous function in the regulation of autophagy. Within the nucleus, p53 can act as an autophagy-inducing transcription factor. Within the cytoplasm, p53 exerts a tonic autophagy-inhibitory function, and its degradation is actually required for the induction of autophagy. The role of autophagy in oncogenesis and anticancer therapy is contradictory. Chronic suppression of autophagy may stimulate oncogenesis. However, once a tumor is formed, autophagy inhibition may be a therapeutic goal for radiosensitization and chemosensitization. Altogether, the current state-of-the art suggests a complex relationship between cancer and deregulated autophagy that must be disentangled by further in-depth investigation.

  10. AMPK: Evidence for an energy-sensing cytokinetic tumor suppressor.

    PubMed

    Vazquez-Martin, Alejandro; Oliveras-Ferraros, Cristina; Lopez-Bonet, Eugeni; Menendez, Javier A

    2009-11-15

    The AMP-activated protein kinase (AMPK) system, an evolutionary conserved low-energy checkpoint, functions as a canonical suppressor of cell proliferation. Proliferating cells, however, should also ensure a proper spatio-temporal bond between AMPK-sensed cell's metabolic status and cell division. A crucial linkage between cell proliferation and AMPK-interpreted cell bioenergetics appears to take place during the M-phase of the cell cycle. A recent description of a physical interplay between the active form the alpha-catalytic AMPK subunit with essential mitotic regulators in the centrosome and midbody has provided direct evidence that tumor-suppressive properties for AMPK closely relate to its ability to exquisitely coordinate sensing of energy resources and the fundamental biological process of genome division during mitosis and cytokinesis. Based on recent findings in our laboratory observing abortive cytokinesis followed by nuclear shape reorganization, mitotic catastrophe, polyploidization events, and cell giantism in p53-null cancer cells pharmacologically manipulated to exhibit sustained activation of AMPK, we now propose that AMPK is a novel and biologically significant participant with a tumor suppressive activity in the mitotic/cytokinetic phase of the cell cycle. In this scenario, molecular co-evolution of the energy-sensing cytokinetic tumor suppressor AMPK within the chronic biophysical constraints of the tumor microenvironment may inherently promote a continuous generation of structural and numerical changes in chromosomes favoring generation of nascent tumor cells and/or tumor-initiating cells over tumor cell death.

  11. Interaction between Nm23 and the tumor suppressor VHL.

    PubMed

    Lin, Chih-Hung; Dammai, Vincent; Adryan, Boris; Hsu, Tien

    2015-02-01

    Among the anti-tumor genes (tumor suppressors and metastasis suppressors), the von-Hippel Lindau gene and the Nm23 family of genes are among the more intriguing ones. Both are small (long and short forms of VHL are 30 and 19 kD, respectively, and Nm23 is ~17 kD), and both possess diverse molecular and cellular functions. Despite extensive studies, the entire spectra of functions and the molecular function-phenotype correlation of these two proteins have not been completely elucidated. In this report, we present data showing these two proteins interact physically. We also summarize and confirm the previous studies that demonstrated the endocytic function of these two genes and further show that the endocytic function of VHL is mediated through the activity of Nm23. These functional and molecular interactions are evolutionarily conserved from Drosophila to human.

  12. Inactivation of X-linked tumor suppressor genes in human cancer

    PubMed Central

    Liu, Runhua; Kain, Mandy; Wang, Lizhong

    2015-01-01

    Cancer cells silence autosomal tumor suppressor genes by Knudson’s two-hit mechanism in which loss-of-function mutations and then loss of heterozygosity occur at the tumor suppressor gene loci. However, the identification of X-linked tumor suppressor genes has challenged the traditional theory of “two-hit inactivation” in tumor suppressor genes, introducing the novel concept that a single genetic hit can cause loss of tumor suppressor function. The mechanism through which these genes are silenced in human cancer is unclear, but elucidating the details will greatly enhance our understanding of the pathogenesis of human cancer. Here, we review the identification of X-linked tumor suppressor genes and discuss the potential mechanisms of their inactivation. In addition, we also discuss how the identification of X-linked tumor suppressor genes can potentially lead to new approaches to cancer therapy. PMID:22515449

  13. Inactivation of X-linked tumor suppressor genes in human cancer.

    PubMed

    Liu, Runhua; Kain, Mandy; Wang, Lizhong

    2012-04-01

    Cancer cells silence autosomal tumor suppressor genes by Knudson's two-hit mechanism in which loss-of-function mutations and then loss of heterozygosity occur at the tumor suppressor gene loci. However, the identification of X-linked tumor suppressor genes has challenged the traditional theory of 'two-hit inactivation' in tumor suppressor genes, introducing the novel concept that a single genetic hit can cause loss of tumor suppressor function. The mechanism through which these genes are silenced in human cancer is unclear, but elucidating the details will greatly enhance our understanding of the pathogenesis of human cancer. Here, we review the identification of X-linked tumor suppressor genes and discuss the potential mechanisms of their inactivation. In addition, we also discuss how the identification of X-linked tumor suppressor genes can potentially lead to new approaches in cancer therapy.

  14. Identification of DOK family genes as lung tumor suppressors

    PubMed Central

    Berger, Alice H.; Niki, Masaru; Morotti, Alessandro; Taylor, Barry S.; Socci, Nicholas D.; Viale, Agnes; Brennan, Cameron; Szoke, Janos; Motoi, Noriko; Rothman, Paul B.; Teruya-Feldstein, Julie; Gerald, William L.; Ladanyi, Marc; Pandolfi, Pier Paolo

    2010-01-01

    Genome-wide analyses in human lung adenocarcinoma have identified regions of consistent copy number gain or loss, but in many cases the oncogenes and tumor suppressors presumed to reside in these loci remain to be determined. Here we identify the “Downstream of tyrosine kinase” (Dok) family members Dok1, Dok2 and Dok3 as lung tumor suppressors. Single, double, or triple compound loss of these genes in the mouse results in lung cancer with penetrance and latency dependent on the number of lost Dok alleles, and which is associated with an aberrant expansion and signaling profile of alveolar type II cells and bronchioalveolar stem cells. In human lung adenocarcinoma, we identify DOK2 as a target of copy number loss and mRNA downregulation and find that DOK2 suppresses lung cancer cell proliferation in vitro and in vivo. Given the genomic localization of DOK2, we propose it as an 8p21.3 haploinsufficient human lung tumor suppressor. PMID:20139980

  15. Jade-1, a candidate renal tumor suppressor that promotes apoptosis.

    PubMed

    Zhou, Mina I; Foy, Rebecca L; Chitalia, Vipul C; Zhao, Jin; Panchenko, Maria V; Wang, Hongmei; Cohen, Herbert T

    2005-08-02

    Medical therapies are lacking for advanced renal cancer, so there is a great need to understand its pathogenesis. Most renal cancers have defects in the von Hippel-Lindau tumor suppressor pVHL. The mechanism by which pVHL protein functions in renal tumor suppression remains unclear. Jade-1 is a short-lived, kidney-enriched transcription factor that is stabilized by direct interaction with pVHL. Loss of Jade-1 stabilization by pVHL correlates with renal cancer risk, making the relationship between Jade-1 and renal cancer compelling. We report that Jade-1 expression was barely detectable in all tested renal cancer cell lines, regardless of VHL status. Strikingly, proteasome inhibitor treatment increased endogenous Jade-1 expression up to 10-fold. Jade-1 inhibited renal cancer cell growth, colony formation, and tumor formation in nude mice. Intriguingly, Jade-1 also affected the pattern of cell growth in monolayer culture and 3D culture. Jade-1 increased apoptosis by 40-50% and decreased levels of antiapoptotic Bcl-2. Antisense Jade-1-expressing cells confirmed these results. Therefore, Jade-1 may suppress renal cancer cell growth in part by increasing apoptosis. Jade-1 may represent a proapoptotic barrier to proliferation that must be overcome generally in renal cancer, perhaps initially by pVHL inactivation and subsequently by increased proteasomal activity. Therefore, Jade-1 may be a renal tumor suppressor.

  16. Jade-1, a candidate renal tumor suppressor that promotes apoptosis

    PubMed Central

    Zhou, Mina I.; Foy, Rebecca L.; Chitalia, Vipul C.; Zhao, Jin; Panchenko, Maria V.; Wang, Hongmei; Cohen, Herbert T.

    2005-01-01

    Medical therapies are lacking for advanced renal cancer, so there is a great need to understand its pathogenesis. Most renal cancers have defects in the von Hippel-Lindau tumor suppressor pVHL. The mechanism by which pVHL protein functions in renal tumor suppression remains unclear. Jade-1 is a short-lived, kidney-enriched transcription factor that is stabilized by direct interaction with pVHL. Loss of Jade-1 stabilization by pVHL correlates with renal cancer risk, making the relationship between Jade-1 and renal cancer compelling. We report that Jade-1 expression was barely detectable in all tested renal cancer cell lines, regardless of VHL status. Strikingly, proteasome inhibitor treatment increased endogenous Jade-1 expression up to 10-fold. Jade-1 inhibited renal cancer cell growth, colony formation, and tumor formation in nude mice. Intriguingly, Jade-1 also affected the pattern of cell growth in monolayer culture and 3D culture. Jade-1 increased apoptosis by 40-50% and decreased levels of antiapoptotic Bcl-2. Antisense Jade-1-expressing cells confirmed these results. Therefore, Jade-1 may suppress renal cancer cell growth in part by increasing apoptosis. Jade-1 may represent a proapoptotic barrier to proliferation that must be overcome generally in renal cancer, perhaps initially by pVHL inactivation and subsequently by increased proteasomal activity. Therefore, Jade-1 may be a renal tumor suppressor. PMID:16046545

  17. ANX7, a candidate tumor suppressor gene for prostate cancer

    PubMed Central

    Srivastava, Meera; Bubendorf, Lukas; Srikantan, Vasantha; Fossom, Linda; Nolan, Lisa; Glasman, Mirta; Leighton, Ximena; Fehrle, Wilfred; Pittaluga, Stefania; Raffeld, Mark; Koivisto, Pasi; Willi, Niels; Gasser, Thomas C.; Kononen, Juha; Sauter, Guido; Kallioniemi, Olli P.; Srivastava, Shiv; Pollard, Harvey B.

    2001-01-01

    The ANX7 gene is located on human chromosome 10q21, a site long hypothesized to harbor a tumor suppressor gene(s) (TSG) associated with prostate and other cancers. To test whether ANX7 might be a candidate TSG, we examined the ANX7-dependent suppression of human tumor cell growth, stage-specific ANX7 expression in 301 prostate specimens on a prostate tissue microarray, and loss of heterozygosity (LOH) of microsatellite markers at or near the ANX7 locus. Here we report that human tumor cell proliferation and colony formation are markedly reduced when the wild-type ANX7 gene is transfected into two prostate tumor cell lines, LNCaP and DU145. Consistently, analysis of ANX7 protein expression in human prostate tumor microarrays reveals a significantly higher rate of loss of ANX7 expression in metastatic and local recurrences of hormone refractory prostate cancer as compared with primary tumors (P = 0.0001). Using four microsatellite markers at or near the ANX7 locus, and laser capture microdissected tumor cells, 35% of the 20 primary prostate tumors show LOH. The microsatellite marker closest to the ANX7 locus showed the highest rate of LOH, including one homozygous deletion. We conclude that the ANX7 gene exhibits many biological and genetic properties expected of a TSG and may play a role in prostate cancer progression. PMID:11287641

  18. [Role of the p53 tumor suppressor in metabolism].

    PubMed

    Lacroix, Matthieu; Linares, Laetitia Karine; Le Cam, Laurent

    2013-12-01

    The p53 tumor suppressor is an essential downstream effector of various cellular stress response pathways that is functionally inactivated in most, if not all, tumors. Since its discovery more than 30 years ago, its role in the control of cell proliferation, senescence and cell survival has been widely described. However, growing evidences from several laboratories indicate that p53 has important transcriptional and non-transcriptional functions in the control of metabolism, including the regulation of glycolysis, glutaminolysis or mitochondrial respiration. Originally identified using in vitro cellular models, this previously underestimated role of p53 has been confirmed in vivo in various genetically engineered mouse models. These recent data suggest that p53 functions in various metabolic pathways significantly contribute to its role in adult tissue homeostasis, aging as well as tumor suppression. © 2013 médecine/sciences – Inserm.

  19. The WTX Tumor Suppressor Regulates Mesenchymal Progenitor Cell Fate Specification

    PubMed Central

    Lotinun, Sutada; Akhavanfard, Sara; Coffman, Erik J.; Cook, Edward B.; Stoykova, Svetlana; Mukherjee, Siddhartha; Schoonmaker, Jesse A.; Burger, Alexa; Kim, Woo Jae; Kronenberg, Henry M.; Baron, Roland; Haber, Daniel A.; Bardeesy, Nabeel

    2014-01-01

    SUMMARY WTX is an X-linked tumor suppressor targeted by somatic mutations in Wilms tumor, a pediatric kidney cancer, and by germline inactivation in osteopathia striata with cranial sclerosis, a bone overgrowth syndrome. Here, we show that Wtx deletion in mice causes neonatal lethality, somatic overgrowth, and malformation of multiple mesenchyme-derived tissues, including bone, fat, kidney, heart, and spleen. Inactivation of Wtx at different developmental stages and in primary mesenchymal progenitor cells (MPCs) reveals that bone mass increase and adipose tissue deficiency are due to altered lineage fate decisions coupled with delayed terminal differentiation. Specification defects in MPCs result from aberrant β-catenin activation, whereas alternative pathways contribute to the subsequently delayed differentiation of lineage-restricted cells. Thus, Wtx is a regulator of MPC commitment and differentiation with stage-specific functions in inhibiting canonical Wnt signaling. Furthermore, the constellation of anomalies in Wtx null mice suggests that this tumor suppressor broadly regulates MPCs in multiple tissues. PMID:21571217

  20. Therapeutic Targets in the ARF Tumor Suppressor Pathway

    PubMed Central

    Saporita, Anthony J.; Maggi, Leonard B.; Apicelli, Anthony J.; Weber, Jason D.

    2008-01-01

    One of the outstanding fundamental questions in cancer cell biology concerns how cells coordinate cellular growth (or macromolecular synthesis) with cell cycle progression and mitosis. Intuitively, rapidly dividing cells must have some control over these processes; otherwise cells would continue to shrink in volume with every passing cycle, similar to the cytoreductive divisions seen in the very early stages of embryogenesis. The problem is easily solved in unicellular organisms, such as yeast, as their growth rates are entirely dependent on nutrient availability. Multicellular organisms such as mammals, however, must have acquired additional levels of control, as nutrient availability is seldom an issue and the organism has a prodigious capacity to store necessary metabolites in the form of glycogen, lipids, and protein. Furthermore, the specific needs and specialized architecture of tissues must constrain growth for growth’s sake; if not, the necessary function of the organ could be lost. While certainly a myriad of mechanisms for preventing this exist via initiating cell death (e.g. apoptosis, autophagy, necrosis), these all depend on some external cue, such as death signals, hypoxia, lack of nutrients or survival signals. However there must also be some cell autonomous method for surveying against inappropriate growth signals (such as oncogenic stress) that occur in a stochastic fashion, possibly as a result of random mutations. The ARF tumor suppressor seems to fulfill that role, as its expression is near undetectable in normal tissues, yet is potently induced by oncogenic stress (such as overexpression of oncogenic Ras or myc). As a result of induced expression of ARF, the tumor suppressor protein p53 is stabilized and promotes cell cycle arrest. Mutations or epigenetic alterations of the INK4a/Arf locus are second only to p53 mutations in cancer cells, and in some cancers, alterations in both Arf and p53 observed, suggesting that these two tumor

  1. Long non-coding RNA tumor suppressor candidate 7 functions as a tumor suppressor and inhibits proliferation in osteosarcoma.

    PubMed

    Cong, Menglin; Li, Jianmin; Jing, Rui; Li, Zhenzhong

    2016-07-01

    Osteosarcoma is the most common malignant tumor of bone. Recent studies have proven long non-coding RNAs (lncRNAs) play important roles in the tumorigenesis and progression of cancer. However, few lncRNAs have been investigated in osteosarcoma. Here, we reported a novel lncRNA, tumor suppressor candidate 7 (TUSC7), was significantly downregulated in osteosarcoma tissues compared with paired non-tumor tissues and low expression of TUSC7 indicated poor survival (HR = 0.313, 95 % confidence interval (CI) 0.092-0.867) of osteosarcoma patients. Further analysis revealed that loss copy number of TUSC7 was correlated with low expression of TUSC7, and additionally, loss of TUSC7 copy number also indicated poor prognosis (HR = 3.994, 95 % CI 1.147-13.91) of osteosarcoma patients. Two osteosarcoma cell lines, HOS and MG63, were utilized to investigate biological function of TUSC7. Cell counting kit 8 (CCK-8) assay revealed that after silence of TUSC7, cell proliferation ability increased and the colony formation ability also increased. Further results showed that cell cycle was not affected by treatment of si-TUSC7, while the percentage of apoptotic cells decreased. Western blot showed that after silence of TUSC7, the proapoptotic Bcl2 expression was downregulated. Finally, we established xenograft tumor models in nude mice with MG63 cells. Compared with negative control group, silence of TUSC7 significantly promoted tumor growth in vivo. Thus, we demonstrated that TUSC7 could be a potential tumor suppressor in osteosarcoma.

  2. The tumor suppressor ARF regulates innate immune responses in mice.

    PubMed

    Través, Paqui G; López-Fontal, Raquel; Luque, Alfonso; Hortelano, Sonsoles

    2011-12-15

    The innate immune system is the first line of defense against invading organisms, and TLRs are the main sensors of microbial components, initiating signaling pathways that induce the production of proinflammatory cytokines and type I IFNs. An antiviral action for the tumor suppressor alternative reading frame (ARF) has been reported; however, the precise role of ARF in innate immunity is unknown. In this study, we show that ARF plays an important role in regulation of inflammatory responses. In peritoneal macrophages and bone marrow-derived macrophages from ARF-deficient animals, the induction of proinflammatory cytokines and chemokines by TLR ligands was severely impaired. The altered responses of ARF(-/-) cells to TLR ligands result from aberrant activation of intracellular signaling molecules including MAPKs, IκBα degradation, and NF-κB activation. Additionally, animals lacking ARF were resistant to LPS-induced endotoxic shock. This impaired activation of inflammation in ARF(-/-) mice was not restricted to TLRs, as it was also shown in response to non-TLR signaling pathways. Thus, ARF(-/-) mice were also unable to trigger a proper inflammatory response in experimental peritonitis or in 12-O-tetradecanoylphorbol-13-acetate-induced edema. Overexpression of ARF, but not its downstream target p53, rescued the ARF-deficient phenotype, increasing TLR4 levels and restoring inflammatory reaction. An increase in the E2F1 protein levels observed in ARF(-/-) macrophages at basal condition and after LPS stimulation may be involved in the impaired response in this system, as E2F1 has been described as an inflammatory suppressor. These results indicate that tumor suppressor ARF is a new regulator of inflammatory cell signaling.

  3. Induction of myeloid-derived suppressor cells by tumor exosomes.

    PubMed

    Xiang, Xiaoyu; Poliakov, Anton; Liu, Cunren; Liu, Yuelong; Deng, Zhong-bin; Wang, Jianhua; Cheng, Ziqiang; Shah, Spandan V; Wang, Gui-Jun; Zhang, Liming; Grizzle, William E; Mobley, Jim; Zhang, Huang-Ge

    2009-06-01

    Myeloid-derived suppressor cells (MDSCs) promote tumor progression. The mechanisms of MDSC development during tumor growth remain unknown. Tumor exosomes (T-exosomes) have been implicated to play a role in immune regulation, however the role of exosomes in the induction of MDSCs is unclear. Our previous work demonstrated that exosomes isolated from tumor cells are taken up by bone marrow myeloid cells. Here, we extend those findings showing that exosomes isolated from T-exosomes switch the differentiation pathway of these myeloid cells to the MDSC pathway (CD11b(+)Gr-1(+)). The resulting cells exhibit MDSC phenotypic and functional characteristics including promotion of tumor growth. Furthermore, we demonstrated that in vivo MDSC mediated promotion of tumor progression is dependent on T-exosome prostaglandin E2 (PGE2) and TGF-beta molecules. T-exosomes can induce the accumulation of MDSCs expressing Cox2, IL-6, VEGF, and arginase-1. Antibodies against exosomal PGE2 and TGF-beta block the activity of these exosomes on MDSC induction and therefore attenuate MDSC-mediated tumor-promoting ability. Exosomal PGE2 and TGF-beta are enriched in T-exosomes when compared with exosomes isolated from the supernatants of cultured tumor cells (C-exosomes). The tumor microenvironment has an effect on the potency of T-exosome mediated induction of MDSCs by regulating the sorting and the amount of exosomal PGE2 and TGF-beta available. Together, these findings lend themselves to developing specific targetable therapeutic strategies to reduce or eliminate MDSC-induced immunosuppression and hence enhance host antitumor immunotherapy efficacy.

  4. Transcriptional Regulation of the p16 Tumor Suppressor Gene.

    PubMed

    Kotake, Yojiro; Naemura, Madoka; Murasaki, Chihiro; Inoue, Yasutoshi; Okamoto, Haruna

    2015-08-01

    The p16 tumor suppressor gene encodes a specific inhibitor of cyclin-dependent kinase (CDK) 4 and 6 and is found altered in a wide range of human cancers. p16 plays a pivotal role in tumor suppressor networks through inducing cellular senescence that acts as a barrier to cellular transformation by oncogenic signals. p16 protein is relatively stable and its expression is primary regulated by transcriptional control. Polycomb group (PcG) proteins associate with the p16 locus in a long non-coding RNA, ANRIL-dependent manner, leading to repression of p16 transcription. YB1, a transcription factor, also represses the p16 transcription through direct association with its promoter region. Conversely, the transcription factors Ets1/2 and histone H3K4 methyltransferase MLL1 directly bind to the p16 locus and mediate p16 induction during replicative and premature senescence. In the present review, we discuss the molecular mechanisms by which these factors regulate p16 transcription. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  5. RB1: a prototype tumor suppressor and an enigma

    PubMed Central

    Dyson, Nicholas J.

    2016-01-01

    The retinoblastoma susceptibility gene (RB1) was the first tumor suppressor gene to be molecularly defined. RB1 mutations occur in almost all familial and sporadic forms of retinoblastoma, and this gene is mutated at variable frequencies in a variety of other human cancers. Because of its early discovery, the recessive nature of RB1 mutations, and its frequency of inactivation, RB1 is often described as a prototype for the class of tumor suppressor genes. Its gene product (pRB) regulates transcription and is a negative regulator of cell proliferation. Although these general features are well established, a precise description of pRB's mechanism of action has remained elusive. Indeed, in many regards, pRB remains an enigma. This review summarizes some recent developments in pRB research and focuses on progress toward answers for the three fundamental questions that sit at the heart of the pRB literature: What does pRB do? How does the inactivation of RB change the cell? How can our knowledge of RB function be exploited to provide better treatment for cancer patients? PMID:27401552

  6. Fastest Time to Cancer by Loss of Tumor Suppressor Genes

    PubMed Central

    Sanchez-Tapia, Cynthia; Wan, Frederic Y.M.

    2014-01-01

    Genetic instability promotes cancer progression (by increasing the probability of cancerous mutations) as well as hinders it (by imposing a higher cell death rate for cells susceptible to cancerous mutation). With the loss of tumor suppressor gene function known to be responsible for a high percentage of breast and colorectal cancer (and a good fraction of lung and other types as well), it is important to understand how genetic instability can be orchestrated toward carcinogenesis. In this context, this paper gives a complete characterization of the optimal (time-varying) cell mutation rate for the fastest time to a target cancerous cell population through the loss of both copies of a tumor suppressor gene (TSG). Similar to the (1-step) oncogene activation model previously analyzed, the optimal mutation rate of the present 2-step model changes qualitatively with the convexity of the (mutation rate dependent) cell death rate. However, the structure of the Hamiltonian for the new model differs significantly and intrinsically from that of the 1-step model and a completely new approach is needed for the solution of the present 2-step problem. Considerable insight on the biology of optimal switching (between corner controls) is extracted from numerical results for cases with nonconvex death rates. PMID:25338553

  7. RB1: a prototype tumor suppressor and an enigma.

    PubMed

    Dyson, Nicholas J

    2016-07-01

    The retinoblastoma susceptibility gene (RB1) was the first tumor suppressor gene to be molecularly defined. RB1 mutations occur in almost all familial and sporadic forms of retinoblastoma, and this gene is mutated at variable frequencies in a variety of other human cancers. Because of its early discovery, the recessive nature of RB1 mutations, and its frequency of inactivation, RB1 is often described as a prototype for the class of tumor suppressor genes. Its gene product (pRB) regulates transcription and is a negative regulator of cell proliferation. Although these general features are well established, a precise description of pRB's mechanism of action has remained elusive. Indeed, in many regards, pRB remains an enigma. This review summarizes some recent developments in pRB research and focuses on progress toward answers for the three fundamental questions that sit at the heart of the pRB literature: What does pRB do? How does the inactivation of RB change the cell? How can our knowledge of RB function be exploited to provide better treatment for cancer patients?

  8. SIRT3: Oncogene and Tumor Suppressor in Cancer.

    PubMed

    Torrens-Mas, Margalida; Oliver, Jordi; Roca, Pilar; Sastre-Serra, Jorge

    2017-07-12

    Sirtuin 3 (SIRT3), the major deacetylase in mitochondria, plays a crucial role in modulating oxygen reactive species (ROS) and limiting the oxidative damage in cellular components. SIRT3 targets different enzymes which regulate mitochondrial metabolism and participate in ROS detoxification, such as the complexes of the respiratory chain, the isocitrate dehydrogenase, or the manganese superoxide dismutase. Thus, SIRT3 activity is essential in maintaining mitochondria homeostasis and has recently received great attention, as it is considered a fidelity protein for mitochondrial function. In some types of cancer, SIRT3 functions as a tumoral promoter, since it keeps ROS levels under a certain threshold compatible with cell viability and proliferation. On the contrary, other studies describe SIRT3 as a tumoral suppressor, as SIRT3 could trigger cell death under stress conditions. Thus, SIRT3 could have a dual role in cancer. In this regard, modulation of SIRT3 activity could be a new target to develop more personalized therapies against cancer.

  9. Role of the p16 tumor suppressor gene in cancer.

    PubMed

    Liggett, W H; Sidransky, D

    1998-03-01

    Since its discovery as a CDKI (cyclin-dependent kinase inhibitor) in 1993, the tumor suppressor p16 (INK4A/MTS-1/CDKN2A) has gained widespread importance in cancer. The frequent mutations and deletions of p16 in human cancer cell lines first suggested an important role for p16 in carcinogenesis. This genetic evidence for a causal role was significantly strengthened by the observation that p16 was frequently inactivated in familial melanoma kindreds. Since then, a high frequency of p16 gene alterations were observed in many primary tumors. In human neoplasms, p16 is silenced in at least three ways: homozygous deletion, methylation of the promoter, and point mutation. The first two mechanisms comprise the majority of inactivation events in most primary tumors. Additionally, the loss of p16 may be an early event in cancer progression, because deletion of at least one copy is quite high in some premalignant lesions. p16 is a major target in carcinogenesis, rivaled in frequency only by the p53 tumor-suppressor gene. Its mechanism of action as a CDKI has been elegantly elucidated and involves binding to and inactivating the cyclin D-cyclin-dependent kinase 4 (or 6) complex, and thus renders the retinoblastoma protein inactive. This effect blocks the transcription of important cell-cycle regulatory proteins and results in cell-cycle arrest. Although p16 may be involved in cell senescence, the physiologic role of p16 is still unclear. Future work will focus on studies of the upstream events that lead to p16 expression and its mechanism of regulation, and perhaps lead to better therapeutic strategies that can improve the clinical course of many lethal cancers.

  10. Phosphorylation is the switch that turns PEA-15 from tumor suppressor to tumor promoter

    PubMed Central

    Sulzmaier, Florian J.; Opoku-Ansah, John; Ramos, Joe W.

    2012-01-01

    Abnormal ERK signaling is implicated in many human diseases including cancer. This signaling cascade is a good target for the therapy of certain malignancies because of its important role in regulating cell proliferation and survival. The small phosphoprotein PEA-15 is a potent regulator of the ERK signaling cascade, and, by acting on this pathway, has been described to have both tumor-suppressor and tumor-promoter functions. However, the exact mechanism by which PEA-15 drives the outcome one way or the other remains unclear. We propose that the cellular environment is crucial in determining PEA-15 protein function by affecting the protein’s phosphorylation state. We hypothesize that only unphosphorylated PEA-15 can act as a tumor-suppressor and that phosphorylation alters the interaction with binding partners to promote tumor development. In order to use PEA-15 as a prognostic marker or therapeutic target it is therefore important to evaluate its phosphorylation status. PMID:22694972

  11. Testosterone regulates thyroid cancer progression by modifying tumor suppressor genes and tumor immunity

    PubMed Central

    Zhang, Lisa J.; Xiong, Yin; Nilubol, Naris; He, Mei; Bommareddi, Swaroop; Zhu, Xuguang; Jia, Li; Xiao, Zhen; Park, Jeong-Won; Xu, Xia; Patel, Dhaval; Willingham, Mark C.; Cheng, Sheue-yann; Kebebew, Electron

    2015-01-01

    Cancer gender disparity has been observed for a variety of human malignancies. Thyroid cancer is one such cancer with a higher incidence in women, but more aggressive disease in men. There is scant evidence on the role of sex hormones on cancer initiation/progression. Using a transgenic mouse model of follicular thyroid cancer (FTC), we found castration led to lower rates of cancer in females and less advanced cancer in males. Mechanistically, less advanced cancer in castrated males was due to increased expression of tumor suppressor (Glipr1, Sfrp1) and immune-regulatory genes and higher tumor infiltration with M1 macrophages and CD8 cells. Functional study showed that GLIPR1 reduced cell growth and increased chemokine secretion (Ccl5) that activates immune cells. Our data demonstrate that testosterone regulates thyroid cancer progression by reducing tumor suppressor gene expression and tumor immunity. PMID:25576159

  12. TANGO is a tumor suppressor of malignant melanoma.

    PubMed

    Arndt, Stephanie; Bosserhoff, Anja K

    2006-12-15

    The TANGO gene was originally identified as a new family member of the melanoma inhibitory activity gene family. The gene codes for a 14 kDa protein of so far unknown function. In our study we revealed that TANGO was downregulated or lost in 9 melanoma cell lines when compared to normal melanocytes and in most of the 8 tumor samples analyzed. The losses were associated with advanced stage of the disease. These results were confirmed in situ by immunohistochemistry on 10 paraffin-embedded sections of human malignant melanoma primary tumors and melanoma skin metastases. A small reduction of TANGO was also seen in different benign and atypical nevi when compared to normal skin. For functional analysis of TANGO we evaluated TANGO re-expressing melanoma cell clones and antisense TANGO cell clones with a complete loss of TANGO. Functional assays with TANGO transfected or treated cell lines revealed that TANGO expression reduces motility, whereas reduction of TANGO enhances migration. Our studies, therefore, indicate that reduction of TANGO expression contributes to tumor progression. These results taken together provide the first indications for a tumor suppressor role of TANGO gene in human malignant melanoma.

  13. Cellular senescence and tumor suppressor gene p16.

    PubMed

    Rayess, Hani; Wang, Marilene B; Srivatsan, Eri S

    2012-04-15

    Cellular senescence is an irreversible arrest of cell growth. Biochemical and morphological changes occur during cellular senescence, including the formation of a unique cellular morphology such as flattened cytoplasm. Function of mitochondria, endoplasmic reticulum and lysosomes are affected resulting in the inhibition of lysosomal and proteosomal pathways. Cellular senescence can be triggered by a number of factors including, aging, DNA damage, oncogene activation and oxidative stress. While the molecular mechanism of senescence involves p16 and p53 tumor suppressor genes and telomere shortening, this review is focused on the mechanism of p16 control. The p16-mediated senescence acts through the retinoblastoma (Rb) pathway inhibiting the action of the cyclin dependant kinases leading to G1 cell cycle arrest. Rb is maintained in a hypophosphorylated state resulting in the inhibition of transcription factor E2F1. Regulation of p16 expression is complex and involves epigenetic control and multiple transcription factors. PRC1 (Pombe repressor complex (1) and PRC2 (Pombe repressor complex (2) proteins and histone deacetylases play an important role in the promoter hypermethylation for suppressing p16 expression. While transcription factors YY1 and Id1 suppress p16 expression, transcription factors CTCF, Sp1 and Ets family members activate p16 transcription. Senescence occurs with the inactivation of suppressor elements leading to the enhanced expression of p16. Copyright © 2011 UICC.

  14. Cellular senescence and tumor suppressor gene p16

    PubMed Central

    Rayess, Hani; Wang, Marilene B.; Srivatsan, Eri S.

    2011-01-01

    Cellular senescence is an irreversible arrest of cell growth. Biochemical and morphological changes occur during cellular senescence, including the formation of a unique cellular morphology such as flattened cytoplasm. Function of mitochondria, endoplasmic reticulum and lysosomes are affected resulting in the inhibition of lysosomal and proteosomal pathways. Cellular senescence can be triggered by a number of factors including, aging, DNA damage, oncogene activation and oxidative stress. While the molecular mechanism of senescence involves p16 and p53 tumor suppressor genes and telomere shortening, this review is focused on the mechanism of p16 control. The p16 mediated senescence acts through the retinoblastoma (Rb) pathway inhibiting the action of the cyclin dependant kinases leading to G1 cell cycle arrest. Rb is maintained in a hypophosphorylated state resulting in the inhibition of transcription factor E2F1. Regulation of p16 expression is complex and involves epigenetic control and multiple transcription factors. PRC1 (Pombe repressor complex 1) and PRC2 (Pombe repressor complex 2) proteins and histone deacetylases play an important role in the promoter hypermethylation for suppressing p16 expression. While transcription factors YY1 and Id1 suppress p16 expression, transcription factors CTCF, Sp1, and Ets family members activate p16 transcription. Senescence occurs with the inactivation of suppressor elements leading to the enhanced expression of p16. PMID:22025288

  15. The human ARF tumor suppressor senses blastema activity and suppresses epimorphic tissue regeneration.

    PubMed

    Hesse, Robert G; Kouklis, Gayle K; Ahituv, Nadav; Pomerantz, Jason H

    2015-11-17

    The control of proliferation and differentiation by tumor suppressor genes suggests that evolution of divergent tumor suppressor repertoires could influence species' regenerative capacity. To directly test that premise, we humanized the zebrafish p53 pathway by introducing regulatory and coding sequences of the human tumor suppressor ARF into the zebrafish genome. ARF was dormant during development, in uninjured adult fins, and during wound healing, but was highly expressed in the blastema during epimorphic fin regeneration after amputation. Regenerative, but not developmental signals resulted in binding of zebrafish E2f to the human ARF promoter and activated conserved ARF-dependent Tp53 functions. The context-dependent activation of ARF did not affect growth and development but inhibited regeneration, an unexpected distinct tumor suppressor response to regenerative versus developmental environments. The antagonistic pleiotropic characteristics of ARF as both tumor and regeneration suppressor imply that inducing epimorphic regeneration clinically would require modulation of ARF -p53 axis activation.

  16. Metastasis Suppressors Regulate the Tumor Microenvironment by Blocking Recruitment of Prometastatic Tumor-Associated Macrophages.

    PubMed

    Frankenberger, Casey; Rabe, Daniel; Bainer, Russell; Sankarasharma, Devipriya; Chada, Kiran; Krausz, Thomas; Gilad, Yoav; Becker, Lev; Rosner, Marsha Rich

    2015-10-01

    Triple-negative breast cancer (TNBC) patients have the highest risk of recurrence and metastasis. Because they cannot be treated with targeted therapies, and many do not respond to chemotherapy, they represent a clinically underserved group. TNBC is characterized by reduced expression of metastasis suppressors such as Raf kinase inhibitory protein (RKIP), which inhibits tumor invasiveness. Mechanisms by which metastasis suppressors alter tumor cells are well characterized; however, their ability to regulate the tumor microenvironment and the importance of such regulation to metastasis suppression are incompletely understood. Here, we use species-specific RNA sequencing to show that RKIP expression in tumors markedly reduces the number and metastatic potential of infiltrating tumor-associated macrophages (TAM). TAMs isolated from nonmetastatic RKIP(+) tumors, relative to metastatic RKIP(-) tumors, exhibit a reduced ability to drive tumor cell invasion and decreased secretion of prometastatic factors, including PRGN, and shed TNFR2. RKIP regulates TAM recruitment by blocking HMGA2, resulting in reduced expression of numerous macrophage chemotactic factors, including CCL5. CCL5 overexpression in RKIP(+) tumors restores recruitment of prometastatic TAMs and intravasation, whereas treatment with the CCL5 receptor antagonist Maraviroc reduces TAM infiltration. These results highlight the importance of RKIP as a regulator of TAM recruitment through chemokines such as CCL5. The clinical significance of these interactions is underscored by our demonstration that a signature comprised of RKIP signaling and prometastatic TAM factors strikingly separates TNBC patients based on survival outcome. Collectively, our findings identify TAMs as a previously unsuspected mechanism by which the metastasis-suppressor RKIP regulates tumor invasiveness, and further suggest that TNBC patients with decreased RKIP activity and increased TAM infiltration may respond to macrophage

  17. SOX17 is a tumor suppressor in endometrial cancer

    PubMed Central

    Zhang, Yongli; Bao, Wei; Wang, Kai; Lu, Wen; Wang, Huihui; Tong, Huan; Wan, Xiaoping

    2016-01-01

    β-catenin is a key regulatory factor for the Wnt signaling pathway. SOX17 is an important β-catenin inhibitor, while MAML3 is a co-activator of β-catenin-mediated transcription. Out of 120 endometrial cancer (EC) patients, we found that those with tumors expressing higher SOX17 (n=68) had longer recurrence-free survival (P=0.024), while higher MAML3 expression (n=76) was associated with shorter recurrence-free survival (P=0.022). Immunohistochemical and immunoprecipitation analyses revealed that SOX17 and MAML3 co-localized in EC cell nuclei, and the MAML3 C-terminal region was necessary for SOX17 binding. SOX17 regulated MAML3 transcription via binding to the MAML3 promoter, decreasing Wnt pathway protein expression and suppressing EC cell growth and colony formation in vitro. In nude mice, SOX17 over-expression inhibited tumor growth, and co-inhibition or co-overexpression of SOX17 and MAML3 rescued this response. Our results suggest that decreasing SOX17 levels may promote EC development and progression, and that by downregulating MAML3 expression and Wnt signaling, SOX17 acts as a tumor suppressor that may improve outcome in patients with EC. PMID:27738313

  18. SOX17 is a tumor suppressor in endometrial cancer.

    PubMed

    Zhang, Yongli; Bao, Wei; Wang, Kai; Lu, Wen; Wang, Huihui; Tong, Huan; Wan, Xiaoping

    2016-11-15

    β-catenin is a key regulatory factor for the Wnt signaling pathway. SOX17 is an important β-catenin inhibitor, while MAML3 is a co-activator of β-catenin-mediated transcription. Out of 120 endometrial cancer (EC) patients, we found that those with tumors expressing higher SOX17 (n=68) had longer recurrence-free survival (P=0.024), while higher MAML3 expression (n=76) was associated with shorter recurrence-free survival (P=0.022). Immunohistochemical and immunoprecipitation analyses revealed that SOX17 and MAML3 co-localized in EC cell nuclei, and the MAML3 C-terminal region was necessary for SOX17 binding. SOX17 regulated MAML3 transcription via binding to the MAML3 promoter, decreasing Wnt pathway protein expression and suppressing EC cell growth and colony formation in vitro. In nude mice, SOX17 over-expression inhibited tumor growth, and co-inhibition or co-overexpression of SOX17 and MAML3 rescued this response. Our results suggest that decreasing SOX17 levels may promote EC development and progression, and that by downregulating MAML3 expression and Wnt signaling, SOX17 acts as a tumor suppressor that may improve outcome in patients with EC.

  19. Vitamin D receptor, a tumor suppressor in skin.

    PubMed

    Bikle, Daniel D

    2015-05-01

    Vitamin D and calcium are well-established regulators of keratinocyte proliferation and differentiation. Therefore, it was not a great surprise that deletion of the vitamin D receptor (VDR) should predispose the skin to tumor formation, and that the combination of deleting both the VDR and calcium sensing receptor (CaSR) should be especially pro-oncogenic. In this review I have examined 4 mechanisms that appear to underlie the means by which VDR acts as a tumor suppressor in skin. First, DNA damage repair is curtailed in the absence of the VDR, allowing mutations in DNA to accumulate. Second and third involve the increased activation of the hedgehog and β-catenin pathways in the epidermis in the absence of the VDR, leading to poorly regulated proliferation with reduced differentiation. Finally, VDR deletion leads to a shift in the expression of long noncoding RNAs toward a more oncogenic profile. How these different mechanisms interact and their relative importance in the predisposition of the VDR null epidermis to tumor formation remain under active investigation.

  20. Notch1 functions as a tumor suppressor in mouse skin.

    PubMed

    Nicolas, Michael; Wolfer, Anita; Raj, Kenneth; Kummer, J Alain; Mill, Pleasantine; van Noort, Mascha; Hui, Chi-chung; Clevers, Hans; Dotto, G Paolo; Radtke, Freddy

    2003-03-01

    Notch proteins are important in binary cell-fate decisions and inhibiting differentiation in many developmental systems, and aberrant Notch signaling is associated with tumorigenesis. The role of Notch signaling in mammalian skin is less well characterized and is mainly based on in vitro studies, which suggest that Notch signaling induces differentiation in mammalian skin. Conventional gene targeting is not applicable to establishing the role of Notch receptors or ligands in the skin because Notch1-/- embryos die during gestation. Therefore, we used a tissue-specific inducible gene-targeting approach to study the physiological role of the Notch1 receptor in the mouse epidermis and the corneal epithelium of adult mice. Unexpectedly, ablation of Notch1 results in epidermal and corneal hyperplasia followed by the development of skin tumors and facilitated chemical-induced skin carcinogenesis. Notch1 deficiency in skin and in primary keratinocytes results in increased and sustained expression of Gli2, causing the development of basal-cell carcinoma-like tumors. Furthermore, Notch1 inactivation in the epidermis results in derepressed beta-catenin signaling in cells that should normally undergo differentiation. Enhanced beta-catenin signaling can be reversed by re-introduction of a dominant active form of the Notch1 receptor. This leads to a reduction in the signaling-competent pool of beta-catenin, indicating that Notch1 can inhibit beta-catenin-mediated signaling. Our results indicate that Notch1 functions as a tumor-suppressor gene in mammalian skin.

  1. The vitamin D receptor: a tumor suppressor in skin.

    PubMed

    Bikle, Daniel David

    2011-01-01

    Epidemiologic evidence supporting a major chemopreventive role for vitamin D in various malignancies is strong. Likewise the use of the active metabolite of vitamin D, 1,25(OH)(2)D(3), and its analogs to prevent and/or treat a wide variety of malignancies in animals is well established. The evidence has been less compelling for epidermal carcinogenesis perhaps because the same agent that produces vitamin D in the skin, UVB radiation (UVR), is also the same agent that results in most epidermal malignancies. However, recent studies indicate that the role of vitamin D and its receptor (VDR) in protecting against the development of epidermal tumors deserves a closer look. One such study found mice lacking the VDR were quite sensitive to epidermal tumor formation following the administration of the carcinogen DMBA. A more recent study showed that these mice were similarly more sensitive to tumor formation following UVR, results we have confirmed. The epidermis of the VDR null mouse is hyperproliferative with gross distortion of hair follicles, structures that may provide the origin for the tumors found in the skin following such treatment. Two interacting pathways critical for epidermal and hair follicle function, beta-catenin and hedgehog (Hh), result in epidermal tumors when they are activated abnormally. Thus, we considered the possibility that loss of VDR predisposes to epidermal tumor formation by activation of either or both beta-catenin and Hh signaling. We determined that all elements of the Hh signaling pathway are upregulated in the epidermis and utricles of the VDR null mouse, and that 1,25(OH)(2)D(3) suppresses the expression of these elements in normal mouse skin. In addition we observed that the transcriptional activity of beta-catenin was increased in keratinocytes lacking the VDR. These results lead us to the hypothesis that the VDR with its ligand 1,25(OH)(2)D(3) functions as a tumor suppressor with respect to epidermal tumor formation in response to

  2. The p27Kip1 tumor suppressor gene: Still a suspect or proven guilty?

    PubMed

    Polyak, Kornelia

    2006-11-01

    The p27Kip1 cyclin-dependent kinase inhibitor is considered to be a tumor suppressor even though somatic mutations in p27Kip1 are only rarely detected in human tumors. On the other hand, overwhelming evidence indicates that its hemizygous or posttranscriptional loss plays an important role in tumorigenesis. Based on these data, p27Kip1 was classified as a haploinsufficient tumor suppressor whose protein level has to be fine-tuned for optimal function. However, a recent study links germline mutations in p27Kip1 to multiple endocrine neoplasia syndrome in rats and humans, thus establishing p27Kip1 as a bona fide tumor suppressor gene.

  3. Cigarette smoke induces methylation of the tumor suppressor gene NISCH

    PubMed Central

    Ostrow, Kimberly Laskie; Michalidi, Christina; Guerrero-Preston, Rafael; Hoque, Mohammad O.; Greenberg, Alissa; Rom, William; Sidransky, David

    2013-01-01

    We have previously identified a putative tumor suppressor gene, NISCH, whose promoter is methylated in lung tumor tissue as well as in plasma obtained from lung cancer patients. NISCH was observed to be more frequently methylated in smoker lung cancer patients than in non-smoker lung cancer patients. Here, we investigated the effect of tobacco smoke exposure on methylation of the NISCH gene. We tested methylation of NISCH after oral keratinocytes were exposed to mainstream and side stream cigarette smoke extract in culture. Methylation of the promoter region of the NISCH gene was also evaluated in plasma obtained from lifetime non-smokers and light smokers (< 20 pack/year), with and without lung tumors, and heavy smokers (20+ pack/year) without disease. Promoter methylation of NISCH was tested by quantitative fluorogenic real-time PCR in all samples. Promoter methylation of NISCH occurred after exposure to mainstream tobacco smoke as well as to side stream tobacco smoke in normal oral keratinocyte cell lines. NISCH methylation was also detected in 68% of high-risk, heavy smokers without detectable tumors. Interestingly, in light smokers, NISCH methylation was present in 69% of patients with lung cancer and absent in those without disease. Our pilot study indicates that tobacco smoke induces methylation changes in the NISCH gene promoter before any detectable cancer. Methylation of the NISCH gene was also found in lung cancer patients’ plasma samples. After confirming these findings in longitudinally collected plasma samples from high-risk populations (such as heavy smokers), examining patients for hypermethylation of the NISCH gene may aid in identifying those who should undergo additional screening for lung cancer. PMID:23503203

  4. TRAF3: a novel tumor suppressor gene in macrophages

    PubMed Central

    Lalani, Almin I.; Luo, Chang; Han, Yeming; Xie, Ping

    2015-01-01

    Tumor necrosis factor receptor-associated factor 3 (TRAF3), a member of the TRAF family of cytoplasmic adaptor proteins with E3 ligase activity, is ubiquitously expressed in various cell types of the immune system. It is shared for signaling by a variety of adaptive and innate immune receptors as well as cytokine receptors. Previous studies examining conditional TRAF3-deficient mouse models that have the Traf3 gene specifically deleted in B lymphocytes or T lymphocytes have revealed the diverse and critical in vivo functions of TRAF3 in adaptive immunity. Although in vitro evidence points to a pivotal and indispensable role for TRAF3 in type I interferon production induced by pattern recognition receptors in macrophages and dendritic cells, the in vivo functions of TRAF3 in the innate immune system had long remained unclear. Three laboratories have recently addressed this gap in knowledge by investigating myeloid cell-specific TRAF3-deficient (genotype: TRAF3flox/floxLysM+/Cre) mice. The new evidence together demonstrates that specific ablation of TRAF3 in myeloid cells leads to inflammatory diseases, altered progression of diabetes, and spontaneous development of different types of tumors and infections in mice. These new findings indicate that TRAF3 acts as an anti-inflammatory factor and is required for optimal innate immunity in myeloid cells. Strikingly, the new evidence also identifies TRAF3 as a novel tumor suppressor gene in macrophages and other myeloid cells. In this review, we discuss and summarize the new findings and current knowledge about the multi-faceted regulatory roles and complex signaling mechanisms of myeloid cell TRAF3 in inflammation, innate immunity, and tumor development. PMID:26661944

  5. Evidence that MIG-6 is a tumor-suppressor gene.

    PubMed

    Zhang, Y-W; Staal, B; Su, Y; Swiatek, P; Zhao, P; Cao, B; Resau, J; Sigler, R; Bronson, R; Vande Woude, G F

    2007-01-11

    Mitogen-inducible gene 6 (MIG-6) is located in human chromosome 1p36, a locus frequently associated with human lung cancer. MIG-6 is a negative regulator of epidermal growth factor (EGF) signaling, and we show that Mig-6 - like EGF - is induced by hepatocyte growth factor/scatter factor (HGF/SF) in human lung cancer cell lines. Frequently, the receptors for both factors, EGFR and Met, are expressed in same lung cancer cell line, and MIG-6 is induced by both factors in a mitogen-activated protein kinase-dependent fashion. However, not all tumor lines express MIG-6 in response to either EGF or HGF/SF. In these cases, we find missense and nonsense mutations in the MIG-6 coding region, as well as evidence for MIG-6 transcriptional silencing. Moreover, germline disruption of Mig-6 in mice leads to the development of animals with epithelial hyperplasia, adenoma, and adenocarcinoma in organs like the lung, gallbladder, and bile duct. These data suggests that MIG-6 is a tumor-suppressor gene and is therefore a candidate gene for the frequent 1p36 genetic alterations found in lung cancer.

  6. T-cell intracellular antigens function as tumor suppressor genes.

    PubMed

    Sánchez-Jiménez, C; Ludeña, M D; Izquierdo, J M

    2015-03-05

    Knockdown of T-cell intracellular antigens TIA1 and TIAR in transformed cells triggers cell proliferation and tumor growth. Using a tetracycline-inducible system, we report here that an increased expression of TIA1 or TIAR in 293 cells results in reduced rates of cell proliferation. Ectopic expression of these proteins abolish endogenous TIA1 and TIAR levels via the regulation of splicing of their pre-mRNAs, and partially represses global translation in a phospho-eukaryotic initiation factor 2 alpha-dependent manner. This is accompanied by cell cycle arrest at G1/S and cell death through caspase-dependent apoptosis and autophagy. Genome-wide profiling illustrates a selective upregulation of p53 signaling pathway-related genes. Nude mice injected with doxycycline-inducible cells expressing TIA1 or TIAR retard, or even inhibit, growth of xenotumors. Remarkably, low expressions of TIA1 and TIAR correlate with poor prognosis in patients with lung squamous cell carcinoma. These findings strongly support the concept that TIA proteins act as tumor suppressor genes.

  7. Epigenetic regulation of putative tumor suppressor TGFBI in human leukemias.

    PubMed

    Fang, Hongbo; Liu, Jing; Guo, Dan; Liu, Peixiang; Zhao, Yongliang

    2014-01-01

    Both in vitro and in vivo data have demonstrated the TGFBI gene functions as a putative tumor suppressor and is frequently downregulated in human tumors of different histological types. The hypermethylation of the TGFBI promoter, as one of the main regulatory mechanisms, is associated with TGFBI silencing. In this study, we used a methylation-specific PCR (MSP) method to evaluate the methylation status of the TGFBI promoter in human leukemias. Real-time RT-PCR and methylation-specific PCR approaches were performed to define the TGFBI expression and promoter methylation in human leukemia cell lines and clinical samples. Genomic DNA was isolated from peripheral blood mononuclear cells from leukemia patients, bisulfite-converted, and analyzed by the MSP method. Hypermethylation of the TGFBI promoter occurred in leukemia cell lines and demethylation treatment reexpressed TGFBI at a substantially increased level in most of leukemia cell lines tested. Furthermore, a much higher level of CpG island methylation and a significantly lower TGFBI expression were also identified in clinical leukemia samples. The results suggest an important role of promoter methylation in regulating TGFBI expression in leukemia, which provides a useful diagnostic marker for clinical management of human leukemias.

  8. Epigenetic regulator Smchd1 functions as a tumor suppressor.

    PubMed

    Leong, Huei San; Chen, Kelan; Hu, Yifang; Lee, Stanley; Corbin, Jason; Pakusch, Miha; Murphy, James M; Majewski, Ian J; Smyth, Gordon K; Alexander, Warren S; Hilton, Douglas J; Blewitt, Marnie E

    2013-03-01

    SMCHD1 is an epigenetic modifier of gene expression that is critical to maintain X chromosome inactivation. Here, we show in mouse that genetic inactivation of Smchd1 accelerates tumorigenesis in male mice. Loss of Smchd1 in transformed mouse embryonic fibroblasts increased tumor growth upon transplantation into immunodeficient nude mice. In addition, loss of Smchd1 in Eμ-Myc transgenic mice that undergo lymphomagenesis reduced disease latency by 50% relative to control animals. In premalignant Eμ-Myc transgenic mice deficient in Smchd1, there was an increase in the number of pre-B cells in the periphery, likely accounting for the accelerated disease in these animals. Global gene expression profiling suggested that Smchd1 normally represses genes activated by MLL chimeric fusion proteins in leukemia, implying that Smchd1 loss may work through the same pathways as overexpressed MLL fusion proteins do in leukemia and lymphoma. Notably, we found that SMCHD1 is underexpressed in many types of human hematopoietic malignancy. Together, our observations collectively highlight a hitherto uncharacterized role for SMCHD1 as a candidate tumor suppressor gene in hematopoietic cancers.

  9. Tumor suppressor VHL functions in the control of mitotic fidelity.

    PubMed

    Hell, Michael P; Duda, Maria; Weber, Thomas C; Moch, Holger; Krek, Wilhelm

    2014-05-01

    The von Hippel-Lindau (VHL) tumor suppressor protein pVHL is commonly mutated in clear cell renal cell carcinoma (ccRCC) and has been implicated in the control of multiple cellular processes that might be linked to tumor suppression, including promoting proper spindle orientation and chromosomal stability. However, it is unclear whether pVHL exerts these mitotic regulatory functions in vivo as well. Here, we applied ischemic kidney injury to stimulate cell division in otherwise quiescent mouse adult kidneys. We show that in the short term (5.5 days after surgery), Vhl-deficient kidney cells demonstrate both spindle misorientation and aneuploidy. The spindle misorientation phenotype encompassed changes in directed cell division, which may manifest in the development of cystic lesions, whereas the aneuploidy phenotype involved the occurrence of lagging chromosomes but not chromosome bridges, indicative of mitotic checkpoint impairment. Intriguingly, in the long term (4 months after the ischemic insult), Vhl-deficient kidneys displayed a heterogeneous pattern of ccRCC precursor lesions, including cysts, clear cell-type cells, and dysplasia. Together, these data provide direct evidence for a key role of pVHL in mediating oriented cell division and faithful mitotic checkpoint function in the renal epithelium, emphasizing the importance of pVHL as a controller of mitotic fidelity in vivo. ©2014 AACR.

  10. Regulation of cell signaling and apoptosis by tumor suppressor WWOX

    PubMed Central

    Lo, Jui-Yen; Chou, Ying-Tsen; Lai, Feng-Jie

    2015-01-01

    Human fragile WWOX gene encodes a tumor suppressor WW domain-containing oxidoreductase (named WWOX, FOR, or WOX1). Functional suppression of WWOX prevents apoptotic cell death induced by a variety of stress stimuli, such as tumor necrosis factor, UV radiation, and chemotherapeutic drug treatment. Loss of WWOX gene expression due to gene deletions, loss of heterozygosity, chromosomal translocations, or epigenetic silencing is frequently observed in human malignant cancer cells. Acquisition of chemoresistance in squamous cell carcinoma, osteosarcoma, and breast cancer cells is associated with WWOX deficiency. WWOX protein physically interacts with many signaling molecules and exerts its regulatory effects on gene transcription and protein stability and subcellular localization to control cell survival, proliferation, differentiation, autophagy, and metabolism. In this review, we provide an overview of the recent advances in understanding the molecular mechanisms by which WWOX regulates cellular functions and stress responses. A potential scenario is that activation of WWOX by anticancer drugs is needed to overcome chemoresistance and trigger cancer cell death, suggesting that WWOX can be regarded as a prognostic marker and a candidate molecule for targeted cancer therapies. PMID:25595191

  11. Sirt3 is a tumor suppressor in lung adenocarcinoma cells.

    PubMed

    Xiao, Kui; Jiang, Jiehan; Wang, Wei; Cao, Shan; Zhu, Liming; Zeng, Huihui; Ouyang, Ruoyun; Zhou, Rui; Chen, Ping

    2013-09-01

    Sirt3, a member of the mammalian sirtuin family protein that is localized to mitochondria, is a NAD+-dependent deacetylase and plays an important role in the control of metabolic activity. Recently, several studies have shown the potential role of Sirt3 in certain types of tumors such as breast cancer and hepatocellular carcinoma. However, the role of Sirt3 in lung adenocarcinoma has never been studied. In the present study, we found that Sirt3 protein expression was downregulated in human lung adenocarcinoma tissue when compared with that in adjacent normal tissue. Overexpression of Sirt3 using adenovirus significantly inhibited the growth of the A549 lung adenocarcinoma cell line. In this cell line, overexpression of Sirt3 induced apoptosis, which was evidenced by Annexin V + PI assay and cleaved caspase-3 immunoblotting. Furthermore, overexpression of Sirt3 increased the bax/bcl-2 and bad/bcl-x/L ratios, and promoted AIF translocation to the nucleus. Finally, Sirt3 overexpression upregulated p53 and p21 protein levels, and decreased intracellular ROS levels. Collectively, our data suggest that Sirt3 is a tumor suppressor in lung adenocarcinoma development and progression and may be a promising therapeutic target for lung adenocarcinoma.

  12. Expression of the p16{sup INK4a} tumor suppressor gene in rodent lung tumors

    SciTech Connect

    Swafford, D.S.; Tesfaigzi, J.; Belinsky, S.A.

    1995-12-01

    Aberrations on the short arm of chromosome 9 are among the earliest genetic changes in human cancer. p16{sup INK4a} is a candidate tumor suppressor gene that lies within human 9p21, a chromosome region associated with frequent loss of heterozygosity in human lung tumors. The p16{sup INK4a} protein functions as an inhibitor of cyclin D{sub 1}-dependent kinases that phosphorylate the retinoblastoma (Rb) tumor suppressor gene product enabling cell-cycle progression. Thus, overexpression of cyclin D{sub 1}, mutation of cyclin-dependent kinase genes, or loss of p16{sup INK4a} function, can all result in functional inactivation of Rb. Inactivation of Rb by mutation or deletion can result in an increase in p16{sup INK4a} transcription, suggesting that an increased p16{sup INK4a} expression in a tumor cell signals dysfunction of the pathway. The p16{sup (INK4a)} gene, unlike some tumor suppressor genes, is rarely inactivated by mutation. Instead, the expression of this gene is suppressed in some human cancers by hypermethylation of the CpG island within the first exon or by homozygous deletion: 686. Chromosome losses have been observed at 9p21 syntenic loci in tumors of the mouse and rat, two species often used as animal models for pulmonary carcinogenesis. Expression of p16{sup INK4a} is lost in some mouse tumor cell lines, often due to homozygous deletion. These observations indicate that p16{sup INK4a} dysfunction may play a role in the development of neoplasia in rodents as well as humans. The purpose of the current investigation was to define the extent to which p16{sup INK4a} dysfunction contributes to the development of rodent lung tumors and to determine the mechanism of inactivation of the gene. There is no evidence to suggest a loss of function of the p16{sup INK4a} tumor suppressor gene in these primary murine lung tumors by mutation, deletion, or methylation.

  13. Diaryl Disulfides as Novel Stabilizers of Tumor Suppressor Pdcd4

    PubMed Central

    Schmid, Tobias; Blees, Johanna S.; Bajer, Magdalena M.; Wild, Janine; Pescatori, Luca; Cuzzucoli Crucitti, Giuliana; Scipione, Luigi; Costi, Roberta; Henrich, Curtis J.; Brüne, Bernhard; Colburn, Nancy H.; Di Santo, Roberto

    2016-01-01

    The translation inhibitor and tumor suppressor Pdcd4 was reported to be lost in various tumors and put forward as prognostic marker in tumorigenesis. Decreased Pdcd4 protein stability due to PI3K-mTOR-p70S6K1 dependent phosphorylation of Pdcd4 followed by β-TrCP1-mediated ubiquitination, and proteasomal destruction of the protein was characterized as a major mechanism contributing to the loss of Pdcd4 expression in tumors. In an attempt to identify stabilizers of Pdcd4, we used a luciferase-based high-throughput compatible cellular assay to monitor phosphorylation-dependent proteasomal degradation of Pdcd4 in response to mitogen stimulation. Following a screen of approximately 2000 compounds, we identified 1,2-bis(4-chlorophenyl)disulfide as a novel Pdcd4 stabilizer. To determine an initial structure-activity relationship, we used 3 additional compounds, synthesized according to previous reports, and 2 commercially available compounds for further testing, in which either the linker between the aryls was modified (compounds 2–4) or the chlorine residues were replaced by groups with different electronic properties (compounds 5 and 6). We observed that those compounds with alterations in the sulfide linker completely lost the Pdcd4 stabilizing potential. In contrast, modifications in the chlorine residues showed only minor effects on the Pdcd4 stabilizing activity. A reporter with a mutated phospho-degron verified the specificity of the compounds for stabilizing the Pdcd4 reporter. Interestingly, the active diaryl disulfides inhibited proliferation and viability at concentrations where they stabilized Pdcd4, suggesting that Pdcd4 stabilization might contribute to the anti-proliferative properties. Finally, computational modelling indicated that the flexibility of the disulfide linker might be necessary to exert the biological functions of the compounds, as the inactive compound appeared to be energetically more restricted. PMID:26982744

  14. Targeting the BRCA1/2 tumor suppressors.

    PubMed

    Rosen, Eliot M; Pishvaian, Michael J

    2014-01-01

    The breast cancer susceptibility genes BRCA1 and BRCA2 are classic tumor suppressor genes that exhibit an autosomal dominant pattern of inheritance with high penetrance. BRCA carriers inherit one mutant BRCA allele and one wild-type allele; and the wild-type allele is invariably deleted or mutated within the tumor. These genes function as caretakers in the maintenance of genomic stability, in part, by participating in homology-directed DNA repair (HDR), an error- free mechanism for the repair of double-strand breaks (DSBs). PARP1 (poly (ADP-ribose) polymerase 1) is an enzyme that functions in the base excision repair (BER) pathway, where its ability to post-translationally modify histones and DNA damage response proteins is required for repair of single-strand breaks (SSBs). In 2005, it was observed that knockdown of PARP1 or treatment with a small molecule PARP inhibitor was far more toxic to cells with BRCA1 or BRCA2 mutations than BRCA1/2-competent cells. This observation is an example of "synthetic lethality", a concept whereby two gene mutations combine to cause cell death, when neither mutation alone is lethal. These results spawned the idea to use PARP inhibitors to treat BRCA1/2 mutant cancers. Here, we will review the basic science underlying the discoveries described above, the preclinical research, and the clinical trials designed to exploit the sensitivity of BRCA1/2 mutant tumor cells to PARP inhibitors. We will also describe problems associated with the use of these agents, including development and mechanisms of drug resistance; and we will provide a forward look at new agents and strategies currently under development.

  15. PML tumor suppressor protein is required for HCV production

    SciTech Connect

    Kuroki, Misao; Ariumi, Yasuo; Hijikata, Makoto; Ikeda, Masanori; Dansako, Hiromichi; Wakita, Takaji; Shimotohno, Kunitada; Kato, Nobuyuki

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer PML tumor suppressor protein is required for HCV production. Black-Right-Pointing-Pointer PML is dispensable for HCV RNA replication. Black-Right-Pointing-Pointer HCV could not alter formation of PML-NBs. Black-Right-Pointing-Pointer INI1 and DDX5, PML-related proteins, are involved in HCV life cycle. -- Abstract: PML tumor suppressor protein, which forms discrete nuclear structures termed PML-nuclear bodies, has been associated with several cellular functions, including cell proliferation, apoptosis and antiviral defense. Recently, it was reported that the HCV core protein colocalizes with PML in PML-NBs and abrogates the PML function through interaction with PML. However, role(s) of PML in HCV life cycle is unknown. To test whether or not PML affects HCV life cycle, we examined the level of secreted HCV core and the infectivity of HCV in the culture supernatants as well as the level of HCV RNA in HuH-7-derived RSc cells, in which HCV-JFH1 can infect and efficiently replicate, stably expressing short hairpin RNA targeted to PML. In this context, the level of secreted HCV core and the infectivity in the supernatants from PML knockdown cells was remarkably reduced, whereas the level of HCV RNA in the PML knockdown cells was not significantly affected in spite of very effective knockdown of PML. In fact, we showed that PML is unrelated to HCV RNA replication using the subgenomic HCV-JFH1 replicon RNA, JRN/3-5B. Furthermore, the infectivity of HCV-like particle in the culture supernatants was significantly reduced in PML knockdown JRN/3-5B cells expressing core to NS2 coding region of HCV-JFH1 genome using the trans-packaging system. Finally, we also demonstrated that INI1 and DDX5, the PML-related proteins, are involved in HCV production. Taken together, these findings suggest that PML is required for HCV production.

  16. One hundred years of tumor suppressor research: crucial achievements and unique perspectives.

    PubMed

    Radulescu, Razvan T

    2014-01-01

    Tumor suppressors constitute the body's primary defense line against malignant transformation. Since Theodor Boveri's initial insight one century ago, a huge amount of knowledge on these molecules has been generated. However, the final step of application of this profound understanding in the clinical setting, i.e., the treatment of cancer patients with tumor suppressors and their derivatives, is still ahead. Nevertheless, the important success achieved with similar biomimetic approaches in the therapy of other diseases suggests that tumor suppressor-based antineoplastic interventions should be accomplished soon as they may be equally rewarding.

  17. Mapping a tumor suppressor gene in 11p15.5

    SciTech Connect

    Reid, L.; West, A.; Gioeli, D.

    1994-09-01

    We are mapping a tumor suppressor gene in 11p15.5 which is associated with Wilms` tumors (WT), a pediatric kidney cancer. This gene was identified in a functional assay that analyzes the effect of human chromosomes on tumorigenicity by transferring them into the G401 WT cell line. WT hybrids containing an introduced t(X;11) chromosome do not form tumors after subcutaneous injection into nude mice, while other hybrids with different introduced chromosomes remain tumorigenic. In order to better map the tumor suppressor gene, we created a series of deletions in the t(X;11) chromosomes by {gamma}-radiation. Interestingly, three of the radiation-reduced chromosomes are indistinguishable as determined by cytogenetic, Southern blot, and PCR analyses. Upon transfer of these chromosomes into the G401 WT cells, one of the chromosomes retains tumor suppressor activity, while the two other chromosomes lack this ability. We propose two hypotheses to explain the functional difference observed between the indistinguishable chromosomes. First, the chromosome with suppressor activity may contain a region of DNA absent in the other two chromosomes. This proposal would localize the tumor suppressor gene to a 200 kb region of 11p15.5 between D11S648 and D11S601. Alternatively, the indistinguishable chromosomes may be derived from the same clone and their functional differences may indicate that the tumor suppressor gene is imprinted. That is, the tumor suppressor gene may be present on each of the three chromosomes, but not expressed on two of them due to imprinting differences. The H19 gene, located in 11p15.5, is imprinted and was recently shown to have tumor suppressor activity. However, H19 expression does not correlate with tumor suppression in our assay. Instead, we may be tracking a new imprinted gene in 11p15.5.

  18. Tumor suppressor gene adenomatous polyposis coli downregulates intestinal transport.

    PubMed

    Rexhepaj, Rexhep; Rotte, Anand; Gu, Shuchen; Michael, Diana; Pasham, Venkanna; Wang, Kan; Kempe, Daniela S; Ackermann, Teresa F; Brücher, Björn; Fend, Falko; Föller, Michael; Lang, Florian

    2011-05-01

    Loss of function mutations of the tumor suppressor gene adenomatous polyposis coli (APC) underly the familial adenomatous polyposis. Mice carrying an inactivating mutation in the apc gene (apc (Min/+)) similarly develop intestinal polyposis. APC is effective at least in part by degrading β-catenin and lack of APC leads to markedly enhanced cellular β-catenin levels. β-Catenin has most recently been shown to upregulate the Na+/K+ ATPase. The present study, thus, explored the possibility that APC could influence intestinal transport. The abundance and localization of β-catenin were determined utilizing Western blotting and confocal microscopy, the activity of the electrogenic glucose carrier (SGLT1) was estimated from the glucose-induced current in jejunal segments utilizing Ussing chamber experiments and the Na+/H+ exchanger (NHE3) activity from Na+ -dependent re-alkalinization of cytosolic pH (ΔpH(i)) following an ammonium pulse employing BCECF fluorescence. As a result, β-catenin abundance in intestinal tissue was significantly higher in apc (Min/+) mice than in wild-type mice (apc (+/+)). The β-catenin protein was localized in the basolateral membrane. Both, the glucose-induced current and ΔpH(i) were significantly higher in apc (Min/+) mice than in apc (+/+) mice. In conclusion, intestinal electrogenic transport of glucose and intestinal Na+/H+ exchanger activity are both significantly enhanced in apc (Min/+) mice, pointing to a role of APC in the regulation of epithelial transport.

  19. Tumor suppressor p53 protects mice against Listeria monocytogenes infection

    PubMed Central

    Wang, Shaohui; Liu, Pingping; Wei, Jianchao; Zhu, Zixiang; Shi, Zixue; Shao, Donghua; Ma, Zhiyong

    2016-01-01

    Tumor suppressor p53 is involved in regulating immune responses, which contribute to antitumor and antiviral activity. However, whether p53 has anti-bacterial functions remains unclear. Listeria monocytogenes (LM) causes listeriosis in humans and animals, and it is a powerful model for studying innate and adaptive immunity. In the present study, we illustrate an important regulatory role of p53 during LM infection. p53 knockout (p53KO) mice were more susceptible to LM infection, which was manifested by a shorter survival time and lower survival rate. p53KO mice showed significant impairments in LM eradication. Knockdown of p53 in RAW264.7 and HeLa cells resulted in increased invasion and intracellular survival of LM. Furthermore, the invasion and intracellular survival of LM was inhibited in p53-overexpressing RAW264.7 and HeLa cells. LM-infected p53KO mice exhibited severe clinical symptoms and organ injury, presumably because of the abnormal production of the pro-inflammatory cytokines TNF-α, IL-6, IL-12, and IL-18. Decreased IFN-γ and GBP1 productions were observed in LM-infected p53-deficient mice or cells. The combination of these defects likely resulted in the overwhelming LM infection in the p53KO mice. These observations indicate that p53 serves as an important regulator of the host innate immune that protects against LM infection. PMID:27644341

  20. The retinoblastoma tumor suppressor and stem cell biology.

    PubMed

    Sage, Julien

    2012-07-01

    Stem cells play a critical role during embryonic development and in the maintenance of homeostasis in adult individuals. A better understanding of stem cell biology, including embryonic and adult stem cells, will allow the scientific community to better comprehend a number of pathologies and possibly design novel approaches to treat patients with a variety of diseases. The retinoblastoma tumor suppressor RB controls the proliferation, differentiation, and survival of cells, and accumulating evidence points to a central role for RB activity in the biology of stem and progenitor cells. In some contexts, loss of RB function in stem or progenitor cells is a key event in the initiation of cancer and determines the subtype of cancer arising from these pluripotent cells by altering their fate. In other cases, RB inactivation is often not sufficient to initiate cancer but may still lead to some stem cell expansion, raising the possibility that strategies aimed at transiently inactivating RB might provide a novel way to expand functional stem cell populations. Future experiments dedicated to better understanding how RB and the RB pathway control a stem cell's decisions to divide, self-renew, or give rise to differentiated progeny may eventually increase our capacity to control these decisions to enhance regeneration or help prevent cancer development.

  1. The retinoblastoma tumor suppressor and stem cell biology

    PubMed Central

    Sage, Julien

    2012-01-01

    Stem cells play a critical role during embryonic development and in the maintenance of homeostasis in adult individuals. A better understanding of stem cell biology, including embryonic and adult stem cells, will allow the scientific community to better comprehend a number of pathologies and possibly design novel approaches to treat patients with a variety of diseases. The retinoblastoma tumor suppressor RB controls the proliferation, differentiation, and survival of cells, and accumulating evidence points to a central role for RB activity in the biology of stem and progenitor cells. In some contexts, loss of RB function in stem or progenitor cells is a key event in the initiation of cancer and determines the subtype of cancer arising from these pluripotent cells by altering their fate. In other cases, RB inactivation is often not sufficient to initiate cancer but may still lead to some stem cell expansion, raising the possibility that strategies aimed at transiently inactivating RB might provide a novel way to expand functional stem cell populations. Future experiments dedicated to better understanding how RB and the RB pathway control a stem cell's decisions to divide, self-renew, or give rise to differentiated progeny may eventually increase our capacity to control these decisions to enhance regeneration or help prevent cancer development. PMID:22751497

  2. Akt phosphorylates and regulates Pdcd4 tumor suppressor protein.

    PubMed

    Palamarchuk, Alexey; Efanov, Alexey; Maximov, Vadim; Aqeilan, Rami I; Croce, Carlo M; Pekarsky, Yuri

    2005-12-15

    Programmed cell death 4 (Pdcd4) is a tumor suppressor protein that interacts with eukaryotic initiation factor 4A and inhibits protein synthesis. Pdcd4 also suppresses the transactivation of activator protein-1 (AP-1)-responsive promoters by c-Jun. The Akt (protein kinase B) serine/threonine kinase is a key mediator of phosphoinositide 3-kinase pathway involved in the regulation of cell proliferation, survival, and growth. Because Pdcd4 has two putative Akt phosphorylation sites at Ser(67) and Ser(457), we investigated whether Akt phosphorylates and regulates Pdcd4. Our results show that Akt specifically phosphorylates Ser(67) and Ser(457) residues of Pdcd4 in vitro and in vivo. We further show that phosphorylation of Pdcd4 by Akt causes nuclear translocation of Pdcd4. Using luciferase assay, we show that phosphorylation of Pdcd4 by Akt also causes a significant decrease of the ability of Pdcd4 to interfere with the transactivation of AP-1-responsive promoter by c-Jun.

  3. Functional involvement of human discs large tumor suppressor in cytokinesis

    SciTech Connect

    Unno, Kenji; Hanada, Toshihiko; Chishti, Athar H.

    2008-10-15

    Cytokinesis is the final step of cell division that completes the separation of two daughter cells. We found that the human discs large (hDlg) tumor suppressor homologue is functionally involved in cytokinesis. The guanylate kinase (GUK) domain of hDlg mediates the localization of hDlg to the midbody during cytokinesis, and over-expression of the GUK domain in U2OS and HeLa cells impaired cytokinesis. Mouse embryonic fibroblasts (MEFs) derived from dlg mutant mice contained an increased number of multinucleated cells and showed reduced proliferation in culture. A kinesin-like motor protein, GAKIN, which binds directly to the GUK domain of hDlg, exhibited a similar intracellular distribution pattern with hDlg throughout mitosis and localized to the midbody during cytokinesis. However, the targeting of hDlg and GAKIN to the midbody appeared to be independent of each other. The midbody localization of GAKIN required its functional kinesin-motor domain. Treatment of cells with the siRNA specific for hDlg and GAKIN caused formation of multinucleated cells and delayed cytokinesis. Together, these results suggest that hDlg and GAKIN play functional roles in the maintenance of midbody architecture during cytokinesis.

  4. A myeloid tumor suppressor role for NOL3

    PubMed Central

    Bartholdy, Boris; Mitchell, Kelly; McKimpson, Wendy M.; Narayanagari, Swathi; Walter, Dagmar; Todorova, Tihomira I.; Makishima, Hideki; Will, Britta; McMahon, Christine; Gritsman, Kira; Maciejewski, Jaroslaw P.; Kitsis, Richard N.

    2017-01-01

    Despite the identification of several oncogenic driver mutations leading to constitutive JAK–STAT activation, the cellular and molecular biology of myeloproliferative neoplasms (MPN) remains incompletely understood. Recent discoveries have identified underlying disease-modifying molecular aberrations contributing to disease initiation and progression. Here, we report that deletion of Nol3 (Nucleolar protein 3) in mice leads to an MPN resembling primary myelofibrosis (PMF). Nol3−/− MPN mice harbor an expanded Thy1+LSK stem cell population exhibiting increased cell cycling and a myelomonocytic differentiation bias. Molecularly, this phenotype is mediated by Nol3−/−-induced JAK–STAT activation and downstream activation of cyclin-dependent kinase 6 (Cdk6) and Myc. Nol3−/− MPN Thy1+LSK cells share significant molecular similarities with primary CD34+ cells from PMF patients. NOL3 levels are decreased in CD34+ cells from PMF patients, and the NOL3 locus is deleted in a subset of patients with myeloid malignancies. Our results reveal a novel genetic PMF-like mouse model and identify a tumor suppressor role for NOL3 in the pathogenesis of myeloid malignancies. PMID:28232469

  5. Allelotyping in Wilms tumors identifies a putative third tumor suppressor gene on chromosome 11

    SciTech Connect

    Radice, P.; Benedetti, V.D.; Mondini, P.

    1995-06-10

    An analysis of loss of heterozygosity for markers on both the short and the long arm of chromosome 11 was performed in 24 sporadic Wilms tumors. Six cases (25%) showed allelic losses involving the entire chromosome. In one case (4%) the loss was restricted solely to the WT1 gene on band p13. Two cases (8%) displayed allelic losses for WT1 and for markers on band p15.5, where the putative tumor suppressor gene WT2 has been mapped, but retained heterozygosity for markers on the long arm. In three tumors (13%) the loss of heterozygosity involved markers mapped to chromosomal regions p15.5 and q23.3-qter, but did not affect WT1 and markers on q12-q13. Altogether, the proportion of cases showing allelic losses at the distal region of 11q (37%) was comparable to that of cases with LOH affecting the WT1 (37%) or the WT2 (46%) loci, thus suggesting the existence of a third chromosome 11 tumor suppressor gene involved in the pathogenesis of Wilms tumors. 51 refs., 1 fig., 1 tab.

  6. CHIP is a novel tumor suppressor in pancreatic cancer and inhibits tumor growth through targeting EGFR

    PubMed Central

    Wang, Tianxiao; Yang, Jingxuan; Xu, Jianwei; Li, Jian; Cao, Zhe; Zhou, Li; You, Lei; Shu, Hong; Lu, Zhaohui; Li, Huihua; Li, Min; Zhang, Taiping; Zhao, Yupei

    2014-01-01

    Carboxyl terminus of heat shock protein 70-interacting protein (CHIP) is an E3 ubiquitin ligase that is involved in protein quality control and mediates several tumor-related proteins in many cancers, but the function of CHIP in pancreatic cancer is not known. Here we show that CHIP interacts and ubiquitinates epidermal growth factor receptor (EGFR) for proteasome-mediated degradation in pancreatic cancer cells, thereby inhibiting the activation of EGFR downstream pathways. CHIP suppressed cell proliferation, anchor-independent growth, invasion and migration, as well as enhanced apoptosis induced by erlotinib in vitro and in vivo. The expression of CHIP was decreased in pancreatic cancer tissues or sera. Low CHIP expression in tumor tissues was correlated with tumor differentiation and shorter overall survival. These observations indicate that CHIP serves as a novel tumor suppressor by down-regulating EGFR pathway in pancreatic cancer cells, decreased expression of CHIP was associated with poor prognosis in pancreatic cancer. PMID:24722501

  7. Common Fragile Site Tumor Suppressor Genes and Corresponding Mouse Models of Cancer

    PubMed Central

    Drusco, Alessandra; Pekarsky, Yuri; Costinean, Stefan; Antenucci, Anna; Conti, Laura; Volinia, Stefano; Aqeilan, Rami I.; Huebner, Kay; Zanesi, Nicola

    2011-01-01

    Chromosomal common fragile sites (CFSs) are specific mammalian genomic regions that show an increased frequency of gaps and breaks when cells are exposed to replication stress in vitro. CFSs are also consistently involved in chromosomal abnormalities in vivo related to cancer. Interestingly, several CFSs contain one or more tumor suppressor genes whose structure and function are often affected by chromosomal fragility. The two most active fragile sites in the human genome are FRA3B and FRA16D where the tumor suppressor genes FHIT and WWOX are located, respectively. The best approach to study tumorigenic effects of altered tumor suppressors located at CFSs in vivo is to generate mouse models in which these genes are inactivated. This paper summarizes our present knowledge on mouse models of cancer generated by knocking out tumor suppressors of CFS. PMID:21318118

  8. Common fragile site tumor suppressor genes and corresponding mouse models of cancer.

    PubMed

    Drusco, Alessandra; Pekarsky, Yuri; Costinean, Stefan; Antenucci, Anna; Conti, Laura; Volinia, Stefano; Aqeilan, Rami I; Huebner, Kay; Zanesi, Nicola

    2011-01-01

    Chromosomal common fragile sites (CFSs) are specific mammalian genomic regions that show an increased frequency of gaps and breaks when cells are exposed to replication stress in vitro. CFSs are also consistently involved in chromosomal abnormalities in vivo related to cancer. Interestingly, several CFSs contain one or more tumor suppressor genes whose structure and function are often affected by chromosomal fragility. The two most active fragile sites in the human genome are FRA3B and FRA16D where the tumor suppressor genes FHIT and WWOX are located, respectively. The best approach to study tumorigenic effects of altered tumor suppressors located at CFSs in vivo is to generate mouse models in which these genes are inactivated. This paper summarizes our present knowledge on mouse models of cancer generated by knocking out tumor suppressors of CFS.

  9. ERF is a Potential ERK Modulated Tumor Suppressor in Prostate Cancer

    DTIC Science & Technology

    2016-10-01

    AWARD NUMBER: W81XWH-15-1-0277 TITLE: ERF is a Potential ERK-Modulated Tumor Suppressor in Prostate Cancer PRINCIPAL INVESTIGATOR: Dr. Rohit...Bose CONTRACTING ORGANIZATION: Sloan Kettering Institute for Cancer Research New York, NY 10065 REPORT DATE: October 2016 TYPE OF REPORT...4. TITLE AND SUBTITLE ERF is a Potential ERK-Modulated Tumor Suppressor in Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-15-1-0277

  10. HCMV IE72 Control Over PML, the Human Breast Cancer Tumor Suppressor

    DTIC Science & Technology

    2001-09-01

    Over PML, the Human Breast Cancer Tumor Suppressor PRINCIPAL INVESTIGATOR: Mary L. Spengler, Ph.D. CONTRACTING ORGANIZATION: Health Research... Cancer Tumor DAMD17-00-1-0654 Suppressor 6. AUTHOR(S) Mary L. Spengler, Ph.D. 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING...identification of these important regulatory phospho-amino acids will allow for the design of a PML based anti- cancer strategy. 14. SUBJECT TERMS 15

  11. The Retinoblastoma Tumor Suppressor Transcriptionally Represses Pak1 in Osteoblasts

    PubMed Central

    Sosa-García, Bernadette; Vázquez-Rivera, Viviana; González-Flores, Jonathan N.; Engel, Brienne E.; Cress, W. Douglas; Santiago-Cardona, Pedro G.

    2015-01-01

    We previously characterized the retinoblastoma tumor suppressor protein (Rb) as a regulator of adherens junction assembly and cell-to-cell adhesion in osteoblasts. This is a novel function since Rb is predominantly known as a cell cycle repressor. Herein, we characterized the molecular mechanisms by which Rb performs this function, hypothesizing that Rb controls the activity of known regulators of adherens junction assembly. We found that Rb represses the expression of the p21-activated protein kinase (Pak1), an effector of the small Rho GTPase Rac1. Rac1 is a well-known regulator of adherens junction assembly whose increased activity in cancer is linked to perturbations of intercellular adhesion. Using nuclear run-on and luciferase reporter transcription assays, we found that Pak1 repression by Rb is transcriptional, without affecting Pak1 mRNA and protein stability. Pak1 promoter bioinformatics showed multiple E2F1 binding sites within 155 base pairs of the transcriptional start site, and a Pak1-promoter region containing these E2F sites is susceptible to transcriptional inhibition by Rb. Chromatin immunoprecipitations showed that an Rb-E2F complex binds to the region of the Pak1 promoter containing the E2F1 binding sites, suggesting that Pak1 is an E2F target and that the repressive effect of Rb on Pak1 involves blocking the trans-activating capacity of E2F. A bioinformatics analysis showed elevated Pak1 expression in several solid tumors relative to adjacent normal tissue, with both Pak1 and E2F increased relative to normal tissue in breast cancer, supporting a cancer etiology for Pak1 up-regulation. Therefore, we propose that by repressing Pak1 expression, Rb prevents Rac1 hyperactivity usually associated with cancer and related to cytoskeletal derangements that disrupt cell adhesion, consequently enhancing cancer cell migratory capacity. This de-regulation of cell adhesion due to Rb loss could be part of the molecular events associated with cancer progression

  12. Positive selection of candidate tumor-suppressor genes by subtractive hybridization

    SciTech Connect

    Lee, S.W.; Tomasetto, C.; Sager, R. )

    1991-04-01

    A positive selection system designed to identify and recover candidate tumor-suppressor genes is described. The system compares mRNA expression of genes from normal and tumor-derived human mammary epithelial cells grown in a special medium that supports similar growth rates of the two cell types. mRNAs uniquely expressed in normal cells are recovered as cDNAs after subtraction with mRNA from tumor cells. Seven different clones, from 0.6 to 4.8 kilobases in transcript size and including both rare and abundant transcripts, were recovered in the first 23 clones analyzed. Among the isolated clones were genes encoding the gap-junction protein connexin 26, two different keratins, and glutathione-S-transferase {pi}, as well as an unknown gene in the S100 family of small calcium-binding proteins. In principle, tumor-suppressor genes include two classes: class I, in which loss of function results from mutation or deletion of DNA and class II, in which loss of function is from a regulatory block to expression. A class II suppressor gene is assumed to be regulated by a different suppressor gene that lost its function by mutation or deletion. Both classes of tumor-suppressor genes may provide valuable proteins with clinical applications in cancer diagnosis or therapy. Class II suppressors may be especially useful because the normal genes are present and their reexpression may be inducible by drugs or other treatments.

  13. Tumor suppressor gene co-operativity in compound Patched1 and Suppressor of fused heterozygous mutant mice

    PubMed Central

    Svärd, Jessica; Rozell, Björn; Toftgård, Rune; Teglund, Stephan

    2008-01-01

    Dysregulation of the Hedgehog signaling pathway is central to the development of certain tumor types, including medulloblastoma and basal cell carcinoma (BCC). Patched1 (Ptch1) and Suppressor of fused (Sufu) are two essential negative regulators of the pathway with tumor suppressor activity. Ptch1+/− mice are predisposed to developing medulloblastoma and rhabdomyosarcoma, while Sufu+/− mice develop a skin phenotype characterized by basaloid epidermal proliferations. Here, we have studied tumor development in Sufu+/−Ptch1+/− mice to determine the effect of compound heterozygosity on the onset, incidence, and spectrum of tumors. We found significantly more (2.3-fold) basaloid proliferations in Sufu+/−Ptch1+/− compared to Sufu+/− female, but not male, mice. For medulloblastoma, the cumulative one-year incidence was 1.5-fold higher in Sufu+/−Ptch1+/− compared to Ptch1+/− female mice but this strong trend was not statistically significant. Together this suggests a weak genetic interaction of the two tumor suppressor genes. We noted a few rhabdomyosarcomas and pancreatic cysts in the Sufu+/−Ptch1+/− mice, but the numbers were not significantly different from the single heterozygous mice. Hydrocephalus developed in ∼20% of the Ptch1+/− and Sufu+/−Ptch1+/− but not in Sufu+/− mice. Interestingly, most of the medulloblastomas from the Sufu+/−Ptch1+/− mice had lost expression of the remaining Ptch1 wild-type allele but not the Sufu wild-type allele. On the contrary, Sufu as well as Gli1 and Gli2 expression was upregulated in the medulloblastomas compared to adult cerebellum in Ptch1+/− and Sufu+/−Ptch1+/− mice. This suggests that Sufu expression may be regulated by Hedgehog pathway activity and could constitute another negative feedback loop in the pathway. PMID:18781608

  14. PEITC treatment suppresses myeloid derived tumor suppressor cells to inhibit breast tumor growth.

    PubMed

    Gupta, Parul; Wright, Stephen E; Srivastava, Sanjay K

    2015-02-01

    Breast tumors are heterogeneous with a complex etiology. The immune system plays a crucial role in the development of tumors and can facilitate tumor growth pleiotropically. Myeloid derived suppressor cells (MDSCs) generate reactive oxygen species (ROS) and cytokines to suppress T cells, dendritic cells and natural killer (NK) cells. Hence, the inhibition of MDSCs could be an important strategy for anticancer therapeutics. Phenethyl isothiocyanate (PEITC), a bioactive compound present in cruciferous vegetables, is known to have anticancer properties. However, the effects of PEITC administration on the immune system have not been previously reported. In the current study, we evaluated the effects of administering PEITC to immunocompromised NOD-SCID IL2Rγ(-/-) (SCID/NSG) host mice bearing MDA-MB-231 xenografts on MDSCs in the peripheral blood. Our results reveal that oral administration of 12 μmol PEITC attenuated tumor growth by 76%. This was marked tumor-inhibitory phenotype was associated with a significant reduction in the levels of MDSCs bearing the surface markers CD33, CD34 and CD11b in PEITC treated mice, indicating that overall tumor growth suppression by PEITC correlates with inhibition of MDSCs. To the best of our knowledge, this is the first study showing effects of PEITC on MDSCs.

  15. Metastasis Suppressor Genes: At the Interface Between the Environment and Tumor Cell Growth

    PubMed Central

    Hurst, Douglas R.; Welch, Danny R.

    2013-01-01

    The molecular mechanisms and genetic programs required for cancer metastasis are sometimes overlapping, but components are clearly distinct from those promoting growth of a primary tumor. Every sequential, rate-limiting step in the sequence of events leading to metastasis requires coordinated expression of multiple genes, necessary signaling events, and favorable environmental conditions or the ability to escape negative selection pressures. Metastasis suppressors are molecules that inhibit the process of metastasis without preventing growth of the primary tumor. The cellular processes regulated by metastasis suppressors are diverse and function at every step in the metastatic cascade. As we gain knowledge into the molecular mechanisms of metastasis suppressors and cofactors with which they interact, we learn more about the process, including appreciation that some are potential targets for therapy of metastasis, the most lethal aspect of cancer. Until now, metastasis suppressors have been described largely by their function. With greater appreciation of their biochemical mechanisms of action, the importance of context is increasingly recognized especially since tumor cells exist in myriad microenvironments. In this review, we assemble the evidence that selected molecules are indeed suppressors of metastasis, collate the data defining the biochemical mechanisms of action, and glean insights regarding how metastasis suppressors regulate tumor cell communication to–from microenvironments. PMID:21199781

  16. Control of Glutamine Metabolism By the Tumor Suppressor Rb

    PubMed Central

    Reynolds, Miriam R.; Lane, Andrew N.; Robertson, Brian; Kemp, Sharen; Liu, Yongqing; Hill, Bradford G.; Dean, Douglas C.; Clem, Brian F.

    2014-01-01

    Retinoblastoma (Rb) protein is a tumor suppressor that is dysregulated in a majority of human cancers. Rb functions to inhibit cell cycle progression in part by directly disabling the E2F family of cell cycle-promoting transcription factors. Because the de novo synthesis of multiple glutamine-derived anabolic precursors is required for cell cycle progression, we hypothesized that Rb also may directly regulate proteins involved in glutamine metabolism. We examined glutamine metabolism in mouse embryonic fibroblasts (MEFs) isolated from mice that have triple knock-outs (TKO) of all three Rb family members (Rb-1, Rbl1, and Rbl2) and found that loss of global Rb function caused a marked increase in 13C-glutamine uptake and incorporation into glutamate and TCA cycle intermediates in part via upregulated expression of the glutamine transporter ASCT2 and the activity of glutaminase 1 (GLS1). The Rb-controlled transcription factor E2F-3 altered glutamine uptake by direct regulation of ASCT2 mRNA and protein expression, and E2F-3 was observed to associate with the ASCT2 promoter. We next examined the functional consequences of the observed increase in glutamine uptake and utilization and found that glutamine exposure potently increased oxygen consumption whereas glutamine deprivation selectively decreased ATP concentration in the Rb TKO MEFs but not the WT MEFs. In addition, TKO MEFs exhibited elevated production of glutathione from exogenous glutamine, and had increased expression of gamma-glutamylcysteine ligase relative to WT MEFs. Importantly, this metabolic shift towards glutamine utilization was required for the proliferation of Rb TKO MEFs but not for the proliferation of the WT MEFs. Last, addition of the TCA cycle intermediate α-ketoglutarate to the Rb TKO MEFs reversed the inhibitory effects of glutamine deprivation on ATP, GSH levels, and viability. Taken together, these studies demonstrate that the Rb/E2F cascade directly regulates a major energetic and

  17. Control of glutamine metabolism by the tumor suppressor Rb.

    PubMed

    Reynolds, M R; Lane, A N; Robertson, B; Kemp, S; Liu, Y; Hill, B G; Dean, D C; Clem, B F

    2014-01-30

    Retinoblastoma (Rb) protein is a tumor suppressor that is dysregulated in a majority of human cancers. Rb functions to inhibit cell cycle progression in part by directly disabling the E2F family of cell cycle-promoting transcription factors. Because the de novo synthesis of multiple glutamine-derived anabolic precursors is required for cell cycle progression, we hypothesized that Rb also may directly regulate proteins involved in glutamine metabolism. We examined glutamine metabolism in mouse embryonic fibroblasts (MEFs) isolated from mice that have triple knock-outs (TKO) of all three Rb family members (Rb-1, Rbl1 and Rbl2) and found that loss of global Rb function caused a marked increase in (13)C-glutamine uptake and incorporation into glutamate and tricarboxylic acid cycle (TCA) intermediates in part via upregulated expression of the glutamine transporter ASCT2 and the activity of glutaminase 1 (GLS1). The Rb-controlled transcription factor E2F-3 altered glutamine uptake by direct regulation of ASCT2 mRNA and protein expression, and E2F-3 was observed to associate with the ASCT2 promoter. We next examined the functional consequences of the observed increase in glutamine uptake and utilization and found that glutamine exposure potently increased oxygen consumption, whereas glutamine deprivation selectively decreased ATP concentration in the Rb TKO MEFs but not the wild-type (WT) MEFs. In addition, TKO MEFs exhibited elevated production of glutathione from exogenous glutamine and had increased expression of gamma-glutamylcysteine ligase relative to WT MEFs. Importantly, this metabolic shift towards glutamine utilization was required for the proliferation of Rb TKO MEFs but not for the proliferation of the WT MEFs. Last, addition of the TCA cycle intermediate α-ketoglutarate to the Rb TKO MEFs reversed the inhibitory effects of glutamine deprivation on ATP, GSH levels and viability. Taken together, these studies demonstrate that the Rb/E2F cascade directly

  18. Mapping of a Breast Carcinoma Tumor Suppressor Gene to Chromosome 11p15.5.

    DTIC Science & Technology

    1996-07-01

    Noblett, B. D., Pedone, C. A. Chromosome llp 15 deletions in human malignant astrocytomas and primitive neuroectodermal tumors . Genomics 14: 799-801...AD GRANT NUMBER: DAMDI7-94-J-4175 TITLE: Mapping of a Breast Carcinoma Tumor Suppressor Gene to Chromosome 11p15.5 PRINCIPAL INVESTIGATOR: Tracy...SUBTITLE 5. FUNDING NUMBERS Mapping of a Breast Carcinoma Tumor Suppressor Gene to Chromosome 11p15.5 DAMD17-94-J-4175 6. AUTHOR(S) Tracy Moore, Ph.D. 7

  19. B7x and myeloid-derived suppressor cells in the tumor microenvironment

    PubMed Central

    Jeon, Hyungjun; Ohaegbulam, Kim C; Abadi, Yael M; Zang, Xingxing

    2013-01-01

    A new study demonstrates the tumorigenic functions of B7x and reveals a link between B7x and myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment. We propose that the binding of B7x to a hitherto unidentified receptor on MDSCs may stimulate their proliferation and/or immunosuppressive functions, hence promoting tumor growth. PMID:24073367

  20. Identifying Breast Tumor Suppressors Using in Vitro and in Vivo RNAi Screens

    DTIC Science & Technology

    2011-10-01

    identification of novel genes involved in the initiation and development of tumors are critical. During this research period we conducted the first whole human ... genome in vivo RNA interference screen to identify functionally important tumor suppressor genes. Using our novel approach, we identified previously

  1. [The activity of nonspecific bone marrow and spleen suppressors in the latent period of tumor growth].

    PubMed

    Ogreba, V I; Kusmartsev, S A; Vasil'ev, N V

    1988-01-01

    Female A/Sn mice aged 2-3 and 11-14 months (with spontaneous adenocarcinomas of the mammary gland and tumor-free) and C57Bl/6 mice were followed after treatment with DMBA. Suppressor cells were tested for the ability to inhibit in vivo antibody responses to sheep erythrocytes by adoptively syngeneically transferred cells. It was demonstrated that the activity of nonspecific suppressors of the bone marrow and spleen increases considerably in the precancer period.

  2. The human ARF tumor suppressor senses blastema activity and suppresses epimorphic tissue regeneration

    PubMed Central

    Hesse, Robert G; Kouklis, Gayle K; Ahituv, Nadav; Pomerantz, Jason H

    2015-01-01

    The control of proliferation and differentiation by tumor suppressor genes suggests that evolution of divergent tumor suppressor repertoires could influence species’ regenerative capacity. To directly test that premise, we humanized the zebrafish p53 pathway by introducing regulatory and coding sequences of the human tumor suppressor ARF into the zebrafish genome. ARF was dormant during development, in uninjured adult fins, and during wound healing, but was highly expressed in the blastema during epimorphic fin regeneration after amputation. Regenerative, but not developmental signals resulted in binding of zebrafish E2f to the human ARF promoter and activated conserved ARF-dependent Tp53 functions. The context-dependent activation of ARF did not affect growth and development but inhibited regeneration, an unexpected distinct tumor suppressor response to regenerative versus developmental environments. The antagonistic pleiotropic characteristics of ARF as both tumor and regeneration suppressor imply that inducing epimorphic regeneration clinically would require modulation of ARF –p53 axis activation. DOI: http://dx.doi.org/10.7554/eLife.07702.001 PMID:26575287

  3. Chromosomal localization of putative tumor-suppressor genes in several human cancers

    SciTech Connect

    Yokota, Jun; Sugimura, Takashi; Terada, Masaaki )

    1991-06-01

    Restriction-fragment-length polymorphism analysis was performed on several different types of human cancers, including carcinoma of the uterine cervix, neuroblastoma, hepatocellular carcinoma, pheochromocytoma, stomach cancer, and small-cell lung carcinoma (SCLC), to determine the chromosomal loci of putative tumor-suppressor genes in each type of tumor because loss of heterozygosity (LOH) is supposed to unmask the recessive mutation of tumor-suppressor gene in the remaining allele. Chromosomal loci showing frequent LOH differed among these tumors, suggesting that there are several tumor-suppressor genes in the human genome and that critical genes for the development of each type of tumor are different. In some cases LOH was observed in the early stage of tumor such as chromosome 3p loss in carcinoma of the uterine cervix, and in other cases it was observed only in the advanced stage of tumor such as chromosomes 4 and 16q loss in hepatocellular carcinoma. These results suggest that there are two different types of tumor-suppressor genes: one is the gene whose inactivation is responsible for malignant transformation of a normal cell and the other is the gene whose inactivation is responsible for the progression of a tumor cell. In SCLC, LOH at three different chromosomal loci, 3p, 13q, and 17p, was simultaneously observed in nearly 100% of tumors. It was observed even in stage I tumors and an untreated tumor, and it occurred prior to N-myc amplification. These results may imply that at least six genetic alterations are necessary to convert a normal cell into a fully malignant cancer cell in SCLC.

  4. Frequent alteration of the tumor suppressor gene APC in sporadic canine colorectal tumors.

    PubMed

    Youmans, Lydia; Taylor, Cynthia; Shin, Edwin; Harrell, Adrienne; Ellis, Angela E; Séguin, Bernard; Ji, Xinglai; Zhao, Shaying

    2012-01-01

    Sporadic canine colorectal cancers (CRCs) should make excellent models for studying the corresponding human cancers. To molecularly characterize canine CRC, we investigated exonic sequence mutations of adenomatous polyposis coli (APC), the best known tumor suppressor gene of human CRC, in 23 sporadic canine colorectal tumors, including 8 adenomas and 15 adenocarcinomas, via exon-resequencing analysis. As a comparison, we also performed the same sequencing analysis on 10 other genes, either located at human 5q22 (the same locus as APC) or 18q21 (also frequently altered in human CRC), or known to play a role in human carcinogenesis. We noted that APC was the most significantly mutated gene in both canine adenomas and adenocarcinomas among the 11 genes examined. Significantly, we detected large deletions of ≥ 10 bases, many clustered near the mutation cluster region, as well as single or two base deletions in ~70% canine tumors of both subtypes. These observations indicate that like in the human, APC is also frequently altered in sporadic colorectal tumors in the dog and its alteration is an early event in canine colorectal tumorigenesis. Our study provides further evidence demonstrating the molecular similarity in pathogenesis between sporadic human and canine CRCs. This work, along with our previous copy number abnormality study, supports that sporadic canine CRCs are valid models of human CRCs at the molecular level.

  5. Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment

    PubMed Central

    Cui, Yan; Guo, Gang

    2016-01-01

    The tumor suppressor p53 is the most frequently mutated gene in human cancers. Most of the mutations are missense leading to loss of p53 function in inducing apoptosis and senescence. In addition to these autonomous effects of p53 inactivation/dysfunction on tumorigenesis, compelling evidence suggests that p53 mutation/inactivation also leads to gain-of-function or activation of non-autonomous pathways, which either directly or indirectly promote tumorigenesis. Experimental and clinical results suggest that p53 dysfunction fuels pro-tumor inflammation and serves as an immunological gain-of-function driver of tumorigenesis via skewing immune landscape of the tumor microenvironment (TME). It is now increasingly appreciated that p53 dysfunction in various cellular compartments of the TME leads to immunosuppression and immune evasion. Although our understanding of the cellular and molecular processes that link p53 activity to host immune regulation is still incomplete, it is clear that activating/reactivating the p53 pathway in the TME also represents a compelling immunological strategy to reverse immunosuppression and enhance antitumor immunity. Here, we review our current understanding of the potential cellular and molecular mechanisms by which p53 participates in immune regulation and discuss how targeting the p53 pathway can be exploited to alter the immunological landscape of tumors for maximizing therapeutic outcome. PMID:27869779

  6. The nature of myeloid-derived suppressor cells in the tumor microenvironment

    PubMed Central

    Gabrilovich, Dmitry I.

    2016-01-01

    Myeloid-derived suppressor cells (MDSC) are one of the major components of the tumor microenvironment. The main feature of these cells is their potent immune suppressive activity. MDSC are generated in the bone marrow, and in tumor-bearing hosts, migrate to peripheral lymphoid organs and the tumor to contribute to the formation of the tumor microenvironment. Recent findings have revealed differences in the function and fate of MDSC in the tumor and peripheral lymphoid organs. We review these findings here, and in this context we discuss the current understanding as to the nature of these differences, the underlying mechanisms, and their potential impact on the regulation of tumor progression. PMID:26858199

  7. BRCA1 and p53 tumor suppressor molecules in Alzheimer's disease.

    PubMed

    Nakanishi, Atsuko; Minami, Akari; Kitagishi, Yasuko; Ogura, Yasunori; Matsuda, Satoru

    2015-01-28

    Tumor suppressor molecules play a pivotal role in regulating DNA repair, cell proliferation, and cell death, which are also important processes in the pathogenesis of Alzheimer's disease. Alzheimer's disease is the most common neurodegenerative disorder, however, the precise molecular events that control the death of neuronal cells are unclear. Recently, a fundamental role for tumor suppressor molecules in regulating neurons in Alzheimer's disease was highlighted. Generally, onset of neurodegenerative diseases including Alzheimer's disease may be delayed with use of dietary neuro-protective agents against oxidative stresses. Studies suggest that dietary antioxidants are also beneficial for brain health in reducing disease-risk and in slowing down disease-progression. We summarize research advances in dietary regulation for the treatment of Alzheimer's disease with a focus on its modulatory roles in BRCA1 and p53 tumor suppressor expression, in support of further therapeutic research in this field.

  8. The potential for tumor suppressor gene therapy in head and neck cancer.

    PubMed

    Birkeland, Andrew C; Ludwig, Megan L; Spector, Matthew E; Brenner, J Chad

    2016-01-01

    Head and neck squamous cell carcinoma remains a highly morbid and fatal disease. Importantly, genomic sequencing of head and neck cancers has identified frequent mutations in tumor suppressor genes. While targeted therapeutics increasingly are being investigated in head and neck cancer, the majority of these agents are against overactive/overexpressed oncogenes. Therapy to restore lost tumor suppressor gene function remains a key and under-addressed niche in trials for head and neck cancer. Recent advances in gene editing have captured the interest of both the scientific community and the public. As our technology for gene editing and gene expression modulation improves, addressing lost tumor suppressor gene function in head and neck cancers is becoming a reality. This review will summarize new techniques, challenges to implementation, future directions, and ethical ramifications of gene therapy in head and neck cancer.

  9. The Potential for Tumor Suppressor Gene Therapy in Head and Neck Cancer

    PubMed Central

    Birkeland, Andrew C.; Ludwig, Megan L.; Spector, Matthew E.; Brenner, J. Chad

    2016-01-01

    Head and neck squamous cell carcinoma remains a highly morbid and fatal disease. Importantly, genomic sequencing of head and neck cancers has identified frequent mutations in tumor suppressor genes. While targeted therapeutics increasingly are being investigated in head and neck cancer, the majority of these agents are against overactive/overexpressed oncogenes. Therapy to restore lost tumor suppressor gene function remains a key and under-addressed niche in trials for head and neck cancer. Recent advances in gene editing have captured the interest of both the scientific community and the public. As our technology for gene editing and gene expression modulation improves, addressing lost tumor suppressor gene function in head and neck cancers is becoming a reality. This review will summarize new techniques, challenges to implementation, future directions, and ethical ramifications of gene therapy in head and neck cancer. PMID:26896601

  10. Epigenetic modulation of endogenous tumor suppressor expression in lung cancer xenografts suppresses tumorigenicity.

    PubMed

    Cantor, Joshua P; Iliopoulos, Dimitrios; Rao, Atul S; Druck, Teresa; Semba, Shuho; Han, Shuang-Yin; McCorkell, Kelly A; Lakshman, Thiru V; Collins, Joshua E; Wachsberger, Phyllis; Friedberg, Joseph S; Huebner, Kay

    2007-01-01

    Epigenetic changes involved in cancer development, unlike genetic changes, are reversible. DNA methyltransferase and histone deacetylase inhibitors show antiproliferative effects in vitro, through tumor suppressor reactivation and induction of apoptosis. Such inhibitors have shown activity in the treatment of hematologic disorders but there is little data concerning their effectiveness in treatment of solid tumors. FHIT, WWOX and other tumor suppressor genes are frequently epigenetically inactivated in lung cancers. Lung cancer cell clones carrying conditional FHIT or WWOX transgenes showed significant suppression of xenograft tumor growth after induction of expression of the FHIT or WWOX transgene, suggesting that treatments to restore endogenous Fhit and Wwox expression in lung cancers would result in decreased tumorigenicity. H1299 lung cancer cells, lacking Fhit, Wwox, p16(INK4a) and Rassf1a expression due to epigenetic modifications, were used to assess efficacy of epigenetically targeted protocols in suppressing growth of lung tumors, by injection of 5-aza-2-deoxycytidine (AZA) and trichostatin A (TSA) in nude mice with established H1299 tumors. High doses of intraperitoneal AZA/TSA suppressed growth of small tumors but did not affect large tumors (200 mm(3)); lower AZA doses, administered intraperitoneally or intratumorally, suppressed growth of small tumors without apparent toxicity. Responding tumors showed restoration of Fhit, Wwox, p16(INKa), Rassf1a expression, low mitotic activity, high apoptotic fraction and activation of caspase 3. These preclinical studies show the therapeutic potential of restoration of tumor suppressor expression through epigenetic modulation and the promise of re-expressed tumor suppressors as markers and effectors of the responses.

  11. Isolation of Breast Tumor Suppressor Genes from Chromosome 11p

    DTIC Science & Technology

    2001-09-01

    vivo. This growth suppression activity requires a functional ILK protein , since expression of wild-type ILK, but not the ankyrin repeat or the catalytic...metastasis suppressor locus on chromosome l1pl5.5 is Integrin-linked kinase (ILK). ILK is a newly identified ankyrin - repeat containing serine/threonine...athymic mice. Conversely, expression of the ankyrin repeat or catalytic domain mutants of ILK failed to suppress the growth of these cells. Growth

  12. Quantitative Methylation Profiles for Multiple Tumor Suppressor Gene Promoters in Salivary Gland Tumors

    PubMed Central

    Durr, Megan L.; Mydlarz, Wojciech K.; Shao, Chunbo; Zahurak, Marianna L.; Chuang, Alice Y.; Hoque, Mohammad O.; Westra, William H.; Liegeois, Nanette J.; Califano, Joseph A.; Sidransky, David; Ha, Patrick K.

    2010-01-01

    Background Methylation profiling of tumor suppressor gene (TSGs) promoters is quickly becoming a powerful diagnostic tool for the early detection, prognosis, and even prediction of clinical response to treatment. Few studies address this in salivary gland tumors (SGTs); hence the promoter methylation profile of various TSGs was quantitatively assessed in primary SGT tissue to determine if tumor-specific alterations could be detected. Methodology DNA isolated from 78 tumor and 17 normal parotid gland specimens was assayed for promoter methylation status of 19 TSGs by fluorescence-based, quantitative methylation-specific PCR (qMSP). The data were utilized in a binary fashion as well as quantitatively (using a methylation quotient) allowing for better profiling and interpretation of results. Principal Findings The average number of methylation events across the studied genes was highest in salivary duct carcinoma (SDC), with a methylation value of 9.6, compared to the normal 4.5 (p<0.0003). There was a variable frequency and individual methylation quotient detected, depending on the TSG and the tumor type. When comparing normal, benign, and malignant SGTs, there was a statistically significant trend for increasing methylation in APC, Mint 1, PGP9.5, RAR-β, and Timp3. Conclusions/Significance Screening promoter methylation profiles in SGTs showed considerable heterogeneity. The methylation status of certain markers was surprisingly high in even normal salivary tissue, confirming the need for such controls. Several TSGs were found to be associated with malignant SGTs, especially SDC. Further study is needed to evaluate the potential use of these associations in the detection, prognosis, and therapeutic outcome of these rare tumors. PMID:20520817

  13. Functional evidence for a second tumor suppressor gene on human chromosome 17.

    PubMed Central

    Chen, P; Ellmore, N; Weissman, B E

    1994-01-01

    The development and progression of human tumors often involves inactivation of tumor suppressor gene function. Observations that specific chromosome deletions correlate with distinct groups of cancer suggest that some types of tumors may share common defective tumor suppressor genes. In support of this notion, our initial studies showed that four human carcinoma cell lines belong to the same complementation group for tumorigenic potential. In this investigation, we have extended these studies to six human soft tissue sarcoma cell lines. Our data showed that hybrid cells between a peripheral neuroepithelioma (PNET) cell line and normal human fibroblasts or HeLa cells were nontumorigenic. However, hybrid cells between the PNET cell line and five other soft tissue sarcoma cell lines remained highly tumorigenic, suggesting at least one common genetic defect in the control of tumorigenic potential in these cells. To determine the location of this common tumor suppressor gene, we examined biochemical and molecular polymorphic markers in matched pairs of tumorigenic and nontumorigenic hybrid cells between the PNET cell line and a normal human fibroblast. The data showed that loss of the fibroblast-derived chromosome 17 correlated with the conversion from nontumorigenic to tumorigenic cells. Transfer of two different chromosome 17s containing a mutant form of the p53 gene into the PNET cell line caused suppression of tumorigenic potential, implying the presence of a second tumor suppressor gene on chromosome 17. Images PMID:8264622

  14. Is Rab25 a tumor promoter or suppressor--context dependency on RCP status?

    PubMed

    Tang, Bor Luen

    2010-08-01

    Conflicting reports in the literature suggest that Rab25 could either be a context dependent promoter or suppressor of tumorigenesis. We hypothesized that whether Rab25 acts as a promoter or suppressor in tumor progression depends on the expression status of its effector, the Rab coupling protein (RCP). An elevated expression of RCP resulting from genomic amplification may enhance Rab25's tumor progression activity. Elevation of Rab25 alone may sequester endogenous RCP, and attenuates its activating effect on other oncogenic products, such as mutant Ras.

  15. Advances in the understanding of the Fanconi anemia tumor suppressor pathway.

    PubMed

    Pickering, Anna; Zhang, Jun; Panneerselvam, Jayabal; Fei, Peiwen

    2013-12-01

    Extremely high cancer incidence in Fanconi anemia (FA) patients has long suggested that the FA signaling pathway is a tumor suppressor pathway. Indeed, our recent findings, for the first time, indicate that the FA pathway plays a significant role in suppressing the development of non-FA human cancer. Also our studies on FA group D2 protein (FANCD2) have, among the first, documented the crosstalks between the FA and Rad6/Rad18 (HHR6) pathways upon DNA damage. In this review, we will discuss how our studies enhance the understanding of the FA tumor suppressor pathway.

  16. Mapping of a Breast Carcinoma Tumor Suppressor Gene to Chromosome 11P15.5

    DTIC Science & Technology

    1997-07-01

    4. Fults, D., Petronio, J., Noblett, B. D., Pedone, C. A. Chromosome 11p15 deletions in human malignant astrocytomas and primitive neuroectodermal ...AD _ GRANT NUMBER DAMDI7-94-J-4175 TITLE: Mapping of a Breast Carcinoma Tumor Suppressor Gene to Chromosome 11P15.5 PRINCIPAL INVESTIGATOR: Tracey...FUNDING NUMBERS Mapping of a Breast Carcinoma Tumor Suppressor Gene to Chromosome llP15.5 DAMD17-94-J-4175 6. AUTHOR(S) Tracey Moore, Ph.D. 7

  17. Identification of Tumor Suppressors and Oncogenes from Genomic and Epigenetic Features in Ovarian Cancer

    PubMed Central

    Wrzeszczynski, Kazimierz O.; Varadan, Vinay; Byrnes, James; Lum, Elena; Kamalakaran, Sitharthan; Levine, Douglas A.; Dimitrova, Nevenka; Zhang, Michael Q.; Lucito, Robert

    2011-01-01

    The identification of genetic and epigenetic alterations from primary tumor cells has become a common method to identify genes critical to the development and progression of cancer. We seek to identify those genetic and epigenetic aberrations that have the most impact on gene function within the tumor. First, we perform a bioinformatic analysis of copy number variation (CNV) and DNA methylation covering the genetic landscape of ovarian cancer tumor cells. We separately examined CNV and DNA methylation for 42 primary serous ovarian cancer samples using MOMA-ROMA assays and 379 tumor samples analyzed by The Cancer Genome Atlas. We have identified 346 genes with significant deletions or amplifications among the tumor samples. Utilizing associated gene expression data we predict 156 genes with altered copy number and correlated changes in expression. Among these genes CCNE1, POP4, UQCRB, PHF20L1 and C19orf2 were identified within both data sets. We were specifically interested in copy number variation as our base genomic property in the prediction of tumor suppressors and oncogenes in the altered ovarian tumor. We therefore identify changes in DNA methylation and expression for all amplified and deleted genes. We statistically define tumor suppressor and oncogenic features for these modalities and perform a correlation analysis with expression. We predicted 611 potential oncogenes and tumor suppressors candidates by integrating these data types. Genes with a strong correlation for methylation dependent expression changes exhibited at varying copy number aberrations include CDCA8, ATAD2, CDKN2A, RAB25, AURKA, BOP1 and EIF2C3. We provide copy number variation and DNA methylation analysis for over 11,500 individual genes covering the genetic landscape of ovarian cancer tumors. We show the extent of genomic and epigenetic alterations for known tumor suppressors and oncogenes and also use these defined features to identify potential ovarian cancer gene candidates. PMID

  18. AZU-1: A Candidate Breast Tumor Suppressor and Biomarker for Tumor Progression

    SciTech Connect

    Chen, Huei-Mei; Schmeichel, Karen L; Mian, I. Saira; Lelie`vre, Sophie; Petersen, Ole W; Bissell, Mina J

    2000-02-04

    To identify genes misregulated in the final stages of breast carcinogenesis, we performed differential display to compare the gene expression patterns of the human tumorigenic mammary epithelial cells, HMT-3522-T4-2, with those of their immediate premalignant progenitors, HMT-3522-S2. We identified a novel gene, called anti-zuai-1 (AZU-1), that was abundantly expressed in non- and premalignant cells and tissues but was appreciably reduced in breast tumor cell types and in primary tumors. The AZU-1 gene encodes an acidic 571-amino-acid protein containing at least two structurally distinct domains with potential protein-binding functions: an N-terminal serine and proline-rich domain with a predicted immunoglobulin-like fold and a C-terminal coiled-coil domain. In HMT-3522 cells, the bulk of AZU-1 protein resided in a detergent-extractable cytoplasmic pool and was present at much lower levels in tumorigenic T4-2 cells than in their nonmalignant counterparts. Reversion of the tumorigenic phenotype of T4-2 cells, by means described previously, was accompanied by the up-regulation of AZU-1. In addition, reexpression of AZU-1 in T4-2 cells, using viral vectors, was sufficient to reduce their malignant phenotype substantially, both in culture and in vivo. These results indicate that AZU-1 is a candidate breast tumor suppressor that may exert its effects by promoting correct tissue morphogenesis.

  19. Tumor suppressor ARF: The new player of innate immunity.

    PubMed

    Través, Paqui G; Luque, Alfonso; Hortelano, Sonsoles

    2012-09-01

    ARF (alternative reading frame) is one of the most important tumor regulator playing critical roles in controlling tumor initiation and progression. Recently, we have demonstrated a novel and unexpected role for ARF as modulator of inflammatory responses.

  20. Monocytic myeloid-derived suppressor cells as a potent suppressor of tumor immunity in non-small cell lung cancer

    PubMed Central

    Pogoda, Katarzyna; Pyszniak, Maria; Rybojad, Paweł; Tabarkiewicz, Jacek

    2016-01-01

    Immunotherapy is a promising therapeutic option for patients with non-small cell lung cancer (NSCLC) who do not qualify for surgery. In patients with advanced NSCLC, systemic immune suppression is frequently observed, therefore, researchers are investigating the tumor microenvironment for less invasive and more effective methods of treating lung cancer. Monocytic myeloid-derived suppressor cells (Mo-MDSCs) are potent suppressors of tumor immunity; therefore, this population may significantly impede the application of immunotherapy to treat cancer. The present study evaluated the distribution of Mo-MDSCs and monocytes/macrophages in the peripheral blood, lymph nodes and tumor tissue of patients with NSCLC. Furthermore, the profiles of cytokines produced by these cell populations, including interleukin (IL)-1β, IL-12/23p40, IL-10, transforming growth factor-β (TGF-β) and tumor necrosis factor (TNF), were compared. The cell populations and the expression of cytokines were assessed by flow cytometry after 4 h in culture with mitogens and Brefeldin A. Mo-MDSCs were more numerous than monocytes/macrophages in all tissues and their prevalence was highest in the peripheral blood; they expressed higher levels of TGF-β than monocytes/macrophages in all tissues and expression of TGF-β produced by Mo-MDSCs was higher in the blood than in lymph nodes and tumor tissues. A higher percentage of monocytes/macrophages was observed in lymph nodes and tumor tissues than in blood. CD14+HLA-DR+ cells also produced more IL-10 in lymph nodes than Mo-MDSCs and more IL-1β and TNF in all tissues. A higher prevalence of cluster of differentiation 14+ human leukocyte antigen-D related+ cells secreting IL-1β, TNF and IL-12/23p40 was observed in peripheral blood. Thus, the results of the current study support the statement that Mo-MDSCs and monocytes/macrophages participate in NSCLC induced immunosuppression, and is consistent with previous research into associations between the TGF

  1. Inferring the location of tumor suppressor genes by modeling frequency of allelic loss.

    PubMed

    Sterrett, Andrew; Wright, Fred A

    2007-03-01

    Allelic loss is often part of a multistep process leading to tumorigenesis. Analysis of genomic markers highlights regions of elevated allelic loss, which in turn suggests a nearby tumor suppressor. Furthermore, pooling published analyses to combine evidence can increase the power to detect a tumor suppressor gene. If the pattern of loss for each tumor, or allelotype, is known, a stochastic model proposed by Newton et al. (1998, Statistics in Medicine 17, 1425-1445) can be used to analyze the correlated binary data. Many studies report only incomplete allelotypes, augmented with frequencies of allelic loss (FAL) at each marker, in which the number of informative tumors showing allelic loss is provided along with the number of informative tumors. We describe an extension of the allelotype model to handle FAL data, using a hidden Markov model or a normal approximation to compute the likelihood. The FAL model is illustrated using data from a study of colorectal cancer.

  2. Macrophages, Inflammation, and Tumor Suppressors: ARF, a New Player in the Game

    PubMed Central

    Través, Paqui G.; Luque, Alfonso; Hortelano, Sonsoles

    2012-01-01

    The interaction between tumor progression and innate immune system has been well established in the last years. Indeed, several lines of clinical evidence indicate that immune cells such as tumor-associated macrophages (TAMs) interact with tumor cells, favoring growth, angiogenesis, and metastasis of a variety of cancers. In most tumors, TAMs show properties of an alternative polarization phenotype (M2) characterized by the expression of a series of chemokines, cytokines, and proteases that promote immunosuppression, tumor proliferation, and spreading of the cancer cells. Tumor suppressor genes have been traditionally linked to the regulation of cancer progression; however, a growing body of evidence indicates that these genes also play essential roles in the regulation of innate immunity pathways through molecular mechanisms that are still poorly understood. In this paper, we provide an overview of the immunobiology of TAMs as well as what is known about tumor suppressors in the context of immune responses. Recent advances regarding the role of the tumor suppressor ARF as a regulator of inflammation and macrophage polarization are also reviewed. PMID:23316105

  3. Macrophages, inflammation, and tumor suppressors: ARF, a new player in the game.

    PubMed

    Través, Paqui G; Luque, Alfonso; Hortelano, Sonsoles

    2012-01-01

    The interaction between tumor progression and innate immune system has been well established in the last years. Indeed, several lines of clinical evidence indicate that immune cells such as tumor-associated macrophages (TAMs) interact with tumor cells, favoring growth, angiogenesis, and metastasis of a variety of cancers. In most tumors, TAMs show properties of an alternative polarization phenotype (M2) characterized by the expression of a series of chemokines, cytokines, and proteases that promote immunosuppression, tumor proliferation, and spreading of the cancer cells. Tumor suppressor genes have been traditionally linked to the regulation of cancer progression; however, a growing body of evidence indicates that these genes also play essential roles in the regulation of innate immunity pathways through molecular mechanisms that are still poorly understood. In this paper, we provide an overview of the immunobiology of TAMs as well as what is known about tumor suppressors in the context of immune responses. Recent advances regarding the role of the tumor suppressor ARF as a regulator of inflammation and macrophage polarization are also reviewed.

  4. Tumor-suppressor genes: cardinal factors in inherited predisposition to human cancers.

    PubMed Central

    Evans, H J; Prosser, J

    1992-01-01

    A predisposition to the development of certain specific and familial cancers is associated with the inheritance of a single mutated gene. In the best-characterized cases, this primary mutation is a loss of function mutation consistent with viability but resulting in neoplastic change consequent to the acquisition of a second somatic mutation at the same locus. Such genes are referred to as tumor-suppressor genes. Classical examples are the Rb-1 gene associated with the development of retinoblastoma and the p53 gene, which is associated with a wider range of neoplasms, including breast cancer. Other tumor-suppressor genes have been isolated which are associated with Wilms' tumor, neurofibromatosis, and inherited and sporadic forms of colorectal cancer. Some of these genes appear to act as negative regulators of mitotic cycle genes, and others may have different properties. The nature of these genes is discussed, as is the evidence for the involvement of tumor-suppressor genes in other inherited, and sporadic, forms of cancer. Some recent data on the Wilms' tumor gene, WT1, and on the involvement of the p53 gene in breast cancer are presented, and the importance of genomic imprinting in contributing to the excess of suppressor gene mutations in chromosomes of paternal origin is considered. PMID:1336726

  5. Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells

    PubMed Central

    1982-01-01

    On the basis of preceding studies showing that tumor-induced, T cell- mediated immunosuppression serves as an obstacle to adoptive immunotherapy of the Meth A fibrosarcoma, it was predicted that cyclophosphamide treatment of tumor bearers would remove this obstacle and allow passively transferred immune T cells to cause tumor regression. It was found that infusion of immune spleen cells alone had no effect on tumor growth, and cyclophosphamide alone caused a temporary halt in tumor progression. In contrast, combination therapy consisting of intravenous injection of 100 mg/kg of cyclophosphamide followed 1 h later by intravenous infusion of tumor-immune spleen cells caused small, as well as large tumors, to completely and permanently regress. Tumor regression caused by combination therapy was completely inhibited by intravenous infusion of splenic T cells from donors with established tumors, but not by spleen cells from normal donors. These suppressor T cells were eliminated from the spleen by treating the tumor-bearing donors with 100 mg/kg of cyclophosphamide. Immune T cells, in contrast, were resistant to this dose of cyclophosphamide. These results show that failure of intravenously-infused, tumor- sensitized T cells to cause regression of the Meth A fibrosarcoma growing in its syngeneic or semi-syngeneic host is caused by the presence of a tumor-induced population of cyclophosphamide-sensitive suppressor T cells. PMID:6460831

  6. A novel repressor domain is required for maximal growth inhibition by the IRF-1 tumor suppressor.

    PubMed

    Eckert, Mirjam; Meek, Sarah E M; Ball, Kathryn L

    2006-08-11

    Interferon regulatory factor-1 (IRF-1) is a transcription factor and tumor suppressor that can regulate gene expression in a manner requiring either its sequence specific DNA binding activity or its ability to bind the p300 coactivator. We show that IRF-1-mediated growth inhibition is dependent on the integrity of a C-terminal transcriptional enhancer domain. An enhancer subdomain (amino acids 301-325) that differentially regulates IRF-1 activity has been identified and this region mediates the repression of Cdk2. The repressor domain encompasses an LXXLL coregulator signature motif and mutations or deletions within this region completely uncouple transcriptional activation from repression. The loss of growth suppressor activity when the Cdk2-repressor domain of IRF-1 is mutated implicates repression as a determinant of its maximal growth inhibitory potential. The data link IRF-1 regulatory domains to its growth inhibitory activity and provide information about how differential gene regulation may contribute to IRF-1 tumor suppressor activity.

  7. NTRK3 Is a Potential Tumor Suppressor Gene Commonly Inactivated by Epigenetic Mechanisms in Colorectal Cancer

    PubMed Central

    Luo, Yanxin; Kaz, Andrew M.; Kanngurn, Samornmas; Welsch, Piri; Morris, Shelli M.; Wang, Jianping; Lutterbaugh, James D.; Markowitz, Sanford D.; Grady, William M.

    2013-01-01

    NTRK3 is a member of the neurotrophin receptor family and regulates cell survival. It appears to be a dependence receptor, and thus has the potential to act as an oncogene or as a tumor suppressor gene. NTRK3 is a receptor for NT-3 and when bound to NT-3 it induces cell survival, but when NT-3 free, it induces apoptosis. We identified aberrantly methylated NTRK3 in colorectal cancers through a genome-wide screen for hypermethylated genes. This discovery led us to assess whether NTRK3 could be a tumor suppressor gene in the colon. NTRK3 is methylated in 60% of colon adenomas and 67% of colon adenocarcinomas. NTRK3 methylation suppresses NTRK3 expression. Reconstitution of NTRK3 induces apoptosis in colorectal cancers, if NT-3 is absent. Furthermore, the loss of NTRK3 expression associates with neoplastic transformation in vitro and in vivo. We also found that a naturally occurring mutant NTRK3 found in human colorectal cancer inhibits the tumor suppressor activity of NTRK3. In summary, our findings suggest NTRK3 is a conditional tumor suppressor gene that is commonly inactivated in colorectal cancer by both epigenetic and genetic mechanisms whose function in the pathogenesis of colorectal cancer depends on the expression status of its ligand, NT-3. PMID:23874207

  8. Power of PTEN/AKT: Molecular switch between tumor suppressors and oncogenes

    PubMed Central

    XIE, YINGQIU; NAIZABEKOV, SANZHAR; CHEN, ZHANLIN; TOKAY, TURSONJAN

    2016-01-01

    An increasing amount of evidence has shown that tumor suppressors can become oncogenes, or vice versa, but the mechanism behind this is unclear. Recent findings have suggested that phosphatase and tensin homolog (PTEN) is one of the powerful switches for the conversion between tumor suppressors and oncogenes. PTEN regulates a number of cellular processes, including cell death and proliferation, through the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Furthermore, a number of studies have suggested that PTEN deletions may alter various functions of certain tumor suppressor and oncogenic proteins. The aim of the present review was to analyze specific cases driven by PTEN loss/AKT activation, including aberrant signaling pathways and novel drug targets for clinical application in personalized medicine. The findings illustrate how PTEN loss and/or AKT activation switches MDM2-dependent p53 downregulation, and induces conversion between oncogene and tumor suppressor in enhancer of zeste homolog 2, BTB domain-containing 7A, alternative reading frame 2, p27 and breast cancer 1, early onset, through multiple mechanisms. This review highlights the genetic basis of complex drug targets and provides insights into the rationale of precision cancer therapy. PMID:27347153

  9. Regulation of The Tumor Suppressor Activity of P53 In Human Breast Cancer

    DTIC Science & Technology

    1999-09-01

    Lenglet, S., Moreau , V., Iggo, R., and Frehourg. T. Michael Datto and Xiao-Fan Wang (Duke University) for the p21 pro- (1998) Oncgene 16, 1369-1372...School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA Depending upon particular cellular conditions, the tumor suppressor protein p53

  10. Antiviral activity of tumor-suppressor pathways: clues from molecular piracy by KSHV.

    PubMed

    Moore, P S; Chang, Y

    1998-04-01

    A common feature of many tumor viruses is that they possess genes that produce specific proteins to inhibit major cellular tumor-suppressor pathways. Despite intensive studies, the reasons why these diverse and unrelated viruses have independently evolved oncogenes remains obscure. Kaposi-sarcoma-associated herpesvirus (KSHV or HHV8) has pirated a number of recognizable cellular genes that are key to cell survival and proliferation. In this review, we provide an overview of the known activities of these viral genes and show that many of these pirated proteins affect the same cellular pathways targeted by other, unrelated tumor viruses. We speculate that tumor-suppressor pathways are used by the cell as a primary defense against persistent virus infection, in addition to their well-known activity in regulating cell proliferation.

  11. Repression of the Androgen Receptor by WT1, a Tumor Suppressor Gene

    DTIC Science & Technology

    2001-09-01

    indications of the portions of this data which are subject to such limitations, shall be included on any reproduction hereof which includes any part of the...Cancer Research 21:1-10 (2001). Motoyoshi Tanaka, Gail C. Fraizer, Jorge De La Cerda , Richard Cristiano, Monica Liebert, H. Barton Grossman, Connexin... Cerda , J. , Diaz M., "Wilms’ Tumor Suppressor Gene WT1 Suppresses tumor formation by Prostate Cancer Cells" (Manuscript in Preparation). Presentations

  12. RBSP3 (HYA22) is a tumor suppressor gene implicated in major epithelial malignancies

    PubMed Central

    Kashuba, Vladimir I.; Li, Jingfeng; Wang, Fuli; Senchenko, Vera N.; Protopopov, Alexey; Malyukova, Alena; Kutsenko, Alexey S.; Kadyrova, Elena; Zabarovska, Veronika I.; Muravenko, Olga V.; Zelenin, Alexander V.; Kisselev, Lev L.; Kuzmin, Igor; Minna, John D.; Winberg, Gösta; Ernberg, Ingemar; Braga, Eleonora; Lerman, Michael I.; Klein, George; Zabarovsky, Eugene R.

    2004-01-01

    Chromosome 3p21.3 region is frequently (>90%) deleted in lung and other major human carcinomas. We subdivided 3p21.3 into LUCA and AP20 subregions and discovered frequent homozygous deletions (10-18%) in both subregions. This finding strongly implies that they harbor multiple tumor suppressor genes involved in the origin and/or development of major epithelial cancers. In this study, we performed an initial analysis of RBSP3/HYA22, a candidate tumor suppressor genes located in the AP20 region. Two sequence splice variants of RBSP3/HYA22 (A and B) were identified, and we provide evidence for their tumor suppressor function. By sequence analysis RBSP3/HYA22 belongs to a gene family of small C-terminal domain phosphatases that may control the RNA polymerase II transcription machinery. Expression of the gene was drastically (>20-fold) decreased in 11 of 12 analyzed carcinoma cell lines and in three of eight tumor biopsies. We report missense and nonsense mutations in tumors where RBSP3/HYA22 was expressed, growth suppression with regulated transgenes in culture, suppression of tumor formation in severe combined immunodeficient mice, and dephosphorylation of ppRB by RBSP3/HYA22, presumably leading to a block of the cell cycle at the G1/S boundary. PMID:15051889

  13. RSUME inhibits VHL and regulates its tumor suppressor function.

    PubMed

    Gerez, J; Tedesco, L; Bonfiglio, J J; Fuertes, M; Barontini, M; Silberstein, S; Wu, Y; Renner, U; Páez-Pereda, M; Holsboer, F; Stalla, G K; Arzt, E

    2015-09-10

    Somatic mutations or loss of von Hippel-Lindau (pVHL) happen in the majority of VHL disease tumors, which present a constitutively active Hypoxia Inducible Factor (HIF), essential for tumor growth. Recently described mechanisms for pVHL modulation shed light on the open question of the HIF/pVHL pathway regulation. The aim of the present study was to determine the molecular mechanism by which RSUME stabilizes HIFs, by studying RSUME effect on pVHL function and to determine the role of RSUME on pVHL-related tumor progression. We determined that RSUME sumoylates and physically interacts with pVHL and negatively regulates the assembly of the complex between pVHL, Elongins and Cullins (ECV), inhibiting HIF-1 and 2α ubiquitination and degradation. We found that RSUME is expressed in human VHL tumors (renal clear-cell carcinoma (RCC), pheochromocytoma and hemangioblastoma) and by overexpressing or silencing RSUME in a pVHL-HIF-oxygen-dependent degradation stability reporter assay, we determined that RSUME is necessary for the loss of function of type 2 pVHL mutants. The functional RSUME/pVHL interaction in VHL-related tumor progression was further confirmed using a xenograft assay in nude mice. RCC clones, in which RSUME was knocked down and express either pVHL wt or type 2 mutation, have an impaired tumor growth, as well as HIF-2α, vascular endothelial growth factor A and tumor vascularization diminution. This work shows a novel mechanism for VHL tumor progression and presents a new mechanism and factor for targeting tumor-related pathologies with pVHL/HIF altered function.

  14. Tumor STAT1 transcription factor activity enhances breast tumor growth and immune suppression mediated by myeloid-derived suppressor cells.

    PubMed

    Hix, Laura M; Karavitis, John; Khan, Mohammad W; Shi, Yihui H; Khazaie, Khashayarsha; Zhang, Ming

    2013-04-26

    Previous studies had implicated the IFN-γ transcription factor signal transducer and activator of transcription 1 (STAT1) as a tumor suppressor. However, accumulating evidence has correlated increased STAT1 activation with increased tumor progression in multiple types of cancer, including breast cancer. Indeed, we present evidence that tumor up-regulation of STAT1 activity in human and mouse mammary tumors correlates with increasing disease progression to invasive carcinoma. A microarray analysis comparing low aggressive TM40D and highly aggressive TM40D-MB mouse mammary carcinoma cells revealed significantly higher STAT1 activity in the TM40D-MB cells. Ectopic overexpression of constitutively active STAT1 in TM40D cells promoted mobilization of myeloid-derived suppressor cells (MDSCs) and inhibition of antitumor T cells, resulting in aggressive tumor growth in tumor-transplanted, immunocompetent mice. Conversely, gene knockdown of STAT1 in the metastatic TM40D-MB cells reversed these events and attenuated tumor progression. Importantly, we demonstrate that in human breast cancer, the presence of tumor STAT1 activity and tumor-recruited CD33(+) myeloid cells correlates with increasing disease progression from ductal carcinoma in situ to invasive carcinoma. We conclude that STAT1 activity in breast cancer cells is responsible for shaping an immunosuppressive tumor microenvironment, and inhibiting STAT1 activity is a promising immune therapeutic approach.

  15. Alternative Polyadenylation of Tumor Suppressor Genes in Small Intestinal Neuroendocrine Tumors

    PubMed Central

    Rehfeld, Anders; Plass, Mireya; Døssing, Kristina; Knigge, Ulrich; Kjær, Andreas; Krogh, Anders; Friis-Hansen, Lennart

    2014-01-01

    The tumorigenesis of small intestinal neuroendocrine tumors (SI-NETs) is poorly understood. Recent studies have associated alternative polyadenylation (APA) with proliferation, cell transformation, and cancer. Polyadenylation is the process in which the pre-messenger RNA is cleaved at a polyA site and a polyA tail is added. Genes with two or more polyA sites can undergo APA. This produces two or more distinct mRNA isoforms with different 3′ untranslated regions. Additionally, APA can also produce mRNAs containing different 3′-terminal coding regions. Therefore, APA alters both the repertoire and the expression level of proteins. Here, we used high-throughput sequencing data to map polyA sites and characterize polyadenylation genome-wide in three SI-NETs and a reference sample. In the tumors, 16 genes showed significant changes of APA pattern, which lead to either the 3′ truncation of mRNA coding regions or 3′ untranslated regions. Among these, 11 genes had been previously associated with cancer, with 4 genes being known tumor suppressors: DCC, PDZD2, MAGI1, and DACT2. We validated the APA in three out of three cases with quantitative real-time-PCR. Our findings suggest that changes of APA pattern in these 16 genes could be involved in the tumorigenesis of SI-NETs. Furthermore, they also point to APA as a new target for both diagnostic and treatment of SI-NETs. The identified genes with APA specific to the SI-NETs could be further tested as diagnostic markers and drug targets for disease prevention and treatment. PMID:24782827

  16. Gangliosides drive the tumor infiltration and function of myeloid-derived suppressor cells

    PubMed Central

    Wondimu, Assefa; Liu, Yihui; Yan, Su; Bobb, Daniel; Ma, Jennifer S.Y.; Chakrabarti, Lina; Radoja, Saša; Ladisch, Stephan

    2014-01-01

    While it is now widely appreciated that anti-tumor immunity is critical to impede tumor growth and progression, there remain significant gaps in knowledge about the mechanisms used by tumors to escape immune control. In tumor cells, we hypothesized that one mechanism of immune escape used by tumors involves the synthesis and extracellular shedding of gangliosides, a class of biologically active cell surface glycosphingolipids with known immunosuppressive properties. In this study, we report that tumor cells engineered to be ganglioside-deficient exhibit impaired tumorigenicity, supporting a link between ganglioside-dependent immune escape and tumor outgrowth. Notably, we documented a dramatic reduction in the numbers and function of tumor-infiltrating myeloid-derived suppressor cells (MDSC) in ganglioside-deficient tumors, in contrast to the large MDSC infiltrates seen in ganglioside-rich littermate control tumors. Transient ganglioside reconstitution of the tumor cell inoculum was sufficient to increase MDSC infiltration, supporting a direct connection between ganglioside production by tumor cells and the recruitment of immunosuppressive MDSC into the tumor microenvironment. Our results reveal a novel mechanism of immune escape that supports tumor growth, with broad implications given that many human tumors produce and shed high levels of gangliosides. PMID:25115301

  17. RASSF10 is epigenetically silenced and functions as a tumor suppressor in gastric cancer

    SciTech Connect

    Wei, Ziran; Chen, Xia; Chen, Ji; Wang, Weimin; Xu, Xudong; Cai, Qingping

    2013-03-22

    Highlights: ► Epigenetic silencing of RASSF10 gene expression in GC cells. ► RASSF10 overexpression inhibits cell growth in vitro and in vivo. ► RASSF10 induces apoptosis in GC cells. ► RASSF10 inhibits Wnt/β-catenin signaling pathway. -- Abstract: Ras association domain family (RASSF) proteins are encoded by several tumor suppressor genes that are frequently silenced in human cancers. In this study, we investigated RASSF10 as a target of epigenetic inactivation and examined its functions as a tumor suppressor in gastric cancer. RASSF10 was silenced in six out of eight gastric cancer cell lines. Loss or downregulation of RASSF10 expression was associated with promoter hypermethylation, and could be restored by a demethylating agent. Overexpression of RASSF10 in gastric cancer cell lines (JRST, BGC823) suppressed cell growth and colony formation, and induced apoptosis, whereas RASSF10 depletion promoted cell growth. In xenograft animal experiments, RASSF10 overexpression effectively repressed tumor growth. Mechanistic investigations revealed that RASSF10 inhibited tumor growth by blocking activation of β-catenin and its downstream targets including c-Myc, cyclinD1, cyclinE1, peroxisome proliferator-activated receptor δ, transcription factor 4, transcription factor 1 and CD44. In conclusion, the results of this study provide insight into the role of RASSF10 as a novel functional tumor suppressor in gastric cancer through inhibition of the Wnt/β-catenin signaling pathway.

  18. CMTM5 exhibits tumor suppressor activity through promoter methylation in oral squamous cell carcinoma

    SciTech Connect

    Zhang, Heyu; Nan, Xu; Li, Xuefen; Chen, Yan; Zhang, Jianyun; Sun, Lisha; Han, Wenlin; Li, Tiejun

    2014-05-02

    Highlights: • Down-regulation of CMTM5 expression in OSCC tissues was found. • The promoter methylation status of CMTM5 was measured. • CMTM5-v1 inhibited cell proliferation and migration and induced apoptosis. • CMTM5 might act as a putative tumor suppressor gene in OSCC. - Abstract: Oral squamous cell carcinoma (OSCC) is one of the most common types of malignancies in the head and neck region. CKLF-like MARVEL transmembrane domain-containing member 5 (CMTM5) has been recently implicated as a tumor suppressor gene in several cancer types. Herein, we examined the expression and function of CMTM5 in oral squamous cell carcinoma. CMTM5 was down-regulated in oral squamous cell lines and tumor samples from patients with promoter methylation. Treatment with the demethylating agent 5-aza-2′-deoxycytidine restored CMTM5 expression. In the OSCC cell lines CAL27 and GNM, the ectopic expression of CMTM5-v1 strongly inhibited cell proliferation and migration and induced apoptosis. In addition, CMTM5-v1 inhibited tumor formation in vivo. Therefore, CMTM5 might act as a putative tumor suppressor gene through promoter methylation in oral squamous cell carcinoma.

  19. Complement component 7 (C7), a potential tumor suppressor, is correlated with tumor progression and prognosis

    PubMed Central

    Pan, Xiaodan; Chen, Kaiyan; Zhang, Nan; Jin, Jiaoyue; Wu, Junzhou; Feng, Jianguo; Yu, Herbert; Jin, Hongchuan; Su, Dan

    2016-01-01

    Our previous study found copy number variation of chromosome fragment 5p13.1-13.3 might involve in the progression of ovarian cancer. In the current study, the alteration was validated and complement component 7 (C7), located on 5p13.1, was identified. To further explore the clinical value of C7 in tumors, 156 malignant, 22 borderline, 33 benign and 24 normal ovarian tissues, as well as 173 non-small cell lung cancer (NSCLC) tissues along with corresponding adjacent and normal tissues from the tissue bank of Zhejiang Cancer Hospital were collected. The expression of C7 was analyzed using reverse transcriptase quantitative polymerase chain reaction. As a result, the C7 expression displayed a gradual downward trend in normal, benign, borderline and malignant ovarian tissues, and the decreased expression of C7 was correlative to poor differentiation in patients with ovarian cancer. Interestingly, a similar change of expression of C7 was found in normal, adjacent and malignant tissues in patients with NSCLC, and low expression of C7 was associated with worse grade and advanced clinical stage. Both results from this cohort and the public database indicated that NSCLC patients with low expression of C7 had a worse outcome. Furthermore, multivariate cox regression analysis showed NSCLC patients with low C7 had a 3.09 or 5.65-fold higher risk for relapse or death than those with high C7 respectively, suggesting C7 was an independent prognostic predictor for prognoses of patients with NSCLC. Additionally, overexpression of C7 inhibited colony formation of NSCLC cells, which hints C7 might be a potential tumor suppressor. PMID:27852032

  20. Gangliosides drive the tumor infiltration and function of myeloid-derived suppressor cells.

    PubMed

    Wondimu, Assefa; Liu, Yihui; Su, Yan; Bobb, Daniel; Ma, Jennifer S Y; Chakrabarti, Lina; Radoja, Saša; Ladisch, Stephan

    2014-10-01

    Although it is now widely appreciated that antitumor immunity is critical to impede tumor growth and progression, there remain significant gaps in knowledge about the mechanisms used by tumors to escape immune control. In tumor cells, we hypothesized that one mechanism of immune escape used by tumors involves the synthesis and extracellular shedding of gangliosides, a class of biologically active cell surface glycosphingolipids with known immunosuppressive properties. In this study, we report that tumor cells engineered to be ganglioside deficient exhibit impaired tumorigenicity, supporting a link between ganglioside-dependent immune escape and tumor outgrowth. Notably, we documented a dramatic reduction in the numbers and function of tumor-infiltrating myeloid-derived suppressor cells (MDSC) in ganglioside-deficient tumors, in contrast with the large MDSC infiltrates seen in ganglioside-rich littermate control tumors. Transient ganglioside reconstitution of the tumor cell inoculum was sufficient to increase MDSC infiltration, supporting a direct connection between ganglioside production by tumor cells and the recruitment of immunosuppressive MDSC into the tumor microenvironment. Our results reveal a novel mechanism of immune escape that supports tumor growth, with broad implications given that many human tumors produce and shed high levels of gangliosides. ©2014 American Association for Cancer Research.

  1. Role of the ARF Tumor Suppressor in Prostate Cancer

    DTIC Science & Technology

    2010-08-01

    literature. We asked Dr. Jeff Arbeit in the department of Surgery here at Washington University for his expertise in mouse prostate tumor development...18070929 6. Lu, Z.H., Wright, J.D., Belt, B., Cardiff, R.D. & Arbeit , J.M. Hypoxia-inducible factor-1 facilitates cervical cancer progression in human

  2. Cables1 is a tumor suppressor gene that regulates intestinal tumor progression in Apc(Min) mice.

    PubMed

    Arnason, Thomas; Pino, Maria S; Yilmaz, Omer; Kirley, Sandra D; Rueda, Bo R; Chung, Daniel C; Zukerberg, Lawrence R

    2013-07-01

    The transformation of colonic mucosal epithelium to adenocarcinoma requires progressive oncogene activation and tumor suppressor gene inactivation. Loss of chromosome 18q is common in colon cancer but not in precancerous adenomas. A few candidate tumor suppressor genes have been identified in this region, including CABLES1 at 18q11.2-12.1. This study investigates the role of CABLES1 in an in vivo mouse model of intestinal adenocarcinoma and in human colon cancer cell culture. Apc(Min/+) mice were crossed with mice harboring targeted inactivation of the Cables1 gene (Cables1(-/-)). The intestinal tumor burden and tumor expression of β-catenin and PCNA was compared in Cables1(+/+)Apc(Min/+) and Cables1(-/-)Apc(Min/+) mice. β-catenin activity in human colon cancer cells with CABLES1 inactivation and intestinal progenitor cell function in Cables1(-/-) mice were assayed in vitro. The mean number of small intestinal tumors per mouse was 3.1 ± 0.6 in Cables1(+/+)Apc(Min/+) mice, compared with 32.4 ± 3.5 in the Cables1(-/-)Apc(Min/+) mice (P < 0.0001). Fewer colonic tumors were observed in Cables1(+/+)Apc(Min/+) mice (mean 0.6 ± 0.1) compared with the Cables1(-/-)Apc(Min/+) mice (mean 1.3 ± 0.3, P = 0.01). Tumors from Cables1(-/-)Apc(Min/+) mice demonstrated increased nuclear expression of β-catenin and an increased number of PCNA-positive cells. In vitro studies revealed that CABLES1 deficiency increased β-catenin dependent transcription and increased intestinal progenitor cell activity. Loss of Cables1 enhances tumor progression in the Apc(Min/+) mouse model and activates the Wnt/β-catenin signaling pathway. Cables1 is a tumor suppressor gene on chromosome 18q in this in vivo mouse model and likely has a similar role in human colon cancer.

  3. The retinoblastoma tumor suppressor modulates DNA repair and radioresponsiveness

    PubMed Central

    Thangavel, Chellappagounder; Liu, Yi; O’Neill, Raymond; Sharma, Ankur; McMahon, Steve B.; Mellert, Hestia; Addya, Sankar; Ertel, Adam; Birbe, Ruth; Fortina, Paolo; Dicker, Adam P; Knudsen, Karen E; Den, Robert B

    2014-01-01

    Purpose Perturbations in the RB pathway are overrepresented in advanced prostate cancer; RB loss promotes bypass of first line hormone therapy. Conversely, preliminary studies suggested that RB-deficient tumors may become sensitized to a subset of DNA damaging agents. Here, the molecular and in vivo consequence of RB status was analyzed in models of clinical relevance. Experimental Design Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAPC4 cells and hormone resistant C42, 22Rv1 cells; stable knockdown of RB using shRNA). Multiple mechanisms were interrogated including cell cycle, apoptosis, and DNA damage repair. Transcriptome analysis was performed, validated, and mechanisms discerned. Cell survival was measured using clonogenic cell survival assay and in vivo analysis was performed in nude mice with human derived tumor xenografts. Results Loss of RB enhanced the radioresponsiveness of both hormone sensitive and castrate resistant prostate cancer. Hypersensitivity to ionizing radiation was not mediated by cell cycle or p53. RB loss led to alteration in DNA damage repair and activation of the NFκB pathway and subsequent cellular apoptosis through PLK3. In vivo xenografts of RB deficient tumors exhibited diminished tumor mass, lower PSA kinetics and decreased tumor growth after treatment with ionizing radiation (p<0.05). Conclusions Loss of RB confers increased radiosensitivity in prostate cancer. This hypersensitization was mediated by alterations in apoptotic signaling. Combined, these not only provide insight into the molecular consequence of RB loss, but also credential RB status as a putative biomarker for predicting response to radiation therapy. PMID:25165096

  4. Estrogen receptor beta, a possible tumor suppressor involved in ovarian carcinogenesis

    PubMed Central

    Lazennec, Gwendal

    2006-01-01

    Ovarian cancer is one of the leading cause of death from gynecological tumors in women. Several lines of evidence suggest that estrogens may play an important role in ovarian carcinogenesis, through their receptors, ERα and ERβ. Interestingly, malignant ovarian tumors originating from epithelial surface constitute about 90% of ovarian cancers and expressed low levels of ERβ, compared to normal tissues. In addition, restoration of ERβ in ovarian cancer cells, leads to strong inhibition of their proliferation and invasion, while apoptosis is enhanced. In this manuscript, recent data suggesting a possible tumor-suppressor role for ERβ in ovarian carcinogenesis are discussed. PMID:16399219

  5. Myeloid-derived suppressor cell role in tumor-related inflammation.

    PubMed

    Dolcetti, Luigi; Marigo, Ilaria; Mantelli, Barbara; Peranzoni, Elisa; Zanovello, Paola; Bronte, Vincenzo

    2008-08-28

    Chronic inflammatory state can create a proper environment for neoplastic onset and sustain cancer growth. The inflammatory state that arises at the tumor edge could contribute to immune escape phenomena in many ways. Myeloid-derived suppressor cells (MDSCs), a cell population that contributes to tumor escape, immune tolerance, and suppression, respond to a variety of pro-inflammatory and anti-inflammatory stimuli, which drive their recruitment and activation. Understanding how the inflammatory milieu favours tumor escape through the accumulation of MDSCs could be very useful to improve the efficacy of cancer immunotherapy.

  6. p16(Ink4a) overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors.

    PubMed

    Romagosa, C; Simonetti, S; López-Vicente, L; Mazo, A; Lleonart, M E; Castellvi, J; Ramon y Cajal, S

    2011-05-05

    p16(Ink4a) is a protein involved in regulation of the cell cycle. Currently, p16(Ink4a) is considered a tumor suppressor protein because of its physiological role and downregulated expression in a large number of tumors. Intriguingly, overexpression of p16(Ink4a) has also been described in several tumors. This review attempts to elucidate when and why p16(Ink4a) overexpression occurs, and to suggest possible implications of p16(Ink4a) in the diagnosis, prognosis and treatment of cancer.

  7. Tumor Suppressor Genes in Early Breast Cancer and its Progression

    DTIC Science & Technology

    1997-09-01

    Yamakawa K., Akiyama F., Kasumi F., Sakamoto G. and Nakamura Y. Allelotype of breast cancer: cumulative allele losses promote tumor progression in...and Cancer 4:113-121,1992. 18. Sato T., Akiyama F., Sakamoto G., Kasumi F. and Nakamura Y. Accumulation of genetic alterations and progression of...identified Proc. Natl. Acad. USA 87; 7737-7741, 1990. 23. Saito H., Inazawa J., Saito S., Kasumi F., Koi S., Sagae S., Kudo R., Saito J., Noda K. and

  8. The vitamin D receptor: a tumor suppressor in skin.

    PubMed

    Bikle, Daniel D

    2014-01-01

    Cutaneous malignancies including melanomas and non melanoma skin cancers (NMSC) are the most common types of cancer, occurring at a rate of over 1 million per year in the United States. The major cell in the epidermis, the keratinocyte, not only produces vitamin D but contains the enzymatic machinery to metabolize vitamin D to its active metabolite, 1,25(OH)2D, and expresses the receptor for this metabolite, the vitamin D receptor (VDR), allowing the cell to respond to the 1,25(OH)2D that it produces. In vitro, 1,25(OH)2D stimulates the differentiation and inhibits the proliferation of these cells and so would be expected to be tumor suppressive. However, epidemiologic evidence demonstrating a negative relationship between circulating levels of the substrate for CYP27B1, 25OHD, and the incidence of these malignancies is mixed, raising the question whether vitamin D is protective in the in vivo setting. UV radiation (UV), both UVB and UVA, as occurs with sunlight exposure is generally regarded as causal for these malignancies, but UVB is also required for vitamin D synthesis in the skin. This complicates conclusions reached from epidemiologic studies in that UVB is associated with higher 25OHD levels as well as increased incidence of cutaneous malignancies. Based on our own data and that reported in the literature we hypothesize that vitamin D signaling in the skin suppresses UVR induced epidermal tumor formation. In this chapter we will first discuss recent data regarding potential mechanisms by which vitamin D signaling suppresses tumor formation, then focus on three general mechanisms that mediate tumor suppression by VDR in the skin: inhibition of proliferation and stimulation of differentiation, immune regulation, and stimulation of DNA damage repair (DDR).

  9. Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells.

    PubMed

    Marigo, Ilaria; Dolcetti, Luigi; Serafini, Paolo; Zanovello, Paola; Bronte, Vincenzo

    2008-04-01

    Emerging evidence indicates that the Achilles' heel of cancer immunotherapies is often the complex interplay of tumor-derived factors and deviant host properties, which involve a wide range of immune elements in the lymphoid and myeloid compartments. Regulatory lymphocytes, tumor-conditioned myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and dysfunctional and immature dendritic cells take part in a complex immunoregulatory network. Despite the fact that some mechanisms governing tumor-induced immune tolerance and suppression are starting to be better understood and their complexity dissected, little is known about the diachronic picture of immune tolerance. Based on observations of MDSCs, we present a time-structured and topologically consistent idea of tumor-dependent tolerance progression in tumor-bearing hosts.

  10. Characterization of a set of tumor suppressor microRNAs in T cell acute lymphoblastic leukemia

    PubMed Central

    Sanghvi, Viraj R.; Mavrakis, Konstantinos J.; Van der Meulen, Joni; Boice, Michael; Wolfe, Andrew L.; Carty, Mark; Mohan, Prathibha; Rondou, Pieter; Socci, Nicholas D.; Benoit, Yves; Taghon, Tom; Van Vlierberghe, Pieter; Leslie, Christina S.; Speleman, Frank; Wendel, Hans-Guido

    2015-01-01

    The posttranscriptional control of gene expression by microRNAs (miRNAs) is highly redundant, and compensatory effects limit the consequences of the inactivation of individual miRNAs. This implies that only a few miRNAs can function as effective tumor suppressors. It is also the basis of our strategy to define functionally relevant miRNA target genes that are not under redundant control by other miRNAs. We identified a functionally interconnected group of miRNAs that exhibited a reduced abundance in leukemia cells from patients with T cell acute lymphoblastic leukemia (T-ALL). To pinpoint relevant target genes, we applied a machine learning approach to eliminate genes that were subject to redundant miRNA-mediated control and to identify those genes that were exclusively targeted by tumor-suppressive miRNAs. This strategy revealed the convergence of a small group of tumor suppressor miRNAs on the Myb oncogene, as well as their effects on HBP1, which encodes a transcription factor. The expression of both genes was increased in T-ALL patient samples, and each gene promoted the progression of T-ALL in mice. Hence, our systematic analysis of tumor suppressor miRNA action identified a widespread mechanism of oncogene activation in T-ALL. PMID:25406379

  11. Identification of new tumor suppressor genes in triple-negative breast cancer.

    PubMed

    Rangel, Roberto; Guzman-Rojas, Liliana; Kodama, Takahiro; Kodama, Michiko; Newberg, Justin Y; Copeland, Neal G; Jenkins, Nancy A

    2017-07-19

    Although genomic sequencing has provided a better understating of the genetic landmarks in triple-negative breast cancer (TNBC), functional validation of candidate cancer genes (CCG) remains unsolved. In this study, we used a transposon mutagenesis strategy based on a two-step Sleeping Beauty (SB) forward genetic screen to identify and validate new tumor suppressors (TS) in this disease. We generated 120 siRNAs targeting 40 SB-identified candidate breast cancer TS genes and used them to downregulate expression of these genes in four human TNBC cell lines. Among CCG whose SB-mediated genetic mutation resulted in increased cellular proliferation in all cell lines tested, the genes ADNP, AP2B1, TOMM70A and ZNF326 showed tumor suppressor (TS) activity in tumor xenograft studies. Subsequent studies showed that ZNF326 regulated expression of multiple EMT and cancer stem cell (CSC) pathway genes. It also modulated expression of TS genes involved in the regulation of migration and cellular invasion and was a direct transcriptional activator of genes that regulate CSC self-renewal. ZNF326 expression associated with TNBC patient survival, with ZNF326 protein levels showing a marked reduction in TNBC. Our validation of several new tumor suppressor genes in TNBC demonstrate the utility of two-step forward genetic screens in mice, and offer an invaluable tool to identify novel candidate therapeutic pathways and targets. Copyright ©2017, American Association for Cancer Research.

  12. Cyclin D1 down-regulation is essential for DBC2's tumor suppressor function

    SciTech Connect

    Yoshihara, Takashi; Collado, Denise; Hamaguchi, Masaaki . E-mail: hamaguchi@fordham.edu

    2007-07-13

    The expression of tumor suppressor gene DBC2 causes certain breast cancer cells to stop growing [M. Hamaguchi, J.L. Meth, C. Von Klitzing, W. Wei, D. Esposito, L. Rodgers, T. Walsh, P. Welcsh, M.C. King, M.H. Wigler, DBC2, a candidate for a tumor suppressor gene involved in breast cancer, Proc. Natl. Acad. Sci. USA 99 (2002) 13647-13652]. Recently, DBC2 was found to participate in diverse cellular functions such as protein transport, cytoskeleton regulation, apoptosis, and cell cycle control [V. Siripurapu, J.L. Meth, N. Kobayashi, M. Hamaguchi, DBC2 significantly influences cell cycle, apoptosis, cytoskeleton, and membrane trafficking pathways. J. Mol. Biol. 346 (2005) 83-89]. Its tumor suppression mechanism, however, remains unclear. In this paper, we demonstrate that DBC2 suppresses breast cancer proliferation through down-regulation of Cyclin D1 (CCND1). Additionally, the constitutional overexpression of CCND1 prevented the negative impact of DBC2 expression on their growth. Under a CCND1 promoter, the expression of CCNE1 exhibited the same protective effect. Our results indicate that the down-regulation of CCND1 is an essential step for DBC2's growth suppression of cancer cells. We believe that this discovery contributes to a better understanding of DBC2's tumor suppressor function.

  13. Selective Ablation of Tumor Suppressors in Parafollicular C Cells Elicits Medullary Thyroid Carcinoma.

    PubMed

    Song, Hai; Lin, Chuwen; Yao, Erica; Zhang, Kuan; Li, Xiaoling; Wu, Qingzhe; Chuang, Pao-Tien

    2017-03-03

    Among the four different types of thyroid cancer, treatment of medullary thyroid carcinoma poses a major challenge because of its propensity of early metastasis. To further investigate the molecular mechanisms of medullary thyroid carcinoma and discover candidates for targeted therapies, we developed a new mouse model of medullary thyroid carcinoma based on our CGRP(CreER) mouse line. This system enables gene manipulation in parafollicular C cells in the thyroid, the purported cells of origin of medullary thyroid carcinoma. Selective inactivation of tumor suppressors, such as p53, Rb, and Pten, in mature parafollicular C cells via an inducible Cre recombinase from CGRP(CreER) led to development of murine medullary thyroid carcinoma. Loss of Pten accelerated p53/Rb-induced medullary thyroid carcinoma, indicating interactions between pathways controlled by tumor suppressors. Moreover, labeling differentiated parafollicular C cells by CGRP(CreER) allows us to follow their fate during malignant transformation to medullary thyroid tumor. Our findings support a model in which mutational events in differentiated parafollicular C cells result in medullary thyroid carcinoma. Through expression analysis including RNA-Seq, we uncovered major signaling pathways and networks that are perturbed following the removal of tumor suppressors. Taken together, these studies not only increase our molecular understanding of medullary thyroid carcinoma but also offer new candidates for designing targeted therapies or other treatment modalities. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Complement inhibitor CSMD1 acts as tumor suppressor in human breast cancer

    PubMed Central

    Escudero-Esparza, Astrid; Okroj, Marcin; Owen, Sioned; Jirström, Karin; Orimo, Akira; Jiang, Wen G.; Pietras, Kristian; Blom, Anna M.

    2016-01-01

    Human CUB and Sushi multiple domains 1 (CSMD1) is a membrane-bound complement inhibitor suggested to act as a putative tumor suppressor gene, since allelic loss of this region encompassing 8p23 including CSMD1 characterizes various malignancies. Here, we assessed the role of CSMD1 as a tumor suppressor gene in the development of breast cancer in vitro and in vivo. We found that human breast tumor tissues expressed CSMD1 at lower levels compared to that in normal mammary tissues. The decreased expression of CSMD1 was linked to a shorter overall survival of breast cancer patients. We also revealed that expression of CSMD1 in human breast cancer cells BT-20 and MDA-MB-231 significantly inhibited their malignant phenotypes, including migration, adhesion and invasion. Conversely, stable silencing of CSMD1 expression in T47D cells enhanced cancer cell migratory, adherent and clonogenic abilities. Moreover, expression of CSMD1 in the highly invasive MDA-MB-231 cells diminished their signaling potential as well as their stem cell-like properties as assessed by measurement of aldehyde dehydrogenase activity. In a xenograft model, expression of CSMD1 blocked the ability of cancer cells to metastasize to secondary sites in vivo, likely via inhibiting local invasion but not the extravasation into distant tissues. Taken together, these findings demonstrate the role of CSMD1 as a tumor suppressor gene in breast cancer. PMID:27764775

  15. Duel nature of TGF-beta signaling: tumor suppressor vs. tumor promoter.

    PubMed

    Bachman, Kurtis E; Park, Ben Ho

    2005-01-01

    Transforming growth factor beta type I (TGF-beta) is a ubiquitous cytokine that is well known for its ability to inhibit epithelial cell proliferation. Somatic mutations abrogating the TGF-beta signal transduction pathway are found in many gastrointestinal cancers, confirming its importance as a tumor suppressor. In contrast, many nongastrointestinal epithelial malignancies lack these somatic alterations, yet these cancers still acquire resistance to the growth-inhibitory effects of TGF-beta. In many instances, this resistance is part of a signaling switch whereby TGF-beta loses its growth inhibitory effects and is then used by the epithelial cell in a growth-promoting fashion. The mechanisms that underlie this change in the phenotypic growth response to TGF-beta are now being elucidated. This review focuses on recent advances in understanding the dual nature of the TGF-beta pathway as it relates to human carcinogenesis. Elucidating the molecular basis that enables epithelial cells to change from a growth-suppressive to growth-stimulatory phenotype on TGF-beta exposure is an area of active research. Besides enhancing cancer cell growth, TGF-beta is also thought to promote a malignant cell's ability to metastasize by mediating changes in the cytoskeletal architecture, known as an epithelial-to-mesenchymal transition. This process enables a cancer cell to invade and spread to distal sites. Strong evidence has now emerged suggesting that the ability of a cell to use TGF-beta as a growth-promoting/invasive cytokine is a result of a number of different cellular and nuclear factors, including the absence or disruption of cyclin-dependent kinase inhibitors. This imbalance in cell cycle regulators may be the key element that dictates a cell's response to TGF-beta as growth-inhibitory versus growth-stimulatory, thus explaining the dual nature of TGF-beta signaling. Current studies are beginning to shed light on the mechanisms that allow some nongastrointestinal epithelial

  16. Transcriptional repression of the tumor suppressor DRO1 by AIB1.

    PubMed

    Ferragud, Juan; Avivar-Valderas, Alvaro; Pla, Antoni; De Las Rivas, Javier; Font de Mora, Jaime

    2011-10-03

    Using transcriptomic gene expression profiling we found tumor suppressor DRO1 being repressed in AIB1 transgenic mice. In agreement, AIB1 represses DRO1 promoter and its expression levels inversely correlate with DRO1 in several cancer cell lines and in ectopic and silencing assays. Estrogen modulators treatment showed a regulation in an estrogen receptor-dependent fashion. Importantly, DRO1 overexpression resulted in BCLAF1 upregulation, a compelling concept given that BCLAF1 is a death-promoting transcriptional repressor. Additionally, DRO1 shuttles from Golgi to the endoplasmic reticulum upon apoptotic stimuli, where it is predicted to facilitate the apoptosis cascade. Finally, DRO1 repression is an important factor for AIB1-mediated inhibition of apoptosis. Collectively, our results reveal DRO1 as an AIB1-targeted tumor suppressor, providing a novel mechanism for AIB1-dependent inhibition of apoptosis. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  17. Functions of the Tumor Suppressors p53 and Rb in Actin Cytoskeleton Remodeling

    PubMed Central

    Ebata, Takahiro; Hirata, Hiroaki

    2016-01-01

    Mechanical microenvironments, such as extracellular matrix stiffness and strain, have crucial roles in cancer progression. Cells sense their microenvironments with mechanosensing biomolecules, which is accompanied by the modulation of actin cytoskeleton structures, and the signals are subsequently transduced downstream as biochemical signals. The tumor suppressors p53 and retinoblastoma protein (Rb) are known to prevent cancer progression. The p53 and Rb signaling pathways are disrupted in many types of cancers. Here, we review recent findings about the roles of these tumor suppressors in the regulation of mechanosensing biomolecules and the actin cytoskeleton. We further discuss how dysfunction in the p53- and/or Rb-mediated mechanosignaling pathways is potentially involved in cancer progression. These pathways might provide good targets for developing anticancer therapies. PMID:28078303

  18. Targeted ablation of the WW domain-containing oxidoreductase tumor suppressor leads to impaired steroidogenesis.

    PubMed

    Aqeilan, Rami I; Hagan, John P; de Bruin, Alain; Rawahneh, Maysoon; Salah, Zaidoun; Gaudio, Eugenio; Siddiqui, Hasan; Volinia, Stefano; Alder, Hansjuerg; Lian, Jane B; Stein, Gary S; Croce, Carlo M

    2009-03-01

    The WW domain-containing oxidoreductase (WWOX) gene encodes a 46-kDa tumor suppressor. The Wwox protein contains two N-terminal WW domains that interact with several transcriptional activators containing proline-tyrosine motifs and a central short-chain dehydrogenase/reductase domain that has been suggested to play a role in steroid metabolism. Recently, we have shown that targeted deletion of the Wwox gene in mice leads to postnatal lethality and defects in bone growth. Here, we report that Wwox-deficient mice display impaired steroidogenesis. Mutant homozygous mice are born with gonadal abnormalities, including failure of Leydig cell development in testis and reduced theca cell proliferation in ovary. Furthermore, Wwox(-/-) mice displayed impaired gene expression of key steroidogenesis enzymes. Affymetrix microarray gene analysis revealed differentially expressed related genes in steroidogenesis in knockout mice testis and ovary as compared with control mice. These results demonstrate the essential requirement for the Wwox tumor suppressor in proper steroidogenesis.

  19. Functional association between Wwox tumor suppressor protein and p73, a p53 homolog.

    PubMed

    Aqeilan, Rami I; Pekarsky, Yuri; Herrero, Juan J; Palamarchuk, Alexey; Letofsky, Jean; Druck, Teresa; Trapasso, Francesco; Han, Shuang-Yin; Melino, Gerry; Huebner, Kay; Croce, Carlo M

    2004-03-30

    The WWOX gene is a recently cloned tumor suppressor gene that spans the FRA16D fragile region. Wwox protein contains two WW domains that are generally known to mediate protein-protein interaction. Here we show that Wwox physically interacts via its first WW domain with the p53 homolog, p73. The tyrosine kinase, Src, phosphorylates Wwox at tyrosine 33 in the first WW domain and enhances its binding to p73. Our results further demonstrate that Wwox expression triggers redistribution of nuclear p73 to the cytoplasm and, hence, suppresses its transcriptional activity. In addition, we show that cytoplasmic p73 contributes to the proapoptotic activity of Wwox. Our findings reveal a functional cross-talk between p73 and Wwox tumor suppressor protein.

  20. Intron retention is a widespread mechanism of tumor-suppressor inactivation.

    PubMed

    Jung, Hyunchul; Lee, Donghoon; Lee, Jongkeun; Park, Donghyun; Kim, Yeon Jeong; Park, Woong-Yang; Hong, Dongwan; Park, Peter J; Lee, Eunjung

    2015-11-01

    A substantial fraction of disease-causing mutations are pathogenic through aberrant splicing. Although genome profiling studies have identified somatic single-nucleotide variants (SNVs) in cancer, the extent to which these variants trigger abnormal splicing has not been systematically examined. Here we analyzed RNA sequencing and exome data from 1,812 patients with cancer and identified ∼900 somatic exonic SNVs that disrupt splicing. At least 163 SNVs, including 31 synonymous ones, were shown to cause intron retention or exon skipping in an allele-specific manner, with ∼70% of the SNVs occurring on the last base of exons. Notably, SNVs causing intron retention were enriched in tumor suppressors, and 97% of these SNVs generated a premature termination codon, leading to loss of function through nonsense-mediated decay or truncated protein. We also characterized the genomic features predictive of such splicing defects. Overall, this work demonstrates that intron retention is a common mechanism of tumor-suppressor inactivation.

  1. The vertebrate Hef ortholog is a component of the Fanconi anemia tumor-suppressor pathway.

    PubMed

    Mosedale, Georgina; Niedzwiedz, Wojciech; Alpi, Arno; Perrina, Franco; Pereira-Leal, Jose B; Johnson, Mark; Langevin, Frederic; Pace, Paul; Patel, Ketan J

    2005-09-01

    The helicase-associated endonuclease for fork-structured DNA (Hef) is an archaeabacterial protein that processes blocked replication forks. Here we have isolated the vertebrate Hef ortholog and investigated its molecular function. Disruption of this gene in chicken DT40 cells results in genomic instability and sensitivity to DNA cross-links. The similarity of this phenotype to that of cells lacking the Fanconi anemia-related (FA) tumor-suppressor genes led us to investigate whether Hef functions in this pathway. Indeed, we found a genetic interaction between the FANCC and Hef genes. In addition, Hef is a component of the FA nuclear protein complex that facilitates its DNA damage-inducible chromatin localization and the monoubiquitination of the FA protein FANCD2. Notably, Hef interacts directly with DNA structures that are intermediates in DNA replication. This discovery sheds light on the origins, regulation and molecular function of the FA tumor-suppressor pathway in the maintenance of genome stability.

  2. MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia.

    PubMed

    Chen, Chong; Liu, Yu; Rappaport, Amy R; Kitzing, Thomas; Schultz, Nikolaus; Zhao, Zhen; Shroff, Aditya S; Dickins, Ross A; Vakoc, Christopher R; Bradner, James E; Stock, Wendy; LeBeau, Michelle M; Shannon, Kevin M; Kogan, Scott; Zuber, Johannes; Lowe, Scott W

    2014-05-12

    Recurring deletions of chromosome 7 and 7q [-7/del(7q)] occur in myelodysplastic syndromes and acute myeloid leukemia (AML) and are associated with poor prognosis. However, the identity of functionally relevant tumor suppressors on 7q remains unclear. Using RNAi and CRISPR/Cas9 approaches, we show that an ∼50% reduction in gene dosage of the mixed lineage leukemia 3 (MLL3) gene, located on 7q36.1, cooperates with other events occurring in -7/del(7q) AMLs to promote leukemogenesis. Mll3 suppression impairs the differentiation of HSPC. Interestingly, Mll3-suppressed leukemias, like human -7/del(7q) AMLs, are refractory to conventional chemotherapy but sensitive to the BET inhibitor JQ1. Thus, our mouse model functionally validates MLL3 as a haploinsufficient 7q tumor suppressor and suggests a therapeutic option for this aggressive disease.

  3. Phosphorylation of the tumor suppressor CYLD by the breast cancer oncogene IKKε promotes cell transformation

    PubMed Central

    Hutti, Jessica E.; Shen, Rhine R.; Abbott, Derek W.; Zhou, Alicia Y.; Sprott, Kam M.; Asara, John M.; Hahn, William C.; Cantley, Lewis C.

    2009-01-01

    Summary The non-canonical IKK family member IKKε is essential for regulating anti-viral signaling pathways and is a recently-discovered breast cancer oncoprotein. Although several IKKε targets have been described, direct IKKε substrates necessary for regulating cell transformation have not been identified. Here, we performed a screen for putative IKKε substrates using an unbiased proteomic and bioinformatic approach. Using a positional scanning peptide library assay we determined the optimal phosphorylation motif for IKKε and used bioinformatic approaches to predict IKKε substrates. Of these potential substrates, serine 418 of the tumor suppressor CYLD was identified as a likely site of IKKε phosphorylation. We confirmed that CYLD is directly phosphorylated by IKKε, and that IKKε phosphorylates serine 418 in vivo. Phosphorylation of CYLD at serine 418 decreases its deubiquitinase activity and is necessary for IKKε-driven transformation. Together, these observations define IKKε and CYLD as an oncogene-tumor suppressor network that participates in tumorigenesis. PMID:19481526

  4. Tumor Suppressor WWOX and p53 Alterations and Drug Resistance in Glioblastomas

    PubMed Central

    Chiang, Ming-Fu; Chou, Pei-Yi; Wang, Wan-Jen; Sze, Chun-I; Chang, Nan-Shan

    2013-01-01

    Tumor suppressor p53 are frequently mutated in glioblastomas (GBMs) and appears to contribute, in part, to resistance to temozolomide (TMZ) and therapeutic drugs. WW domain-containing oxidoreductase WWOX (FOR or WOX1) is a proapoptotic protein and is considered as a tumor suppressor. Loss of WWOX gene expression is frequently seen in malignant cancer cells due to promoter hypermethylation, genetic alterations, and translational blockade. Intriguingly, ectopic expression of wild type WWOX preferentially induces apoptosis in human glioblastoma cells harboring mutant p53. WWOX is known to physically bind and stabilize wild type p53. Here, we provide an overview for the updated knowledge in p53 and WWOX, and postulate potential scenarios that wild type and mutant p53, or isoforms, modulate the apoptotic function of WWOX. We propose that triggering WWOX activation by therapeutic drugs under p53 functional deficiency is needed to overcome TMZ resistance and induce GBM cell death. PMID:23459853

  5. Isolation of a Breast Cancer Tumor Suppressor Gene from Chromosome 3p

    DTIC Science & Technology

    1995-10-01

    regions) of 3p that most consistently undergo LOH in breast cancer and to further narrow the critical region in order to facilitate molecular cloning of...tumorigenesis. In the identification and molecular cloning of tumor suppressor genes, homozygous deletions have played a very major role in directing gene...narrow the critical region in order to facilitate molecular cloning of the disease gene. Fluorescence in situ hybridization will be employed as an

  6. The Tumor Suppressor Actions of the Vitamin D Receptor in Skin

    DTIC Science & Technology

    2014-10-01

    Vitamin D Receptor in Skin PRINCIPAL INVESTIGATOR: Daniel D. Bikle, M.D., Ph.D. CONTRACTING ORGANIZATION: Northern California Institute for...SUBTITLE The Tumor Suppressor Actions of the Vitamin D Receptor in Skin 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-12-1-0235 5c. PROGRAM...13. SUPPLEMENTARY NOTES 14. ABSTRACT The epidermis of the mouse lacking the vitamin D receptor (VDR) is susceptible to chemical and UVB

  7. Role of the Rb and p53 Tumor Suppressor Pathways in Mammary Tumorigenesis

    DTIC Science & Technology

    2012-09-01

    kinase screen and off-patent drug screen) REPORTABLE OUTCOMES Jones, Robert., Jiang, Zhe ., Deng, Tao., Schimmer, AD., Moffat, J and...Robert., Jiang, Zhe ., Deng, Tao., Schimmer, AD., Moffat, J and Zacksenhaus, E. Role of the RB and p53 tumor suppressor pathways in mammary tumorigenesis...CDMRP 2011 Era of Hope Conference Jiang Z, Jones R, Liu JC, Deng T, Robinson T, Chung PE, Wang S, Herschkowitz Jl, Egan SE, Perou CM

  8. Markers for Sebaceoma Show a Spectrum of Cell Cycle Regulators, Tumor Suppressor Genes, and Oncogenes

    PubMed Central

    Velez, Ana Maria Abreu; Howard, Michael S; Kim, Jinah; Googe, Paul B

    2015-01-01

    Background: Sebaceoma is a tumor for which the causative oncogenes are not well-understood. Sebaceomas demonstrate some histopathologic features similar to basal cell carcinoma (BCC), such as palisading borders and basaloid cells with additional features, including foamy cytoplasm and indented nuclei. Aims: We examine multiple cell-cycle, oncogene, and tumor suppressor gene markers in sebaceomas, to try to find some suitable biological markers for this tumor, and compare with other published studies. Materials and Methods: We investigated a panel of immunohistochemical (IHC) stains that are important for cellular signaling, including a cell cycle regulator, tumor suppressor gene, oncogene, hormone receptor, and genomic stability markers in our cohort of sebaceomas. We collected 30 sebaceomas from three separate USA dermatopathology laboratories. The following IHC panel: Epithelial membrane antigen (EMA)/CD227, cytokeratin AE1/AE3, cyclin D1, human breast cancer 1 protein (BRCA-1), C-erb-2, Bcl-2, human androgen receptor (AR), cyclin-dependent kinase inhibitor 1B (p27kip1), p53, topoisomerase II alpha, proliferating cell nuclear antigen, and Ki-67 were tested in our cases. Results: EMA/CD227 was positive in the well-differentiated sebaceomas (13/30). Cyclin-dependent kinase inhibitor 1B was positive in tumors with intermediate differentiation (22/30). The less well-differentiated tumors failed to stain with EMA and AR. Most of the tumors with well-differentiated palisaded areas demonstrated positive staining for topoisomerase II alpha, p27kip1, and p53, with positive staining in tumoral basaloid areas (22/30). Numerous tumors were focally positive with multiple markers, indicating a significant degree of variability in the complete group. Conclusions: Oncogenes, tumor suppressor genes, cell cycle regulators, and hormone receptors are variably expressed in sebaceomas. Our results suggest that in these tumors, selected marker staining seems to correlate with tumor

  9. Identification of Fat4 as a candidate tumor suppressor gene in breast cancers

    PubMed Central

    Qi, Chao; Zhu, Yiwei Tony; Hu, Liping; Zhu, Yi-Jun

    2009-01-01

    Fat, a candidate tumor suppressor in drosophila, is a component of Hippo signaling pathway involved in controlling organ size. We found that a ~3Mbp deletion in mouse chromosome 3 caused tumorigenesis of a non-tumorigenic mammary epithelial cell line. The expression of Fat4 gene, one member of the Fat family, in the deleted region was inactivated, which resulted from promoter methylation of another Fat4 allele following the deletion of one Fat4 allele. Re-expression of Fat4 in Fat4-deficient tumor cells suppressed the tumorigenecity while suppression of Fat4 expression in the non-tumorigenic mammary epithelial cell line induced tumorigenesis. We also found that Fat4 expression was lost in a large fraction of human breast tumor cell lines and primary tumors. Loss of Fat4 expression in breast tumors was associated with human Fat4 promoter methylation. Together, these findings suggest that Fat4 is a strong candidate for a breast tumor suppressor gene. PMID:19048595

  10. Curcumin Reactivates Silenced Tumor Suppressor Gene RARβ by Reducing DNA Methylation.

    PubMed

    Jiang, Apei; Wang, Xuemin; Shan, Xiaoyun; Li, Yuan; Wang, Pengqi; Jiang, Pan; Feng, Qing

    2015-08-01

    Reactivation of tumor suppressor genes by nontoxic bioactive food component represents a promising strategy for cancer chemoprevention. Retinoic acid receptor β (RARβ), one member of the RAR receptor family, is considered as a tumor suppressor. Reduced expression of RARβ has been reported in lung cancer and other solid tumors. DNA hypermethylation of the promoter region of RARβ is a major mechanism for its silencing in tumors. Recently, curcumin has been considered as a potential DNA methyltransferase inhibitor. Herein, we demonstrated that curcumin significantly elevate RARβ expression at the mRNA and protein levels in tested cancer cells. Additionally, curcumin decreased RARβ promoter methylation in lung cancer A549 and H460 cells. Mechanistic study demonstrated that curcumin was able to downregulate the mRNA levels of DNMT3b. In a lung cancer xenograft node mice model, curcumin exhibited protective effect against weight loss because of tumor burden. Tumor growth was strongly repressed by curcumin treatment. As the results from in vitro, RARβ mRNA were increased and DNMT3b mRNA were decreased by curcumin treatment compared with the mice in control group. Altogether, this study reveals a novel molecular mechanism of curcumin as a chemo-preventive agent for lung cancer through reactivation of RARβ. Copyright © 2015 John Wiley & Sons, Ltd.

  11. Proline oxidase functions as a mitochondrial tumor suppressor in human cancers

    PubMed Central

    Liu, Yongmin; Borchert, Gregory L.; Donald, Steve; Diwan, Bhalchandra; Anver, Miriam; Phang, James M.

    2009-01-01

    Tumor metabolism and bioenergetics have become important topics for cancer research and are promising targets for anticancer therapy. Although glucose serves as the main source of energy, proline, an alternative substrate, is important, especially during nutrient stress. Proline oxidase (POX), catalyzing the first step in proline catabolism, is induced by p53 and can regulate cell survival as well as mediate programmed cell death. In a mouse xenograft tumor model, we found that POX greatly reduced tumor formation by causing G2 cell cycle arrest. Furthermore, immunohistochemical staining showed decreased POX expression in tumor tissues. Importantly, HIF-1α signaling was impaired with POX expression due to the increased production of α-ketoglutarate, a critical substrate for prolyl hydroxylation and degradation of HIF-1α. Combined with previous in vitro findings and reported clinical genetic associations, these new findings lead us to propose POX as a mitochondrial tumor suppressor and a potential target for cancer therapy. PMID:19654292

  12. 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.

  13. Tumor suppressor WWOX regulates glucose metabolism via HIF1α modulation

    PubMed Central

    Abu-Remaileh, M; Aqeilan, R I

    2014-01-01

    The WW domain-containing oxidoreductase (WWOX) encodes a tumor suppressor that is frequently lost in many cancer types. Wwox-deficient mice develop normally but succumb to a lethal hypoglycemia early in life. Here, we identify WWOX as a tumor suppressor with emerging role in regulation of aerobic glycolysis. WWOX controls glycolytic genes' expression through hypoxia-inducible transcription factor 1α (HIF1α) regulation. Specifically, WWOX, via its first WW domain, physically interacts with HIF1α and modulates its levels and transactivation function. Consistent with this notion, Wwox-deficient cells exhibited increased HIF1α levels and activity and displayed increased glucose uptake. Remarkably, WWOX deficiency is associated with enhanced glycolysis and diminished mitochondrial respiration, conditions resembling the ‘Warburg effect'. Furthermore, Wwox-deficient cells are more tumorigenic and display increased levels of GLUT1 in vivo. Finally, WWOX expression is inversely correlated with GLUT1 levels in breast cancer samples highlighting WWOX as a modulator of cancer metabolism. Our studies uncover an unforeseen role for the tumor-suppressor WWOX in cancer metabolism. PMID:25012504

  14. Tumor suppressor WWOX regulates glucose metabolism via HIF1α modulation.

    PubMed

    Abu-Remaileh, M; Aqeilan, R I

    2014-11-01

    The WW domain-containing oxidoreductase (WWOX) encodes a tumor suppressor that is frequently lost in many cancer types. Wwox-deficient mice develop normally but succumb to a lethal hypoglycemia early in life. Here, we identify WWOX as a tumor suppressor with emerging role in regulation of aerobic glycolysis. WWOX controls glycolytic genes' expression through hypoxia-inducible transcription factor 1α (HIF1α) regulation. Specifically, WWOX, via its first WW domain, physically interacts with HIF1α and modulates its levels and transactivation function. Consistent with this notion, Wwox-deficient cells exhibited increased HIF1α levels and activity and displayed increased glucose uptake. Remarkably, WWOX deficiency is associated with enhanced glycolysis and diminished mitochondrial respiration, conditions resembling the 'Warburg effect'. Furthermore, Wwox-deficient cells are more tumorigenic and display increased levels of GLUT1 in vivo. Finally, WWOX expression is inversely correlated with GLUT1 levels in breast cancer samples highlighting WWOX as a modulator of cancer metabolism. Our studies uncover an unforeseen role for the tumor-suppressor WWOX in cancer metabolism.

  15. KLF10, transforming growth factor-{beta}-inducible early gene 1, acts as a tumor suppressor

    SciTech Connect

    Song, Ki-Duk; Kim, Duk-Jung; Lee, Jong Eun; Yun, Cheol-Heui; Lee, Woon Kyu

    2012-03-09

    Highlights: Black-Right-Pointing-Pointer KLF10{sup -/-} mice exhibited accelerated papilloma development after DMBA/TPA treatment. Black-Right-Pointing-Pointer KLF10{sup -/-} keratinocytes showed increased proliferation and apoptosis. Black-Right-Pointing-Pointer KLF10{sup -/-} MEFs yielded more colonies than wild-type one with H-Ras transfection. Black-Right-Pointing-Pointer KLF10 dose-dependently activated p21{sup WAF1/CIP1} transcription. Black-Right-Pointing-Pointer KLF10 is a tumor suppressor and that it targets p21{sup WAF1/CIP1} transcription. -- Abstract: Krueppel-like factor 10 (KLF10) has been suggested to be a putative tumor suppressor. In the present study, we generated KLF10 deficient mice to explore this hypothesis in vivo. KLF10 deficient mice exhibited increased predisposition to skin tumorigenesis and markedly accelerated papilloma development after DMBA/TPA treatment. On the other hand, KLF10 deficient keratinocytes showed increased proliferation and apoptosis. In colony formation assays after oncogenic H-Ras transfection, KLF10 deficient mouse embryonic fibroblasts (MEFs) yielded more colonies than wild-type MEFs. Furthermore, KLF10 dose-dependently activated p21{sup WAF1/CIP1} transcription, which was independent of p53 and Sp1 binding sites in p21{sup WAF1/CIP1} promoter. This study demonstrates that KLF10 is a tumor suppressor and that it targets p21{sup WAF1/CIP1} transcription.

  16. FAT4 functions as a tumor suppressor in triple-negative breast cancer.

    PubMed

    Hou, Lingmi; Chen, Maoshan; Zhao, Xiaobo; Li, Jingdong; Deng, Shishan; Hu, Jiani; Yang, Hongwei; Jiang, Jun

    2016-11-28

    Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is often associated with biologic behavior with frequent distant metastasis. FAT tumor suppressor homolog 4 (FAT4), a cadherin-related protein, is involved in a variety of biological processes as a tumor suppressor; however, the role of FAT4 in TNBC is still unclear. The aim of our study was to identify the role of FAT4 in TNBC and examine the underlying molecular mechanisms. The expression of FAT4 was evaluated by immunohistochemistry, western blotting, and qRT-PCR in a series of TNBC tissues. The effects of FAT4 on the ability of cell proliferation, migration, and invasion were assessed by MTT assay and migration and invasion assays. We demonstrated that the repression of FAT4 by shRNA could promote TNBC progression. Taken together, our findings provide evidence for a role of the FAT4 cluster as a tumor suppressor in TNBC patients and may serve as potential novel targets for the treatment of TNBC.

  17. The Chromatin Remodeling Component Arid1a Is a Suppressor of Spontaneous Mammary Tumors in Mice.

    PubMed

    Kartha, Nithya; Shen, Lishuang; Maskin, Carolyn; Wallace, Marsha; Schimenti, John C

    2016-08-01

    Human cancer genome studies have identified the SWI/SNF chromatin remodeling complex member ARID1A as one of the most frequently altered genes in several tumor types. Its role as an ovarian tumor suppressor has been supported in compound knockout mice. Here, we provide genetic and functional evidence that Arid1a is a bona fide mammary tumor suppressor, using the Chromosome aberrations occurring spontaneously 3 (Chaos3) mouse model of sporadic breast cancer. About 70% of mammary tumors that formed in these mice contained a spontaneous deletion removing all or part of one Arid1a allele. Restoration of Arid1a expression in a Chaos3 mammary tumor line with low Arid1a levels greatly impaired its ability to form tumors following injection into cleared mammary glands, indicating that ARID1A insufficiency is crucial for maintenance of these Trp53-proficient tumors. Transcriptome analysis of tumor cells before and after reintroduction of Arid1a expression revealed alterations in growth signaling and cell-cycle checkpoint pathways, in particular the activation of the TRP53 pathway. Consistent with the latter, Arid1a reexpression in tumor cells led to increased p21 (Cdkn1a) expression and dramatic accumulation of cells in G2 phase of the cell cycle. These results not only provide in vivo evidence for a tumor suppressive and/or maintenance role in breast cancer, but also indicate a potential opportunity for therapeutic intervention in ARID1A-deficient human breast cancer subtypes that retain one intact copy of the gene and also maintain wild-type TRP53 activity. Copyright © 2016 by the Genetics Society of America.

  18. Cellular senescence checkpoint function determines differential Notch1-dependent oncogenic and tumor-suppressor activities.

    PubMed

    Kagawa, S; Natsuizaka, M; Whelan, K A; Facompre, N; Naganuma, S; Ohashi, S; Kinugasa, H; Egloff, A M; Basu, D; Gimotty, P A; Klein-Szanto, A J; Bass, A J; Wong, K-K; Diehl, J A; Rustgi, A K; Nakagawa, H

    2015-04-30

    Notch activity regulates tumor biology in a context-dependent and complex manner. Notch may act as an oncogene or a tumor-suppressor gene even within the same tumor type. Recently, Notch signaling has been implicated in cellular senescence. Yet, it remains unclear as to how cellular senescence checkpoint functions may interact with Notch-mediated oncogenic and tumor-suppressor activities. Herein, we used genetically engineered human esophageal keratinocytes and esophageal squamous cell carcinoma cells to delineate the functional consequences of Notch activation and inhibition along with pharmacological intervention and RNA interference experiments. When expressed in a tetracycline-inducible manner, the ectopically expressed activated form of Notch1 (ICN1) displayed oncogene-like characteristics inducing cellular senescence corroborated by the induction of G0/G1 cell-cycle arrest, Rb dephosphorylation, flat and enlarged cell morphology and senescence-associated β-galactosidase activity. Notch-induced senescence involves canonical CSL/RBPJ-dependent transcriptional activity and the p16(INK4A)-Rb pathway. Loss of p16(INK4A) or the presence of human papilloma virus (HPV) E6/E7 oncogene products not only prevented ICN1 from inducing senescence but permitted ICN1 to facilitate anchorage-independent colony formation and xenograft tumor growth with increased cell proliferation and reduced squamous-cell differentiation. Moreover, Notch1 appears to mediate replicative senescence as well as transforming growth factor-β-induced cellular senescence in non-transformed cells and that HPV E6/E7 targets Notch1 for inactivation to prevent senescence, revealing a tumor-suppressor attribute of endogenous Notch1. In aggregate, cellular senescence checkpoint functions may influence dichotomous Notch activities in the neoplastic context.

  19. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression.

    PubMed

    Bunt, Stephanie K; Yang, Linglin; Sinha, Pratima; Clements, Virginia K; Leips, Jeff; Ostrand-Rosenberg, Suzanne

    2007-10-15

    Chronic inflammation is frequently associated with malignant growth and is thought to promote and enhance tumor progression, although the mechanisms which regulate this relationship remain elusive. We reported previously that interleukin (IL)-1beta promoted tumor progression by enhancing the accumulation of myeloid-derived suppressor cells (MDSC), and hypothesized that inflammation leads to cancer through the production of MDSC which inhibit tumor immunity. If inflammation-induced MDSC promote tumor progression by blocking antitumor immunity, then a reduction in inflammation should reduce MDSC levels and delay tumor progression, whereas an increase in inflammation should increase MDSC levels and hasten tumor progression. We have tested this hypothesis using the 4T1 mammary carcinoma and IL-1 receptor (IL-1R)-deficient mice which have a reduced potential for inflammation, and IL-1R antagonist-deficient mice, which have an increased potential for inflammation. Consistent with our hypothesis, IL-1R-deficient mice have a delayed accumulation of MDSC and reduced primary and metastatic tumor progression. Accumulation of MDSC and tumor progression are partially restored by IL-6, indicating that IL-6 is a downstream mediator of the IL-1beta-induced expansion of MDSC. In contrast, excessive inflammation in IL-1R antagonist-deficient mice promotes the accumulation of MDSC and produces MDSC with enhanced suppressive activity. These results show that immune suppression by MDSC and tumor growth are regulated by the inflammatory milieu and support the hypothesis that the induction of suppressor cells which down-regulate tumor immunity is one of the mechanisms linking inflammation and cancer.

  20. Functional evidence for a nasopharyngeal carcinoma tumor suppressor gene that maps at chromosome 3p21.3

    PubMed Central

    Cheng, Yue; Poulos, Nicholas E.; Lung, Maria L.; Hampton, Garret; Ou, Baoxiang; Lerman, Michael I.; Stanbridge, Eric J.

    1998-01-01

    Nasopharyngeal carcinoma is a malignancy that is prevalent among populations from Southeast Asia. Epidemiological studies indicate that genetic predisposition, Epstein–Barr virus, and environmental conditions may play a role in determining incidence. Molecular studies have implicated a tumor suppressor gene(s) on the short arm of chromosome 3. In this study we provide functional evidence, via monochromosome transfer, for a tumor suppressor gene(s) activity in chromosome 3p21.3. PMID:9501212

  1. Emotional functioning of patients with neurofibromatosis tumor suppressor syndrome

    PubMed Central

    Wang, Daphne L.; Smith, Kelly B.; Esparza, Sonia; Leigh, Fawn A.; Muzikansky, Alona; Park, Elyse R.; Plotkin, Scott R.

    2013-01-01

    Purpose Although patients with neurofibromatosis are predisposed to multiple nerve sheath tumors that can develop anywhere in the body and cause significant morbidity (e.g., hearing loss; pain), little research has examined emotional correlates of neurofibromatosis. The purpose of this study was to examine emotional functioning among adult patients with neurofibromatosis. Methods A total of 248 patients with neurofibromatosis (neurofibromatosis 1, neurofibromatosis 2, or schwannomatosis) who received care at a specialized clinic completed validated measures to assess symptoms of depression and anxiety, level of perceived stress, and self-esteem. Results Patients with neurofibromatosis reported significantly more symptoms of depression and anxiety, higher levels of perceived stress, and lower levels of self-esteem as compared with general population norms. No significant differences were found among patients with neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis, and emotional functioning was not significantly associated with disease severity. However, increased symptoms of depression and anxiety, higher levels of perceived stress, and lower levels of self-esteem were associated with a higher frequency of self-reported medical visits in the past year (P values ≤0.05). Conclusion Neurofibromatosis appears to be associated with reduced emotional functioning. Although further research is needed, these findings suggest a role for a multidisciplinary treatment approach to address emotional distress among adult patients with neurofibromatosis. PMID:22878510

  2. Emotional functioning of patients with neurofibromatosis tumor suppressor syndrome.

    PubMed

    Wang, Daphne L; Smith, Kelly B; Esparza, Sonia; Leigh, Fawn A; Muzikansky, Alona; Park, Elyse R; Plotkin, Scott R

    2012-12-01

    Although patients with neurofibromatosis are predisposed to multiple nerve sheath tumors that can develop anywhere in the body and cause significant morbidity (e.g., hearing loss; pain), little research has examined emotional correlates of neurofibromatosis. The purpose of this study was to examine emotional functioning among adult patients with neurofibromatosis. A total of 248 patients with neurofibromatosis (neurofibromatosis 1, neurofibromatosis 2, or schwannomatosis) who received care at a specialized clinic completed validated measures to assess symptoms of depression and anxiety, level of perceived stress, and self-esteem. Patients with neurofibromatosis reported significantly more symptoms of depression and anxiety, higher levels of perceived stress, and lower levels of self-esteem as compared with general population norms. No significant differences were found among patients with neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis, and emotional functioning was not significantly associated with disease severity. However, increased symptoms of depression and anxiety, higher levels of perceived stress, and lower levels of self-esteem were associated with a higher frequency of self-reported medical visits in the past year (P values ≤0.05). Neurofibromatosis appears to be associated with reduced emotional functioning. Although further research is needed, these findings suggest a role for a multidisciplinary treatment approach to address emotional distress among adult patients with neurofibromatosis.

  3. Dnmt3a Is a Haploinsufficient Tumor Suppressor in CD8+ Peripheral T Cell Lymphoma

    PubMed Central

    Opavska, Jana; Klinkebiel, David; Roy, Sohini; Dutta, Samikshan; Datta, Kaustubh; Opavsky, Rene

    2016-01-01

    DNA methyltransferase 3A (DNMT3A) is an enzyme involved in DNA methylation that is frequently mutated in human hematologic malignancies. We have previously shown that inactivation of Dnmt3a in hematopoietic cells results in chronic lymphocytic leukemia in mice. Here we show that 12% of Dnmt3a-deficient mice develop CD8+ mature peripheral T cell lymphomas (PTCL) and 29% of mice are affected by both diseases. 10% of Dnmt3a+/- mice develop lymphomas, suggesting that Dnmt3a is a haploinsufficient tumor suppressor in PTCL. DNA methylation was deregulated genome-wide with 10-fold more hypo- than hypermethylated promoters and enhancers, demonstrating that hypomethylation is a major event in the development of PTCL. Hypomethylated promoters were enriched for binding sites of transcription factors AML1, NF-κB and OCT1, implying the transcription factors potential involvement in Dnmt3a-associated methylation. Whereas 71 hypomethylated genes showed an increased expression in PTCL, only 3 hypermethylated genes were silenced, suggesting that cancer-specific hypomethylation has broader effects on the transcriptome of cancer cells than hypermethylation. Interestingly, transcriptomes of Dnmt3a+/- and Dnmt3aΔ/Δ lymphomas were largely conserved and significantly overlapped with those of human tumors. Importantly, we observed downregulation of tumor suppressor p53 in Dnmt3a+/- and Dnmt3aΔ/Δ lymphomas as well as in pre-tumor thymocytes from 9 months old but not 6 weeks old Dnmt3a+/- tumor-free mice, suggesting that p53 downregulation is chronologically an intermediate event in tumorigenesis. Decrease in p53 is likely an important event in tumorigenesis because its overexpression inhibited proliferation in mouse PTCL cell lines, suggesting that low levels of p53 are important for tumor maintenance. Altogether, our data link the haploinsufficient tumor suppressor function of Dnmt3a in the prevention of mouse mature CD8+ PTCL indirectly to a bona fide tumor suppressor of T cell

  4. Regulation of protein phosphatase 2A (PP2A) tumor suppressor function by PME-1.

    PubMed

    Kaur, Amanpreet; Westermarck, Jukka

    2016-12-15

    Protein phosphatase 2A (PP2A) plays a major role in maintaining cellular signaling homeostasis by dephosphorylation of a variety of signaling proteins and acts as a tumor suppressor. Protein phosphatase methylesterase-1 (PME-1) negatively regulates PP2A activity by highly complex mechanisms that are reviewed here. Importantly, recent studies have shown that PME-1 promotes oncogenic MAPK/ERK and AKT pathway activities in various cancer types. In human glioma, high PME-1 expression correlates with tumor progression and kinase inhibitor resistance. We discuss the emerging cancer-associated function of PME-1 and its potential clinical relevance.

  5. Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterozygosity

    PubMed Central

    Baker, Darren J.; Jin, Fang; Jeganathan, Karthik B.; van Deursen, Jan M.

    2010-01-01

    Summary Genetic alterations that promote chromosome missegregation have been proposed to drive tumorigenesis through loss of whole chromosomes containing key tumor suppressor genes. To test this unproven idea, we bred Bub1 mutant mice that inaccurately segregate their chromosomes onto p53+/−, ApcMin/+, Rb+/− or Pten+/− backgrounds. Bub1 insufficiency predisposed p53+/− mice to thymic lymphomas and ApcMin/+ mice to colonic tumors. These tumors consistently lacked the non-mutated tumor suppressor allele, but had gained a copy of the mutant allele. In contrast, Bub1 insufficiency had no impact on tumorigenesis in Rb+/− mice and inhibited prostatic intraepithelial neoplasia formation in Pten+/− mice. Thus, Bub1 insufficiency can drive tumor formation through tumor suppressor gene loss of heterozygosity, but only in restricted genetic and cellular contexts. PMID:19962666

  6. The ETS transcription factor MEF is a candidate tumor suppressor gene on the X chromosome.

    PubMed

    Seki, Yoshiyuki; Suico, Mary Ann; Uto, Ayako; Hisatsune, Akinobu; Shuto, Tsuyoshi; Isohama, Yoichiro; Kai, Hirofumi

    2002-11-15

    Although X chromosome transfer experiments indicated that tumor suppressor genes are present on the X chromosome, they have not been previously identified. In this report, we show that the ETS transcription factor MEF (ELF4), which is located on chromosome Xq26.1, possesses tumor suppressive capability. MEF expression was up-regulated by 5-azacytidine in some cancer cell lines. MEF overexpression induced morphological changes, such as the conversion of normally loose cell-cell contacts to strong interactions similar to those seen in the presence of matrix metalloproteinase (MMP) inhibitor BB94. In the colony formation assay, A549 cells, but not MEF-overexpressing cells, formed colonies in soft agar culture. Furthermore, MEF-overexpressing cells s.c. injected in the nude mice did not grow, whereas the control cells did. The A549 tumors were poorly differentiated, whereas the MEF-overexpressing tumors were well differentiated. By immunostaining with CD31, a marker on vascular endothelial cells, we found that tumor angiogenesis was significantly suppressed in the tumors formed from MEF-overexpressing cells. In addition, the conditioned media from A549 cell cultures stimulated the migration of human umbilical vein endothelial cells, whereas conditioned media from MEF-overexpressing cell cultures had less of an effect. By gelatin zymography, Western blotting analysis, and immunohistochemistry, we found that the expression levels of MMP-9 and MMP-2 were significantly reduced in MEF-overexpressing tumors. Immunohistochemical analyses showed that interleukin (IL)-8 expression was reduced in the MEF-overexpressing tumors in nude mice. Furthermore, IL-8 mRNA expression in vitro was significantly down-regulated in MEF-overexpressing cells, compared with A549 cells. MEF suppressed the transcription and promoter activities of the genes encoding MMP-9 and IL-8, whereas ETS-2 up-regulated these activities. Therefore, we propose that MEF is a candidate tumor suppressor gene on the

  7. BOK displays cell death-independent tumor suppressor activity in non-small-cell lung carcinoma.

    PubMed

    Moravcikova, Erika; Krepela, Evzen; Donnenberg, Vera S; Donnenberg, Albert D; Benkova, Kamila; Rabachini, Tatiana; Fernandez-Marrero, Yuniel; Bachmann, Daniel; Kaufmann, Thomas

    2017-11-15

    As the genomic region containing the Bcl-2-related ovarian killer (BOK) locus is frequently deleted in certain human cancers, BOK is hypothesized to have a tumor suppressor function. In the present study, we analyzed primary non-small-cell lung carcinoma (NSCLC) tumors and matched lung tissues from 102 surgically treated patients. We show that BOK protein levels are significantly downregulated in NSCLC tumors as compared to lung tissues (p < 0.001). In particular, we found BOK downregulation in NSCLC tumors of grades two (p = 0.004, n = 35) and three (p = 0.031, n = 39) as well as in tumors with metastases to hilar (pN1) (p = 0.047, n = 31) and mediastinal/subcarinal lymph nodes (pN2) (p = 0.021, n = 18) as opposed to grade one tumors (p = 0.688, n = 7) and tumors without lymph node metastases (p = 0.112, n = 51). Importantly, in lymph node-positive patients, BOK expression greater than the median value was associated with longer survival (p = 0.002, Mantel test). Using in vitro approaches, we provide evidence that BOK overexpression is inefficient in inducing apoptosis but that it inhibits TGFβ-induced migration and epithelial-to-mesenchymal transition (EMT) in lung adenocarcinoma-derived A549 cells. We have identified epigenetic mechanisms, in particular BOK promoter methylation, as an important means to silence BOK expression in NSCLC cells. Taken together, our data point toward a novel mechanism by which BOK acts as a tumor suppressor in NSCLC by inhibiting EMT. Consequently, the restoration of BOK levels in low-BOK-expressing tumors might favor the overall survival of NSCLC patients. © 2017 UICC.

  8. LSAMP, a novel candidate tumor suppressor gene in human osteosarcomas, identified by array comparative genomic hybridization.

    PubMed

    Kresse, Stine H; Ohnstad, Hege O; Paulsen, Erik B; Bjerkehagen, Bodil; Szuhai, Karoly; Serra, Massimo; Schaefer, Karl-Ludwig; Myklebost, Ola; Meza-Zepeda, Leonardo A

    2009-08-01

    Osteosarcomas are the most common primary malignant tumor of bone, and almost all conventional osteosarcomas are high-grade tumors with complex karyotypes. We have examined DNA copy number changes in 36 osteosarcoma tumors and 20 cell lines using microarray-based comparative genomic hybridization. The most frequent minimal recurrent regions of gain identified in the tumor samples were in 1q21.2-q21.3 (78% of the samples), 1q21.3-q22 (78%), and 8q22.1 (72%). Minimal recurrent regions in 10q22.1-q22.2 (81%), 6q16.1 (67%), 13q14.2 (67%), and 13q21.1 (67%) were most frequently lost. A small region in 3q13.31 (2.1 Mb) containing the gene limbic system-associated membrane protein (LSAMP) was frequently deleted (56%). LSAMP has previously been reported to be a candidate tumor suppressor gene in other cancer types. The deletion was validated using fluorescence in situ hybridization, and the expression level and promoter methylation status of LSAMP were investigated using quantitative real-time reverse transcription PCR and methylation-specific PCR, respectively. LSAMP showed low expression compared to two normal bone samples in 6/15 tumors and 5/9 cell lines with deletion of 3q13.31, and also in 5/14 tumors and 3/11 cell lines with normal copy number or gain. Partial or full methylation of the investigated CpG island was identified in 3/30 tumors and 7/20 cell lines. Statistical analyses revealed that loss of 11p15.4-p15.3 and low expression of LSAMP (both P = 0.011) were significantly associated with poor survival. Our results show that LSAMP is a novel candidate tumor suppressor gene in osteosarcomas.

  9. Hypergrowth mTORC1 Signals Translationally Activate the ARF Tumor Suppressor Checkpoint

    PubMed Central

    Miceli, Alexander P.; Saporita, Anthony J.

    2012-01-01

    The ARF tumor suppressor is a potent sensor of hyperproliferative cues emanating from oncogenic signaling. ARF responds to these cues by eliciting a cell cycle arrest, effectively abating the tumorigenic potential of these stimuli. Prior reports have demonstrated that oncogenic RasV12 signaling induces ARF through a mechanism mediated by the Dmp1 transcription factor. However, we now show that ARF protein is still induced in response to RasV12 in the absence of Dmp1 through the enhanced translation of existing Arf mRNAs. Here, we report that the progrowth Ras/tuberous sclerosis complex (TSC)/mTORC1 signaling pathway regulates ARF protein expression and triggers ARF-mediated tumor suppression through a novel translational mechanism. Hyperactivation of mTORC1 through Tsc1 loss resulted in a significant increase in ARF expression, activation of the p53 pathway, and a dramatic cell cycle arrest, which were completely reversed upon Arf deletion. ARF protein induced from RasV12 in the absence of Dmp1 repressed anchorage-independent colony formation in soft agar and tumor burden in an allograft model. Taken together, our data demonstrate the ability of the ARF tumor suppressor to respond to hypergrowth stimuli to prevent unwarranted tumor formation. PMID:22064482

  10. Inactivation of the candidate tumor suppressor par-4 in endometrial cancer.

    PubMed

    Moreno-Bueno, Gema; Fernandez-Marcos, Pablo J; Collado, Manuel; Tendero, Mercedes J; Rodriguez-Pinilla, Socorro M; Garcia-Cao, Isabel; Hardisson, David; Diaz-Meco, Maria T; Moscat, Jorge; Serrano, Manuel; Palacios, Jose

    2007-03-01

    Recently, it has been shown that mice deficient in the proapoptotic protein prostate apoptosis response 4 (Par-4) are specifically prone to develop endometrial carcinomas. Based on this, we have examined here the possible role of Par-4 as a tumor suppressor gene in human endometrial cancer. Using cDNA arrays, quantitative reverse transcription-PCR, and immunohistochemistry, we detected Par-4 down-regulation in approximately 40% of endometrial carcinomas. This alteration was not associated with phosphatase and tensin homologue (PTEN), K-RAS, or beta-catenin mutations, but was more frequent among tumors showing microsatellite instability (MSI) or among tumors that were estrogen receptor positive. Mutational analysis of the complete coding sequence of Par-4 in endometrial cancer cell lines (n = 6) and carcinomas (n = 69) detected a mutation in a single carcinoma, which was localized in exon 3 [Arg (CGA) 189 (TGA) Stop]. Interestingly, Par-4 promoter hypermethylation was detected in 32% of the tumors in association with low levels of Par-4 protein and was more common in MSI-positive carcinomas. Par-4 promoter hypermethylation and silencing was also detected in endometrial cancer cell lines SKUT1B and AN3CA, and reexpression was achieved by treatment with the demethylating agent 5'-aza-2'-deoxycytidine. Together, these data show that Par-4 is a relevant tumor suppressor gene in human endometrial carcinogenesis.

  11. 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.

  12. A tumor suppressor role of the Bub3 spindle checkpoint protein after apoptosis inhibition

    PubMed Central

    Moutinho-Santos, Tatiana

    2013-01-01

    Most solid tumors contain aneuploid cells, indicating that the mitotic checkpoint is permissive to the proliferation of chromosomally aberrant cells. However, mutated or altered expression of mitotic checkpoint genes accounts for a minor proportion of human tumors. We describe a Drosophila melanogaster tumorigenesis model derived from knocking down spindle assembly checkpoint (SAC) genes and preventing apoptosis in wing imaginal discs. Bub3-deficient tumors that were also deficient in apoptosis displayed neoplastic growth, chromosomal aneuploidy, and high proliferative potential after transplantation into adult flies. Inducing aneuploidy by knocking down CENP-E and preventing apoptosis does not induce tumorigenesis, indicating that aneuploidy is not sufficient for hyperplasia. In this system, the aneuploidy caused by a deficient SAC is not driving tumorigenesis because preventing Bub3 from binding to the kinetochore does not cause hyperproliferation. Our data suggest that Bub3 has a nonkinetochore-dependent function that is consistent with its role as a tumor suppressor. PMID:23609535

  13. Gene trapping identifies a putative tumor suppressor and a new inducer of cell migration

    SciTech Connect

    Guardiola-Serrano, Francisca; Haendeler, Judith; Lukosz, Margarete; Sturm, Karsten; Melchner, Harald von; Altschmied, Joachim

    2008-11-28

    Tumor necrosis factor alpha (TNF{alpha}) is a pleiotropic cytokine involved in apoptotic cell death, cellular proliferation, differentiation, inflammation, and tumorigenesis. In tumors it is secreted by tumor associated macrophages and can have both pro- and anti-tumorigenic effects. To identify genes regulated by TNF{alpha}, we performed a gene trap screen in the mammary carcinoma cell line MCF-7 and recovered 64 unique, TNF{alpha}-induced gene trap integration sites. Among these were the genes coding for the zinc finger protein ZC3H10 and for the transcription factor grainyhead-like 3 (GRHL3). In line with the dual effects of TNF{alpha} on tumorigenesis, we found that ZC3H10 inhibits anchorage independent growth in soft agar suggesting a tumor suppressor function, whereas GRHL3 strongly stimulated the migration of endothelial cells which is consistent with an angiogenic, pro-tumorigenic function.

  14. ANRIL: a pivotal tumor suppressor long non-coding RNA in human cancers.

    PubMed

    Li, Zheng; Yu, Xin; Shen, Jianxiong

    2016-05-01

    Long non-coding RNAs (lncRNAs) are a family of non-protein-coding RNAs with length more than 200 nucleotides. LncRNAs played important roles in many biological processes such as cell development, proliferation, invasion and migration. Deregulation of LncRNAs was found in multiple tumors where they can act as a tumor suppressor gene or oncogene. LncRNA ANRIL was identified as an oncogene involved in a number of tumors such as gastric cancer, lung cancer, hepatocellular carcinoma, and esophageal squamous cell carcinoma. Inhibition of ANRIL suppressed the cancer cell proliferation, migration and invasion. Increasing data has showed that ANRIL may act as a diagnostic and prognostic biomarker for some tumors. In our review, we summarize an overview of current knowledge concerning the expression and role of ANRIL in various cancers.

  15. Inhibition of tumor-induced myeloid-derived suppressor cell function by a nanoparticulated adjuvant.

    PubMed

    Fernández, Audry; Mesa, Circe; Marigo, Ilaria; Dolcetti, Luigi; Clavell, Marilyn; Oliver, Liliana; Fernández, Luis E; Bronte, Vincenzo

    2011-01-01

    The interaction between cancer vaccine adjuvants and myeloid-derived suppressor cells (MDSCs) is currently poorly understood. Very small size proteoliposomes (VSSP) are a nanoparticulated adjuvant under investigation in clinical trials in patients with renal carcinoma, breast cancer, prostate cancer, and cervical intraepithelial neoplasia grade III. We found that VSSP adjuvant induced a significant splenomegaly due to accumulation of CD11b(+)Gr-1(+) cells. However, VSSP-derived MDSCs showed a reduced capacity to suppress both allogeneic and Ag-specific CTL response compared with that of tumor-induced MDSCs. Moreover, splenic MDSCs isolated from tumor-bearing mice treated with VSSP were phenotypically more similar to those isolated from VSSP-treated tumor-free mice and much less suppressive than tumor-induced MDSCs, both in vitro and in vivo. Furthermore, different from dendritic cell vaccination, inoculation of VSSP-based vaccine in EG.7-OVA tumor-bearing mice was sufficient to avoid tumor-induced tolerance and stimulate an immune response against OVA Ag, similar to that observed in tumor-free mice. This effect correlated with an accelerated differentiation of MDSCs into mature APCs that was promoted by VSSP. VSSP used as a cancer vaccine adjuvant might thus improve antitumor efficacy not only by stimulating a potent immune response against tumor Ags but also by reducing tumor-induced immunosuppression.

  16. A novel role for an RCAN3-derived peptide as a tumor suppressor in breast cancer.

    PubMed

    Martínez-Høyer, Sergio; Solé-Sánchez, Sònia; Aguado, Fernando; Martínez-Martínez, Sara; Serrano-Candelas, Eva; Hernández, José Luis; Iglesias, Mar; Redondo, Juan Miguel; Casanovas, Oriol; Messeguer, Ramon; Pérez-Riba, Mercè

    2015-07-01

    The members of the human regulators of calcineurin (RCAN) protein family are endogenous regulators of the calcineurin (CN)-cytosolic nuclear factor of activated T-cells (NFATc) pathway activation. This function is explained by the presence of a highly conserved calcipressin inhibitor of calcineurin (CIC) motif in RCAN proteins, which has been shown to compete with NFATc for the binding to CN and therefore are able to inhibit NFATc dephosphorylation and activation by CN. Very recently, emerging roles for NFATc proteins in transformation, tumor angiogenesis and metastasis have been described in different cancer cell types. In this work, we report that the overexpression of RCAN3 dramatically inhibits tumor growth and tumor angiogenesis in an orthotopic human breast cancer model. We suggest that RCAN3 exerts these effects in a CN-dependent manner, as mutation of the CIC motif in RCAN3 abolishes the tumor suppressor effect. Moreover, the expression of the EGFP-R3(178-210) peptide, spanning the CIC motif of RCAN3, is able to reproduce all the antitumor effects of RCAN3 full-length protein. Finally, we show that RCAN3 and the EGFP-R3(178-210) peptide inhibit the CN-NFATc signaling pathway and the induction of the NFATc-dependent gene cyclooxygenase-2. Our work suggests that the EGFP-R3(178-210) peptide possess potent tumor suppressor properties and therefore constitutes a novel lead for the development of potent and specific antitumoral agents. Moreover, we propose the targeting of the CN-NFATc pathway in the tumor cells constitutes an effective way to hamper tumor progression by impairing the paracrine network among tumor, endothelial and polymorphonucleated cells. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  17. Tumor suppressor function of Betaig-H3 gene in radiation carcinogenesis

    NASA Astrophysics Data System (ADS)

    Zhao, Y. L.; Piao, C. Q.; Hei, T. K.

    Interaction between cell and extracellular matrix (ECM) plays a crucial role in tumor invasiveness and metastasis. Using an immortalized human bronchial epithelial (BEP2D) cell model, we showed previously that expression of a list of genes including Betaig-h3 (induced by transforming growth factor-β) DCC (deleted in colorectal cancer), p21 cip1, c-fos , Heat shock protein (HSP27) and cytokeratin 14 were differentially expressed in several independently generated, radiation-induced tumor cell lines (TL1-TL5) relative to parental BEP2D cells. Our previous data further demonstrated that loss of tumor suppressor gene(s) as a likely mechanism of radiation carcinogenesis. In the present study, we chose Betaig-h3 and DCC that were downregulated in tumorigenic cells for further study. Restored expression of Betaig-h3 gene, not DCC gene, by transfecting cDNA into tumor cells resulted in a significant reduction in tumor growth. While integrin receptor α5β1 was overexpressed in tumor cells, its expression was corrected to the level found in control BEP2D cells after Betaig-h3 transfection. These data suggest that Betaig-h3 gene is involved in tumor progression by regulating integrin α5β1 receptor. Furthermore, exogenous TGF-β1 induced expression of Betaig-h3 gene and inhibited the growth of both control and tumorigenic BEP2D cells. Therefore, downregulation of Betaig-h3 gene may results from the decreased expression of upstream mediators such as TGF-β. The findings provide strong evidence that the Betaig-h3 gene has tumor suppressor function in radiation-induced tumorigenic human bronchial epithelial cells and suggest a potential target for interventional therapy.

  18. Molecular chaperone Hsp27 regulates the Hippo tumor suppressor pathway in cancer

    PubMed Central

    Vahid, Sepideh; Thaper, Daksh; Gibson, Kate F.; Bishop, Jennifer L.; Zoubeidi, Amina

    2016-01-01

    Heat shock protein 27 (Hsp27) is a molecular chaperone highly expressed in aggressive cancers, where it is involved in numerous pro-tumorigenic signaling pathways. Using functional genomics we identified for the first time that Hsp27 regulates the gene signature of transcriptional co-activators YAP and TAZ, which are negatively regulated by the Hippo Tumor Suppressor pathway. The Hippo pathway inactivates YAP by phosphorylating and increasing its cytoplasmic retention with the 14.3.3 proteins. Gain and loss of function experiments in prostate, breast and lung cancer cells showed that Hsp27 knockdown induced YAP phosphorylation and cytoplasmic localization while overexpression of Hsp27 displayed opposite results. Mechanistically, Hsp27 regulates the Hippo pathway by accelerating the proteasomal degradation of ubiquitinated MST1, the core Hippo kinase, resulting in reduced phosphorylation/activity of LATS1 and MOB1, its downstream effectors. Importantly, our in vitro results were supported by data from human tumors; clinically, high expression of Hsp27 in prostate tumors is correlated with increased expression of YAP gene signature and reduced phosphorylation of YAP in lung and invasive breast cancer clinical samples. This study reveals for the first time a link between Hsp27 and the Hippo cascade, providing a novel mechanism of deregulation of this tumor suppressor pathway across multiple cancers. PMID:27555231

  19. Mitochondria, calcium, and tumor suppressor Fus1: At the crossroad of cancer, inflammation, and autoimmunity

    PubMed Central

    Uzhachenko, Roman; Shanker, Anil; Yarbrough, Wendell G.; Ivanova, Alla V.

    2015-01-01

    Mitochondria present a unique set of key intracellular functions such as ATP synthesis, production of reactive oxygen species (ROS) and Ca2+ buffering. Mitochondria both encode and decode Ca2+ signals and these interrelated functions have a direct impact on cell signaling and metabolism. High proliferative potential is a key energy-demanding feature shared by cancer cells and activated T lymphocytes. Switch of a metabolic state mediated by alterations in mitochondrial homeostasis plays a fundamental role in maintenance of the proliferative state. Recent studies show that tumor suppressors have the ability to affect mitochondrial homeostasis controlling both cancer and autoimmunity. Herein, we discuss established and putative mechanisms of calcium–dependent regulation of both T cell and tumor cell activities. We use the mitochondrial protein Fus1 as a case of tumor suppressor that controls immune response and tumor growth via maintenance of mitochondrial homeostasis. We focus on the regulation of mitochondrial Ca2+ handling as a key function of Fus1 and highlight the mechanisms of a crosstalk between Ca2+ accumulation and mitochondrial homeostasis. Given the important role of Ca2+ signaling, mitochondrial Ca2+ transport and ROS production in the activation of NFAT and NF-κB transcription factors, we outline the importance of Fus1 activities in this context. PMID:26246474

  20. MicroRNA-103 promotes colorectal cancer by targeting tumor suppressor DICER and PTEN.

    PubMed

    Geng, Li; Sun, Bing; Gao, Bo; Wang, Zheng; Quan, Cheng; Wei, Feng; Fang, Xue-Dong

    2014-05-13

    MicroRNAs (miRNAs) are a class of small, noncoding RNAs that act as key regulators in various physiological and pathological processes. However, the regulatory mechanisms for miRNAs in colorectal cancer remain largely unknown. Here, we found that miR-103 is up-regulated in colorectal cancer and its overexpression is closely associated with tumor proliferation and migration. In addition, repressing the expression of miR-103 apparently inhibits colorectal cancer cell proliferation and migration in vitro and HCT-116 xenograft tumor growth in vivo. Subsequent software analysis and dual-luciferase reporter assay identified two tumor suppressor genes DICER and PTEN as direct targets of miR-103, and up-regulation of DICER and PTEN obtained similar results to that occurred in the silencing of miR-103. In addition, restoration of DICER and PTEN can inhibit miR-103-induced colorectal cancer cell proliferation and migration. Our data collectively demonstrate that miR-103 is an oncogene miRNA that promotes colorectal cancer proliferation and migration through down-regulation of the tumor suppressor genes DICER and PTEN. Thus, miR-103 may represent a new potential diagnostic and therapeutic target for colorectal cancer treatment.

  1. The retinoblastoma gene functions as a growth and tumor suppressor in human bladder carcinoma cells

    SciTech Connect

    Takahashi, Rei; Hashimoto, Tomoko; Hongji Xu; Shixu Hu; Bigo-Marshall, H.; Benedict, W.F. ); Matsui, Toshimitsu Kobe Univ. School of Medicine ); Miki, Toru; Aaronson, S.A. )

    1991-06-15

    The product of the human retinoblastoma gene (RB) is a nuclear phosphoprotein that is thought to function as a tumor suppressor. Mutations of RB frequently occur in human bladder carcinoma. To investigate the significance of the functional loss of this gene in bladder cancer, an RB expression plasmid (pBARB) under control of the human {beta}-actin promoter was transfected into the bladder carcinoma cell line HTB9, which lacks RB expression. Marker-selected transfectants that expressed RB protein were identified by immunoblotting and immunohistochemical staining. In selected clones, stable RB expression has persisted over 1 yr under standard culture conditions with 10% serum. However, RB expression caused major alterations of HTB9 growth properties both in vitro and in vivo. RB{sup +} tranfectants lacked the ability to form colonies in semi-solid medium, and their growth rate was significantly decreased in 3% serum. In addition, the tumorigenicity of these transfectants was markedly decreased. Tumors that formed in nude mice were much smaller and had a longer latency period but were indistinguishable microscopically from those produced by parental cells. Slower growing tumors were RB{sup +}, as measured by nuclear staining of their RB protein and by a normal RB protein pattern on immunoblots. These findings support the concept that the RB gene acts as both a growth and tumor suppressor in bladder cancer cells.

  2. Connection between Tumor Suppressor BRCA1 and PTEN in Damaged DNA Repair.

    PubMed

    Minami, Akari; Nakanishi, Atsuko; Ogura, Yasunori; Kitagishi, Yasuko; Matsuda, Satoru

    2014-01-01

    Genomic instability finally induces cell death or apoptosis. The tumor suppressor, phosphatase and tensin homolog on chromosome 10 (PTEN), is a dual-specificity phosphatase, which has protein phosphatase activity and lipid phosphatase activity that antagonizes PI3K activity. Cells that lack PTEN have constitutively higher levels of PIP3 and activated downstream PI3K/AKT targets. BRCA1, a well-known breast cancer tumor suppressor, is to associate with breast cancer risk and genetic susceptibility. Many studies have demonstrated that PTEN, as well as BRCA1, plays a critical role in DNA damage responses. The BRCA1 functionally cooperates with PTEN and might be an essential blockage in the development of several tumors. Actually, the PTEN and BRCA1 genes are recognized as one of the most frequently deleted and/or mutated in many human cancers. The PI3K/AKT pathway is constitutively active in BRCA1-defective human cancer cells. Loss or decrease of these PTEN or BRCA1 function, by either mutation or reduced expression, has a role in various tumor developments. This review summarizes recent findings of the function of BRCA1 and PTEN involved in genomic stability and cancer cell signaling.

  3. Myoepithelial mRNA expression profiling reveals a common tumor-suppressor phenotype.

    PubMed

    Barsky, Sanford H

    2003-04-01

    A series of myoepithelial cell lines and xenografts derived from benign human myoepithelial tumors of diverse sources (salivary gland, breast, and lung) exhibit common mRNA expression profiles indicative of a tumor-suppressor phenotype. Previously established myoepithelial cell lines and xenografts (HMS-#; HMS-#X) were compared to nonmyoepithelial breast carcinoma cells (MDA-MB-231 and MDA-MB-468, and inflammatory breast carcinoma samples, IBCr, and IBCw), a normal mammary epithelial cell line (HMEC) and individual cases of human breast cancer (zcBT#T), and matched normal human breast tissues (zcBT#N) (overall samples = 22). The global gene expression profile (22,000 genes) of these individual samples was examined using Affymetrix Microarray Gene Chips and subsequently analyzed with both Affymetrix and DChip algorithms. The myoepithelial cell lines/xenografts were distinct and very different from the nonmyoepithelial breast carcinoma cells and the normal breast and breast tumor biopsies. Two hundred and seven specifically selected genes represented a subset of genes that distinguished (P < 0.05) all the myoepithelial cell lines/xenografts from all the other samples and which themselves exhibited hierarchical clustering. Further analysis of these genes revealed increased expression in genes belonging to the classes of extracellular matrix proteins, angiogenic inhibitors, and proteinase inhibitors and decreased expression belonging to the classes of angiogenic factors and proteinases. Developmental genes were also differentially expressed (either over or underexpressed). These studies confirm our previous impression that human myoepithelial cells express a distinct tumor-suppressor phenotype.

  4. Simultaneous loss of the DLC1 and PTEN tumor suppressors enhances breast cancer cell migration

    SciTech Connect

    Heering, Johanna; Erlmann, Patrik; Olayioye, Monilola A.

    2009-09-10

    The phosphatase and tensin homolog (PTEN) gene is a tumor suppressor frequently deleted or mutated in sporadic tumors of the breast, prostate, endometrium and brain. The protein acts as a dual specificity phosphatase for lipids and proteins. PTEN loss confers a growth advantage to cells, protects from apoptosis and favors cell migration. The deleted in liver cancer 1 (DLC1) gene has emerged as a novel tumor suppressor downregulated in a variety of tumor types including those of the breast. DLC1 contains a Rho GTPase activating domain that is involved in the inhibition of cell proliferation, migration and invasion. To investigate how simultaneous loss of PTEN and DLC1 contributes to cell transformation, we downregulated both proteins by RNA interference in the non-invasive MCF7 breast carcinoma cell line. Joint depletion of PTEN and DLC1 resulted in enhanced cell migration in wounding and chemotactic transwell assays. Interestingly, both proteins were found to colocalize at the plasma membrane and interacted physically in biochemical pulldowns and coimmunoprecipitations. We therefore postulate that the concerted local inactivation of signaling pathways downstream of PTEN and DLC1, respectively, is required for the tight control of cell migration.

  5. Aggregation and Prion-Like Properties of Misfolded Tumor Suppressors: Is Cancer a Prion Disease?

    PubMed

    Costa, Danielly C F; de Oliveira, Guilherme A P; Cino, Elio A; Soares, Iaci N; Rangel, Luciana P; Silva, Jerson L

    2016-10-03

    Prion diseases are disorders that share several characteristics that are typical of many neurodegenerative diseases. Recently, several studies have extended the prion concept to pathological aggregation in malignant tumors involving misfolded p53, a tumor-suppressor protein. The aggregation of p53 and its coaggregation with p53 family members, p63 and p73, have been shown. Certain p53 mutants exert a dominant-negative regulatory effect on wild-type (WT) p53. The basis for this dominant-negative effect is that amyloid-like mutant p53 converts WT p53 into an aggregated species, leading to a gain-of-function (GoF) phenotype and the loss of its tumor-suppressor function. Recently, it was shown that p53 aggregates can be internalized by cells and can coaggregate with endogenous p53, corroborating the prion-like properties of p53 aggregates. The prion-like behavior of oncogenic p53 mutants provides an explanation for its dominant-negative and GoF properties, including the high metastatic potential of cancer cells carrying p53 mutations. The inhibition of p53 aggregation appears to represent a promising target for therapeutic intervention in patients with malignant tumors.

  6. The PTPN14 Tumor Suppressor Is a Degradation Target of Human Papillomavirus E7.

    PubMed

    Szalmás, Anita; Tomaić, Vjekoslav; Basukala, Om; Massimi, Paola; Mittal, Suruchi; Kónya, József; Banks, Lawrence

    2017-04-01

    Activation of signaling pathways ensuring cell growth is essential for the proliferative competence of human papillomavirus (HPV)-infected cells. Tyrosine kinases and phosphatases are key regulators of cellular growth control pathways. A recently identified potential cellular target of HPV E7 is the cytoplasmic protein tyrosine phosphatase PTPN14, which is a potential tumor suppressor and is linked to the control of the Hippo and Wnt/beta-catenin signaling pathways. In this study, we show that the E7 proteins of both high-risk and low-risk mucosal HPV types can interact with PTPN14. This interaction is independent of retinoblastoma protein (pRb) and involves residues in the carboxy-terminal region of E7. We also show that high-risk E7 induces proteasome-mediated degradation of PTPN14 in cells derived from cervical tumors. This degradation appears to be independent of cullin-1 or cullin-2 but most likely involves the UBR4/p600 ubiquitin ligase. The degree to which E7 downregulates PTPN14 would suggest that this interaction is important for the viral life cycle and potentially also for the development of malignancy. In support of this we find that overexpression of PTPN14 decreases the ability of HPV-16 E7 to cooperate with activated EJ-ras in primary cell transformation assays.IMPORTANCE This study links HPV E7 to the deregulation of protein tyrosine phosphatase signaling pathways. PTPN14 is classified as a potential tumor suppressor protein, and here we show that it is very susceptible to HPV E7-induced proteasome-mediated degradation. Intriguingly, this appears to use a mechanism that is different from that employed by E7 to target pRb. Therefore, this study has important implications for our understanding of the molecular basis for E7 function and also sheds important light on the potential role of PTPN14 as a tumor suppressor. Copyright © 2017 American Society for Microbiology.

  7. p18Ink4cand p53 act as tumor suppressors in Cyclin D1-driven primitive neuroectodermal tumor

    PubMed Central

    Saab, Raya; Rodriguez-Galindo, Carlos; Matmati, Kelly; Rehg, Jerold E.; Baumer, Shannon H.; Khoury, Joseph D.; Billups, Catherine; Neale, Geoffrey; Helton, Kathleen J.; Skapek, Stephen X.

    2008-01-01

    The RB tumor suppressor pathway is likely important in primitive neuroectodermal tumors (PNET) of the brain. In fact, 10-15% of children born with RB mutations develop brain PNETs, commonly in the pineal gland. Cyclin D1, which in association with Cyclin-dependent kinases (Cdk) 4 and 6 phosphorylates and inactivates the RB protein, is expressed in 40% of sporadic medulloblastoma, a PNET of the cerebellum. To understand tumorigenic events cooperating with RB pathway disruption in brain PNET, we generated a transgenic mouse where Cyclin D1 was expressed in pineal cells. Cyclin D1 enhanced pinealocyte proliferation, causing pineal gland enlargement. However, proliferation ceased beyond 2 weeks of age with reversal of Cdk4-mediated Rb phosphorylation despite continued expression of the transgene, and the pineal cells showed heterochromatin foci suggestive of a senescent-like state. In the absence of the p53 tumor suppressor, cell proliferation continued, resulting in pineal PNET that limited mouse survival to ~ 4 months. Interestingly, the Cdk-inhibitor p18Ink4c was induced in the transgenic pineal glands independently of p53, and transgenic mice that lacked Ink4c developed invasive PNET, though at an older age than those lacking p53. Analogous to our mouse model, we found that children with heritable retinoblastoma often had asymptomatic pineal gland enlargement that only rarely progressed to PNET. Our finding that the Cdk4-inhibitor p18Ink4c is a tumor suppressor in Cyclin D1-driven PNET suggests that pharmacological interventions to inhibit Cdk4 activity may be a useful chemoprevention or therapeutic strategy in cancer driven by primary Rb pathway disruption. PMID:19147556

  8. ZBTB7A acts as a tumor suppressor through the transcriptional repression of glycolysis

    PubMed Central

    Liu, Xue-Song; Haines, Jenna E.; Mehanna, Elie K.; Genet, Matthew D.; Ben-Sahra, Issam; Asara, John M.; Manning, Brendan D.

    2014-01-01

    Elevated glycolysis is a common metabolic trait of cancer, but what drives such metabolic reprogramming remains incompletely clear. We report here a novel transcriptional repressor-mediated negative regulation of glycolysis. ZBTB7A, a member of the POK (POZ/BTB and Krüppel) transcription repressor family, directly binds to the promoter and represses the transcription of critical glycolytic genes, including GLUT3, PFKP, and PKM. Analysis of The Cancer Genome Atlas (TCGA) data sets reveals that the ZBTB7A locus is frequently deleted in many human tumors. Significantly, reduced ZBTB7A expression correlates with up-regulation of the glycolytic genes and poor survival in colon cancer patients. Remarkably, while ZBTB7A-deficient tumors progress exceedingly fast, they exhibit an unusually heightened sensitivity to glycolysis inhibition. Our study uncovers a novel tumor suppressor role of ZBTB7A in directly suppressing glycolysis. PMID:25184678

  9. ZBTB7A acts as a tumor suppressor through the transcriptional repression of glycolysis.

    PubMed

    Liu, Xue-Song; Haines, Jenna E; Mehanna, Elie K; Genet, Matthew D; Ben-Sahra, Issam; Asara, John M; Manning, Brendan D; Yuan, Zhi-Min

    2014-09-01

    Elevated glycolysis is a common metabolic trait of cancer, but what drives such metabolic reprogramming remains incompletely clear. We report here a novel transcriptional repressor-mediated negative regulation of glycolysis. ZBTB7A, a member of the POK (POZ/BTB and Krüppel) transcription repressor family, directly binds to the promoter and represses the transcription of critical glycolytic genes, including GLUT3, PFKP, and PKM. Analysis of The Cancer Genome Atlas (TCGA) data sets reveals that the ZBTB7A locus is frequently deleted in many human tumors. Significantly, reduced ZBTB7A expression correlates with up-regulation of the glycolytic genes and poor survival in colon cancer patients. Remarkably, while ZBTB7A-deficient tumors progress exceedingly fast, they exhibit an unusually heightened sensitivity to glycolysis inhibition. Our study uncovers a novel tumor suppressor role of ZBTB7A in directly suppressing glycolysis. © 2014 Liu et al.; Published by Cold Spring Harbor Laboratory Press.

  10. A CRISPR/Cas9 Functional Screen Identifies Rare Tumor Suppressors

    PubMed Central

    Katigbak, Alexandra; Cencic, Regina; Robert, Francis; Sénécha, Patrick; Scuoppo, Claudio; Pelletier, Jerry

    2016-01-01

    An enormous amount of tumor sequencing data has been generated through large scale sequencing efforts. The functional consequences of the majority of mutations identified by such projects remain an open, unexplored question. This problem is particularly complicated in the case of rare mutations where frequency of occurrence alone or prediction of functional consequences are insufficient to distinguish driver from passenger or bystander mutations. We combine genome editing technology with a powerful mouse cancer model to uncover previously unsuspected rare oncogenic mutations in Burkitt’s lymphoma. We identify two candidate tumor suppressors whose loss cooperate with MYC over-expression to accelerate lymphomagenesis. Our results highlight the utility of in vivo CRISPR/Cas9 screens combined with powerful mouse models to identify and validate rare oncogenic modifier events from tumor mutational data. PMID:27982060

  11. A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer.

    PubMed

    Mello, Stephano S; Valente, Liz J; Raj, Nitin; Seoane, Jose A; Flowers, Brittany M; McClendon, Jacob; Bieging-Rolett, Kathryn T; Lee, Jonghyeob; Ivanochko, Danton; Kozak, Margaret M; Chang, Daniel T; Longacre, Teri A; Koong, Albert C; Arrowsmith, Cheryl H; Kim, Seung K; Vogel, Hannes; Wood, Laura D; Hruban, Ralph H; Curtis, Christina; Attardi, Laura D

    2017-10-09

    The p53 transcription factor is a critical barrier to pancreatic cancer progression. To unravel mechanisms of p53-mediated tumor suppression, which have remained elusive, we analyzed pancreatic cancer development in mice expressing p53 transcriptional activation domain (TAD) mutants. Surprisingly, the p53(53,54) TAD2 mutant behaves as a "super-tumor suppressor," with an enhanced capacity to both suppress pancreatic cancer and transactivate select p53 target genes, including Ptpn14. Ptpn14 encodes a negative regulator of the Yap oncoprotein and is necessary and sufficient for pancreatic cancer suppression, like p53. We show that p53 deficiency promotes Yap signaling and that PTPN14 and TP53 mutations are mutually exclusive in human cancers. These studies uncover a p53-Ptpn14-Yap pathway that is integral to p53-mediated tumor suppression. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  12. γ-Catenin acts as a tumor suppressor through context-dependent mechanisms in colorectal cancer.

    PubMed

    Nagel, Jutta Maria; Lahm, Harald; Ofner, Andrea; Göke, Burkhard; Kolligs, Frank Thomas

    2017-07-06

    γ-Catenin is a protein closely related to β-catenin. While the overexpression of β-catenin has been linked with impaired prognosis and survival in various malignancies, both oncogenic and tumor suppressor functions have been described for γ-catenin. Thus, its role in cancer remains controversial. In this study, we examined the impact of γ-catenin expression on the malignant potential of colorectal cancer cells. γ-Catenin was knocked down by short interfering RNA in the γ-catenin-proficient DLD-1 cell line and stably overexpressed in the γ-catenin-deficient cell line RKO. The effects of these molecular manipulations on the malignant potential of the cell lines were tested in vitro and in vivo in a xenograft tumor model. γ-Catenin contributed to Wnt signaling independent of the cellular context. Unlike its sister molecule β-catenin, γ-catenin inhibited cellular invasion and anoikis in cells endogenously expressing γ-catenin. In line with this tumor suppressor function, its de novo expression in RKO cells inhibited proliferation via cell cycle arrest. In a xenograft tumor model, overexpression of γ-catenin starkly reduced tumor growth in vivo. This is the first report demonstrating a tumor-suppressive effect of γ-catenin in colorectal cancer both in vitro and in vivo. Detailed in vitro analysis revealed that effects of γ-catenin differ in γ-catenin proficient and deficient cells, indicating that its function in colorectal cancer is dependent on the cellular context. This finding adds to our understanding of γ-catenin and may have implications for future studies of catenin/Wnt targeted cancer therapies.

  13. Interleukin 6 supports the maintenance of p53 tumor suppressor gene promoter methylation.

    PubMed

    Hodge, David R; Peng, Benjamin; Cherry, James C; Hurt, Elaine M; Fox, Stephen D; Kelley, James A; Munroe, David J; Farrar, William L

    2005-06-01

    A strong association exists between states of chronic inflammation and cancer, and it is believed that mediators of inflammation may be responsible for this phenomenon. Interleukin 6 (IL-6) is an inflammatory cytokine known to play a role in the growth and survival of many types of tumors, yet the mechanisms employed by this pleomorphic cytokine to accomplish this feat are still poorly understood. Another important factor in tumor development seems to be the hypermethylation of CpG islands located within the promoter regions of tumor suppressor genes. This common epigenetic alteration enables tumor cells to reduce or inactivate the expression of important tumor suppressor and cell cycle regulatory genes. Here we show that in the IL-6-responsive human multiple myeloma cell line KAS 6/1, the promoter region of p53 is epigenetically modified by methyltransferases, resulting in decreased levels of expression. Furthermore, cells treated with IL-6 exhibit an increase in the expression of the DNA maintenance methylation enzyme, DNMT-1. The DNA methyltransferase inhibitor zebularine reverses the methylation of the p53 promoter, allowing the resumption of its expression. However, when zebularine is withdrawn from the cells, the reestablishment of the original CpG island methylation within the p53 promoter does not occur in the absence of IL-6, and cells which do not receive IL-6 eventually die, as p53 expression continues unchecked by remethylation. Interestingly, this loss of viability seems to involve not the withdrawal of cytokine, but the inability of the cell to resilence the promoter. Consistent with this model, when cells that express IL-6 in an autocrine fashion are subjected to identical treatment, p53 expression is reduced shortly after withdrawal of zebularine. Therefore, it seems IL-6 is capable of maintaining promoter methylation thus representing one of the possible mechanisms used by inflammatory mediators in the growth and survival of tumors.

  14. Tumor suppressor ARF regulates tissue microenvironment and tumor growth through modulation of macrophage polarization

    PubMed Central

    Jiménez-García, Lidia; Herranz, Sandra; Higueras, María Angeles

    2016-01-01

    Tumor microenvironment has been described to play a key role in tumor growth, progression, and metastasis. Macrophages are a major cellular constituent of the tumor stroma, and particularly tumor associated macrophages (TAMs or M2-like macrophages) exert important immunosuppressive activity and a pro-tumoral role within the tumor microenvironment. Alternative-reading frame (ARF) gene is widely inactivated in human cancer. We have previously demonstrated that ARF deficiency severely impairs inflammatory response establishing a new role for ARF in the regulation of innate immunity. On the basis of these observations, we hypothesized that ARF may also regulates tumor growth through recruitment and modulation of the macrophage phenotype in the tumor microenvironment. Xenograft assays of B16F10 melanoma cells into ARF-deficient mice resulted in increased tumor growth compared to those implanted in WT control mice. Tumors from ARF-deficient mice exhibited significantly increased number of TAMs as well as microvascular density. Transwell assays showed crosstalk between tumor cells and macrophages. On the one hand, ARF-deficient macrophages modulate migratory ability of the tumor cells. And on the other, tumor cells promote the skewing of ARF−/− macrophages toward a M2-type polarization. In conclusion, these results demonstrate that ARF deficiency facilitates the infiltration of macrophages into the tumor mass and favors their polarization towards a M2 phenotype, thus promoting tumor angiogenesis and tumor growth. This work provides novel information about the critical role of ARF in the modulation of tumor microenvironment. PMID:27572316

  15. Tumor suppressor ARF regulates tissue microenvironment and tumor growth through modulation of macrophage polarization.

    PubMed

    Jiménez-García, Lidia; Herranz, Sandra; Higueras, María Angeles; Luque, Alfonso; Hortelano, Sonsoles

    2016-10-11

    Tumor microenvironment has been described to play a key role in tumor growth, progression, and metastasis. Macrophages are a major cellular constituent of the tumor stroma, and particularly tumor associated macrophages (TAMs or M2-like macrophages) exert important immunosuppressive activity and a pro-tumoral role within the tumor microenvironment. Alternative-reading frame (ARF) gene is widely inactivated in human cancer. We have previously demonstrated that ARF deficiency severely impairs inflammatory response establishing a new role for ARF in the regulation of innate immunity. On the basis of these observations, we hypothesized that ARF may also regulates tumor growth through recruitment and modulation of the macrophage phenotype in the tumor microenvironment. Xenograft assays of B16F10 melanoma cells into ARF-deficient mice resulted in increased tumor growth compared to those implanted in WT control mice. Tumors from ARF-deficient mice exhibited significantly increased number of TAMs as well as microvascular density. Transwell assays showed crosstalk between tumor cells and macrophages. On the one hand, ARF-deficient macrophages modulate migratory ability of the tumor cells. And on the other, tumor cells promote the skewing of ARF-/- macrophages toward a M2-type polarization. In conclusion, these results demonstrate that ARF deficiency facilitates the infiltration of macrophages into the tumor mass and favors their polarization towards a M2 phenotype, thus promoting tumor angiogenesis and tumor growth. This work provides novel information about the critical role of ARF in the modulation of tumor microenvironment.

  16. Regulatory T cells as suppressors of anti-tumor immunity: Role of metabolism.

    PubMed

    De Rosa, Veronica; Di Rella, Francesca; Di Giacomo, Antonio; Matarese, Giuseppe

    2017-06-01

    Novel concepts in immunometabolism support the hypothesis that glucose consumption is also used to modulate anti-tumor immune responses, favoring growth and expansion of specific cellular subsets defined in the past as suppressor T cells and currently reborn as regulatory T (Treg) cells. During the 1920s, Otto Warburg and colleagues observed that tumors consumed high amounts of glucose compared to normal tissues, even in the presence of oxygen and completely functioning mitochondria. However, the role of the Warburg Effect is still not completely understood, particularly in the context of an ongoing anti-tumor immune response. Current experimental evidence suggests that tumor-derived metabolic restrictions can drive T cell hyporesponsiveness and immune tolerance. For example, several glycolytic enzymes, deregulated in cancer, contribute to tumor progression independently from their canonical metabolic activity. Indeed, they can control apoptosis, gene expression and activation of specific intracellular pathways, thus suggesting a direct link between metabolic switches and pro-tumorigenic transcriptional programs. Focus of this review is to define the specific metabolic pathways controlling Treg cell immunobiology in the context of anti-tumor immunity and tumor progression. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation

    PubMed Central

    Mauti, Laetitia A.; Le Bitoux, Marie-Aude; Baumer, Karine; Stehle, Jean-Christophe; Golshayan, Dela; Provero, Paolo; Stamenkovic, Ivan

    2011-01-01

    Metastasis depends on the ability of tumor cells to establish a relationship with the newly seeded tissue that is conducive to their survival and proliferation. However, the factors that render tissues permissive for metastatic tumor growth have yet to be fully elucidated. Breast tumors arising during pregnancy display early metastatic proclivity, raising the possibility that pregnancy may constitute a physiological condition of permissiveness for tumor dissemination. Here we have shown that during murine gestation, metastasis is enhanced regardless of tumor type, and that decreased NK cell activity is responsible for the observed increase in experimental metastasis. Gene expression changes in pregnant mouse lung and liver were shown to be similar to those detected in premetastatic sites and indicative of myeloid cell infiltration. Indeed, myeloid-derived suppressor cells (MDSCs) accumulated in pregnant mice and exerted an inhibitory effect on NK cell activity, providing a candidate mechanism for the enhanced metastatic tumor growth observed in gestant mice. Although the functions of MDSCs are not yet understood in the context of pregnancy, our observations suggest that they may represent a shared mechanism of immune suppression occurring during gestation and tumor growth. PMID:21646719

  18. Remodeling epigenetic modifications at tumor suppressor gene promoters with bovine oocyte extract.

    PubMed

    Wang, Zhenfei; Yue, Yongli; Han, Pengyong; Sa, Rula; Ren, Xiaolv; Wang, Jie; Bai, Haidong; Yu, Haiquan

    2013-09-01

    Epigenetic silencing of tumor suppressor genes by aberrant DNA methylation and histone modifications at their promoter regions plays an important role in the initiation and progression of cancer. The therapeutic effect of the widely used epigenetic drugs, including DNA methyltransferase inhibitors and histone deacetylase inhibitors, remains unsatisfactory. One important underlying factor in the ineffectiveness of these drugs is that their actions lack specificity. To investigate whether oocyte extract can be used for epigenetic re-programming of cancer cells, H460 human lung cancer cells were reversibly permeabilized and incubated with bovine oocyte extract. Bisulfite sequencing showed that bovine oocyte extract induced significant demethylation at hypermethylated promoter CpG islands of the tumor suppressor genes RUNX3 and CDH1; however, the DNA methylation levels of repetitive sequences were not affected. Chromatin immunoprecipitation showed that bovine oocyte extract significantly reduced transcriptionally repressive histone modifications and increased transcriptionally activating histone modifications at the promoter regions of RUNX3 and CDH1. Bovine oocyte extract reactivated the expression of RUNX3 and CDH1 at both the messenger RNA and the protein levels without up-regulating the transcription of pluripotency-associated genes. At the functional level, anchorage-independent proliferation, migration and invasion of H460 cells was strongly inhibited. These results demonstrate that bovine oocyte extract reactivates epigenetically silenced tumor suppressor genes by remodeling the epigenetic modifications at their promoter regions. Bovine oocyte extract may provide a useful tool for investigating epigenetic mechanisms in cancer and a valuable source for developing novel safe therapeutic approaches that target epigenetic alterations. Copyright © 2013 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  19. Isoform-specific interactions of the von Hippel-Lindau tumor suppressor protein

    PubMed Central

    Minervini, Giovanni; Mazzotta, Gabriella M.; Masiero, Alessandro; Sartori, Elena; Corrà, Samantha; Potenza, Emilio; Costa, Rodolfo; Tosatto, Silvio C. E.

    2015-01-01

    Deregulation of the von Hippel-Lindau tumor suppressor protein (pVHL) is considered one of the main causes for malignant renal clear-cell carcinoma (ccRCC) insurgence. In human, pVHL exists in two isoforms, pVHL19 and pVHL30 respectively, displaying comparable tumor suppressor abilities. Mutations of the p53 tumor suppressor gene have been also correlated with ccRCC insurgence and ineffectiveness of treatment. A recent proteomic analysis linked full length pVHL30 with p53 pathway regulation through complex formation with the p14ARF oncosuppressor. The alternatively spliced pVHL19, missing the first 53 residues, lacks this interaction and suggests an asymmetric function of the two pVHL isoforms. Here, we present an integrative bioinformatics and experimental characterization of the pVHL oncosuppressor isoforms. Predictions of the pVHL30 N-terminus three-dimensional structure suggest that it may exist as an ensemble of structured and disordered forms. The results were used to guide Yeast two hybrid experiments to highlight isoform-specific binding properties. We observed that the physical pVHL/p14ARF interaction is specifically mediated by the 53 residue long pVHL30 N-terminal region, suggesting that this N-terminus acts as a further pVHL interaction interface. Of note, we also observed that the shorter pVHL19 isoform shows an unexpected high tendency to form homodimers, suggesting an additional isoform-specific binding specialization. PMID:26211615

  20. MiRNA-34 intrinsically links p53 tumor suppressor and Wnt signaling.

    PubMed

    Cha, Yong Hoon; Kim, Nam Hee; Park, Changbum; Lee, Inhan; Kim, Hyun Sil; Yook, Jong In

    2012-04-01

    Though tumor suppressor p53 and the canonical Wnt cascade have been extensively studied for the last 30 years, due to their important physiological roles, the two signaling pathways have been largely considered independent. Recently, the miR-34 family was found to directly link p53 and Wnt, revealing the tight connection between loss of tumor suppressor function and activation of oncogenic signaling. These observations demonstrate that miR-34, known to be directly downstream of p53, targets a set of highly conserved sites in the UTR of Wnt and EMT genes, specifically WNT1, WNT3, LRP6, AXIN2, β-catenin, LEF1 and Snail, resulting in suppression of TCF/LEF transcriptional activity and the EMT program. The loss of p53 function increases Wnt activities and promotes the Snail-dependent EMT program at multiple levels in a miR-34/UTR-specific manner. The TCF/LEF transcriptional signature was closely associated with functionality of p53 and miR-34 in clinical samples, suggesting the pervasive impact of miR-34 loss on the oncogenic pathway in human cancer. Here, we review recent findings on ceRNA in light of novel data to elucidate the physiological relevance of the p53-miR-34-Wnt network, which encompasses sets of genes and directions of signaling. As loss of wt-p53 or hyperactivation of Wnt is critical in maintaining cancer stem cell properties and in establishing the metastatic program, these observations indicate a mechanism of miR-mediated quasi-sufficiency which connects tumor suppressor and oncogenic signaling pathways, supporting a continuum model of human cancer.

  1. Neuron-Specific Deletion of the Nf2 Tumor Suppressor Impairs Functional Nerve Regeneration

    PubMed Central

    Schulz, Alexander; Büttner, Robert; Toledo, Andrea; Baader, Stephan L.; von Maltzahn, Julia; Irintchev, Andrey; Bauer, Reinhard; Morrison, Helen

    2016-01-01

    In contrast to axons of the central nervous system (CNS), axons of the peripheral nervous system (PNS) show better, but still incomplete and often slow regeneration following injury. The tumor suppressor protein merlin, mutated in the hereditary tumor syndrome Neurofibromatosis type 2 (NF2), has recently been shown to have RhoA regulatory functions in PNS neurons—in addition to its well-characterized, growth-inhibitory activity in Schwann cells. Here we report that the conditional knockout of merlin in PNS neurons leads to impaired functional recovery of mice following sciatic nerve crush injury, in a gene-dosage dependent manner. Gross anatomical or electrophysiological alterations of sciatic nerves could not be detected. However, correlating with attenuated RhoA activation due to merlin deletion, ultrastructural analysis of nerve samples indicated enhanced sprouting of axons with reduced caliber size and increased myelination compared to wildtype animals. We conclude that deletion of the tumor suppressor merlin in the neuronal compartment of peripheral nerves results in compromised functional regeneration after injury. This mechanism could explain the clinical observation that NF2 patients suffer from higher incidences of slowly recovering facial nerve paralysis after vestibular schwannoma surgery. PMID:27467574

  2. The structure and function of NKAIN2-a candidate tumor suppressor

    PubMed Central

    Zhao, Shan-Chao; Zhou, Bo-Wei; Luo, Fei; Mao, Xueying; Lu, Yong-Jie

    2015-01-01

    The deletion of chromosomal region 6q was commonly found in several types of human cancers, although the tumor suppressor genes (TSGs) located within this genomic region are not well established. Our recent work detected recurrent chromosomal truncation at the Na+/K+ transporting ATPase interacting 2 (NKAIN2) gene in prostate cancer, which was also found to be truncated in leukemia and lymphoma, suggesting that NKAIN2 is potentially one of the TSGs located in the 6q commonly deleted region in human cancers. NKAIN2 gene consists of eight coding exons that span approximately 1 Mb of genomic DNA on chromosome 6q and there are four main splice variants. The function of this gene is not well investigated and the limited knowledge of this gene pointed to nervous system development. The chromosomal translocations in nervous development disorders usually lead to inactivation of this gene. In human tumors, both chromosomal deletion and translocation may also inactivate this gene and consequently contribute to tumorigenesis. Further genetic and cellular functional studies are required to establish its tumor suppressor role. PMID:26770299

  3. In vivo activation of the p53 tumor suppressor pathway by an engineered cyclotide

    PubMed Central

    Neamati, Nouri; Shekhtman, Alexander; Camarero, Julio A.

    2013-01-01

    The overexpression of Hdm2 and HdmX is a common mechanism used by many tumor cells to inactive the p53 tumor suppressor pathway promoting cell survival. Targeting Hdm2 and HdmX has emerged as a validated therapeutic strategy for treating cancers with wild-type p53. Small linear peptides mimicking the N-terminal fragment of p53 have been shown to be potent Hdm2/HdmX antagonists. The potential therapeutic use of these peptides, however, is limited by their poor stability and bioavailability. Here, we report the engineering of the cyclotide MCoTI-I to efficiently antagonize intracellular p53 degradation. The resulting cyclotide MCo-PMI was able to bind with low nanomolar affinity to both Hdm2 and HdmX, showed high stability in human serum and was cytotoxic to wild-type p53 cancer cell lines by activating the p53 tumor suppressor pathway both in vitro and in vivo. These features make the cyclotide MCoTI-I an optimal scaffold for targeting intracellular protein-protein interactions. PMID:23848581

  4. Dnmt3b is a haploinsufficient tumor suppressor gene in Myc-induced lymphomagenesis.

    PubMed

    Vasanthakumar, Aparna; Lepore, Janet B; Zegarek, Matthew H; Kocherginsky, Masha; Singh, Mahi; Davis, Elizabeth M; Link, Petra A; Anastasi, John; Le Beau, Michelle M; Karpf, Adam R; Godley, Lucy A

    2013-03-14

    The drivers of abnormal DNA methylation in human cancers include widespread aberrant splicing of the DNMT3B gene, producing abnormal transcripts that encode truncated proteins that may act as dominant negative isoforms. To test whether reduced Dnmt3b dosage can alter tumorigenesis, we bred Dnmt3b(+/-) mice to Eµ-Myc mice, a mouse model susceptible to B-cell lymphomas. Eµ-Myc/Dnmt3b(+/-) mice showed a dramatic acceleration of lymphomagenesis, greater even than that observed in Eµ-Myc mice that express a truncated DNMT3B isoform found in human tumors, DNMT3B7. This finding indicates that Dnmt3b can act as a haploinsufficient tumor suppressor gene. Although reduction in both Dnmt3b dosage and expression of DNMT3B7 within the Eµ-Myc system had similar effects on tumorigenesis and DNA hypermethylation, different molecular mechanisms appear to underlie these changes. This study offers insight into how de novo DNA methyltransferases function as tumor suppressors and the sensitivity of Myc-induced lymphomas to DNA methylation.

  5. The Regulation of Tumor Suppressor p63 by the Ubiquitin-Proteasome System

    PubMed Central

    Armstrong, Stephen R.; Wu, Hong; Wang, Benfan; Abuetabh, Yasser; Sergi, Consolato; Leng, Roger P.

    2016-01-01

    The protein p63 has been identified as a homolog of the tumor suppressor protein p53 and is capable of inducing apoptosis, cell cycle arrest, or senescence. p63 has at least six isoforms, which can be divided into two major groups: the TAp63 variants that contain the N-terminal transactivation domain and the ΔNp63 variants that lack the N-terminal transactivation domain. The TAp63 variants are generally considered to be tumor suppressors involved in activating apoptosis and suppressing metastasis. ΔNp63 variants cannot induce apoptosis but can act as dominant negative inhibitors to block the function of TAp53, TAp73, and TAp63. p63 is rarely mutated in human tumors and is predominately regulated at the post-translational level by phosphorylation and ubiquitination. This review focuses primarily on regulation of p63 by the ubiquitin E-3 ligase family of enzymes via ubiquitination and proteasome-mediated degradation, and introduces a new key regulator of the p63 protein. PMID:27929429

  6. PAX5 is a tumor suppressor in mouse mutagenesis models of acute lymphoblastic leukemia

    PubMed Central

    Dang, Jinjun; Wei, Lei; de Ridder, Jeroen; Su, Xiaoping; Rust, Alistair G.; Roberts, Kathryn G.; Payne-Turner, Debbie; Cheng, Jinjun; Ma, Jing; Qu, Chunxu; Wu, Gang; Song, Guangchun; Huether, Robert G.; Schulman, Brenda; Janke, Laura; Zhang, Jinghui; Downing, James R.; van der Weyden, Louise; Adams, David J.

    2015-01-01

    Alterations of genes encoding transcriptional regulators of lymphoid development are a hallmark of B-progenitor acute lymphoblastic leukemia (B-ALL) and most commonly involve PAX5, encoding the DNA-binding transcription factor paired-box 5. The majority of PAX5 alterations in ALL are heterozygous, and key PAX5 target genes are expressed in leukemic cells, suggesting that PAX5 may be a haploinsufficient tumor suppressor. To examine the role of PAX5 alterations in leukemogenesis, we performed mutagenesis screens of mice heterozygous for a loss-of-function Pax5 allele. Both chemical and retroviral mutagenesis resulted in a significantly increased penetrance and reduced latency of leukemia, with a shift to B-lymphoid lineage. Genomic profiling identified a high frequency of secondary genomic mutations, deletions, and retroviral insertions targeting B-lymphoid development, including Pax5, and additional genes and pathways mutated in ALL, including tumor suppressors, Ras, and Janus kinase-signal transducer and activator of transcription signaling. These results show that in contrast to simple Pax5 haploinsufficiency, multiple sequential alterations targeting lymphoid development are central to leukemogenesis and contribute to the arrest in lymphoid maturation characteristic of ALL. This cross-species analysis also validates the importance of concomitant alterations of multiple cellular growth, signaling, and tumor suppression pathways in the pathogenesis of B-ALL. PMID:25855603

  7. PARP6 acts as a tumor suppressor via downregulating Survivin expression in colorectal cancer

    PubMed Central

    Liu, Tian; Jin, Shengjian; Liu, Jing; Zuo, Xiaoxu; Mi, Sisi; Shao, Wenhuan; Ma, Xiaojuan; Tsunematsu, Takaaki; Ishimaru, Naozumi; Zeng, Sien; Tatsuka, Masaaki; Shimamoto, Fumio

    2016-01-01

    Poly (ADP-ribose) polymerases (PARPs) are enzymes that transfer ADP-ribose groups to target proteins and are involved in a variety of biological processes. PARP6 is a novel member, and our previous findings suggest that PARP6 may act as a tumor suppressor via suppressing cell cycle progression. However, it is still unclear that PARP6 function besides growth suppression in colorectal cancer (CRC). In this study, we examined tumor suppressive roles of PAPR6 in CRC cells both in vitro and in vivo. We found that PARP6 inhibited colony formation, invasion and migration as well as cell proliferation. Moreover, ectopic overexpression of PARP6 decreased Survivin expression, which acts as an oncogene and is involved in apoptosis and mitosis. We confirmed the inverse correlation between PARP6 and Survivin expression in CRC cases by immunohistochemistry. Importantly, CRC cases with downregulation of PARP6 and upregulation of Survivin showed poor prognosis. In summary, PARP6 acts as a tumor suppressor via downregulating Survivin expression in CRC. PARP6 can be a novel diagnostic and therapeutic target together with Survivin for CRC. PMID:26934315

  8. [HINT1--a novel tumor suppressor protein of the HIT superfamily].

    PubMed

    Ozga, Magdalena

    2010-01-01

    The histidine triad nucleotide binding protein1 (Hint1) belongs to the first branch of the HIT superfamily. Hint1 catalyses the process of hydrolysis of the P-N bond in AMP-lysine, AMP-alanine, AMP-NH2. The physiological role of this enzyme is still unclear. There is accumulating evidence that HINT1 is a novel tumor suppressor protein, albeit the mechanism of action of HINT1 in respect to tumor suppression is not fully understood. Recent findings have shown that Hint1 inhibits the activity of the transcription factors AP1, MITF and USF2, as well as influences the transcription process of some genes of Wnt/beta-catenin pathway. Thereby, it seems that Hint1 exerts its major cellular function as gene transcription regulator, and thus, this function provides its potential role as a tumor suppressor protein. The clinical relevance of impairments in the Hint1 expression with the respect to specific human cancers is still a matter of extensive studies.

  9. The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment

    PubMed Central

    Rolny, Charlotte; Capparuccia, Lorena; Casazza, Andrea; Mazzone, Massimiliano; Vallario, Antonella; Cignetti, Alessandro; Medico, Enzo; Carmeliet, Peter; Comoglio, Paolo M.; Tamagnone, Luca

    2008-01-01

    Semaphorins are a large family of evolutionarily conserved morphogenetic molecules originally identified for their repelling role in axonal guidance. Intriguingly, semaphorins have recently been implicated in cancer progression (Neufeld, G., T. Lange, A. Varshavsky, and O. Kessler. 2007. Adv. Exp. Med. Biol. 600:118–131). In particular, semaphorin 3B (SEMA3B) is considered a putative tumor suppressor, and yet we found that it is expressed at high levels in many invasive and metastatic human cancers. By investigating experimental tumor models, we confirmed that SEMA3B expression inhibited tumor growth, whereas metastatic dissemination was surprisingly increased. We found that SEMA3B induced the production of interleukin (IL) 8 by tumor cells by activating the p38–mitogen-activated protein kinase pathway in a neuropilin 1–dependent manner. Silencing the expression of endogenous SEMA3B in tumor cells impaired IL-8 transcription. The release of IL-8, in turn, induced the recruitment of tumor-associated macrophages and metastatic dissemination to the lung, which could be rescued by blocking IL-8 with neutralizing antibodies. In conclusion, we report that SEMA3B exerts unexpected functions in cancer progression by fostering a prometastatic environment through elevated IL-8 secretion and recruitment of macrophages coupled to the suppression of tumor growth. PMID:18458115

  10. The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment.

    PubMed

    Rolny, Charlotte; Capparuccia, Lorena; Casazza, Andrea; Mazzone, Massimiliano; Vallario, Antonella; Cignetti, Alessandro; Medico, Enzo; Carmeliet, Peter; Comoglio, Paolo M; Tamagnone, Luca

    2008-05-12

    Semaphorins are a large family of evolutionarily conserved morphogenetic molecules originally identified for their repelling role in axonal guidance. Intriguingly, semaphorins have recently been implicated in cancer progression (Neufeld, G., T. Lange, A. Varshavsky, and O. Kessler. 2007. Adv. Exp. Med. Biol. 600:118-131). In particular, semaphorin 3B (SEMA3B) is considered a putative tumor suppressor, and yet we found that it is expressed at high levels in many invasive and metastatic human cancers. By investigating experimental tumor models, we confirmed that SEMA3B expression inhibited tumor growth, whereas metastatic dissemination was surprisingly increased. We found that SEMA3B induced the production of interleukin (IL) 8 by tumor cells by activating the p38-mitogen-activated protein kinase pathway in a neuropilin 1-dependent manner. Silencing the expression of endogenous SEMA3B in tumor cells impaired IL-8 transcription. The release of IL-8, in turn, induced the recruitment of tumor-associated macrophages and metastatic dissemination to the lung, which could be rescued by blocking IL-8 with neutralizing antibodies. In conclusion, we report that SEMA3B exerts unexpected functions in cancer progression by fostering a prometastatic environment through elevated IL-8 secretion and recruitment of macrophages coupled to the suppression of tumor growth.

  11. Fibronectin is a hypoxia-independent target of the tumor suppressor VHL.

    PubMed

    Bluyssen, Hans A R; Lolkema, Martijn P J K; van Beest, Moniek; Boone, Michelle; Snijckers, Cristel M J T; Los, Maartje; Gebbink, Martijn F B G; Braam, Branko; Holstege, Frank C P; Giles, Rachel H; Voest, Emile E

    2004-01-02

    The von Hippel-Lindau (VHL) tumor suppressor gene regulates the extracellular matrix by controlling fibronectin deposition. To identify novel VHL target genes, we subjected mRNA from VHL-deficient RCC cells (786-0-pRC) and a transfectant re-expressing wildtype VHL (786-0-VHL) to differential expression profiling. Among the differentially expressed genes, we detected that fibronectin is upregulated in the presence of VHL, while it is not affected by hypoxia. Thus regulation of fibronectin deposition by VHL occurs at the transcriptional level, irrespective of oxygen levels.

  12. The tumor suppressor WW domain-containing oxidoreductase modulates cell metabolism.

    PubMed

    Abu-Remaileh, Muhannad; Aqeilan, Rami I

    2015-03-01

    The WW domain-containing oxidoreductase (WWOX) encodes a tumor suppressor that is frequently altered in cancer. WWOX binds several proteins and thus is postulated to be involved in a variety of cellular processes. Interestingly, Wwox-knockout mice develop normally in utero but succumb to hypoglycemia and other metabolic defects early in life resulting in their death by 3-4 weeks of age. Cumulative evidence has linked WWOX with cellular metabolism including steroid metabolism, high-density lipoprotein cholesterol (HDL-C) metabolism, bone metabolism and, more recently, glucose metabolism. In this review, we discuss these evolving functions for WWOX and how its deletion affects cellular metabolism and neoplastic progression.

  13. Hydroxylation-Dependent Interaction of Substrates to the Von Hippel-Lindau Tumor Suppressor Protein (VHL).

    PubMed

    Heir, Pardeep; Ohh, Michael

    2016-01-01

    Oxygen-dependent hydroxylation of critical proline residues, catalyzed by prolyl hydroxylase (PHD1-3) enzymes, is a crucial posttranslational modification (PTM) within the canonical hypoxia-inducible factor (HIF)-centric cellular oxygen-sensing pathway. Alteration of substrates in this way often leads to proteasomal degradation mediated by the von Hippel-Lindau Tumor Suppressor protein (VHL) containing E3-ubiquitin ligase complex known as ECV (Elongins B/C, CUL2, VHL). Here, we outline in vitro protocols to demonstrate the ability of VHL to bind to a prolyl-hydroxylated substrate.

  14. The role of ING tumor suppressors in UV stress response and melanoma progression.

    PubMed

    Li, Jun; Wang, Yemin; Wong, Ronald P C; Li, Gang

    2009-05-01

    The INhibitor of Growth (ING) genes were discovered during the past decade and identified as type II tumor suppressor genes. Previous studies demonstrated that ING family members participate in various cellular stress responses and thus play important roles in the pathogenesis of various types of cancers, including melanoma. Epidemiological studies showed that UV radiation is the primary etiological factor in melanoma development. Here we review the studies on the role of ING proteins in cellular responses to UV irradiation, melanoma cell motility, and melanoma progression.

  15. An in vivo screen identifies ependymoma oncogenes and tumor-suppressor genes.

    PubMed

    Mohankumar, Kumarasamypet M; Currle, David S; White, Elsie; Boulos, Nidal; Dapper, Jason; Eden, Christopher; Nimmervoll, Birgit; Thiruvenkatam, Radhika; Connelly, Michele; Kranenburg, Tanya A; Neale, Geoffrey; Olsen, Scott; Wang, Yong-Dong; Finkelstein, David; Wright, Karen; Gupta, Kirti; Ellison, David W; Thomas, Arzu Onar; Gilbertson, Richard J

    2015-08-01

    Cancers are characterized by non-random chromosome copy number alterations that presumably contain oncogenes and tumor-suppressor genes (TSGs). The affected loci are often large, making it difficult to pinpoint which genes are driving the cancer. Here we report a cross-species in vivo screen of 84 candidate oncogenes and 39 candidate TSGs, located within 28 recurrent chromosomal alterations in ependymoma. Through a series of mouse models, we validate eight new ependymoma oncogenes and ten new ependymoma TSGs that converge on a small number of cell functions, including vesicle trafficking, DNA modification and cholesterol biosynthesis, identifying these as potential new therapeutic targets.

  16. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected

    PubMed Central

    Marvel, Douglas; Gabrilovich, Dmitry I.

    2015-01-01

    Our understanding of the role of myeloid-derived suppressor cells (MDSCs) in cancer is becoming increasingly complex. In addition to their eponymous role in suppressing immune responses, they directly support tumor growth, differentiation, and metastasis in a number of ways that are only now beginning to be appreciated. It is because of this increasingly complex role that these cells may become an important factor in the treatment of human cancer. In this Review, we discuss the most pertinent and controversial issues of MDSC biology and their role in promoting cancer progression and highlight how these cells may be used in the clinic, both as prognostic factors and as therapeutic targets. PMID:26168215

  17. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected.

    PubMed

    Marvel, Douglas; Gabrilovich, Dmitry I

    2015-09-01

    Our understanding of the role of myeloid-derived suppressor cells (MDSCs) in cancer is becoming increasingly complex. In addition to their eponymous role in suppressing immune responses, they directly support tumor growth, differentiation, and metastasis in a number of ways that are only now beginning to be appreciated. It is because of this increasingly complex role that these cells may become an important factor in the treatment of human cancer. In this Review, we discuss the most pertinent and controversial issues of MDSC biology and their role in promoting cancer progression and highlight how these cells may be used in the clinic, both as prognostic factors and as therapeutic targets.

  18. Brush border Myosin Ia has tumor suppressor activity in the intestine

    PubMed Central

    Mazzolini, Rocco; Dopeso, Higinio; Mateo-Lozano, Silvia; Chang, Wakam; Rodrigues, Paulo; Bazzocco, Sarah; Alazzouzi, Hafid; Landolfi, Stefania; Hernández-Losa, Javier; Andretta, Elena; Alhopuro, Pia; Espín, Eloy; Armengol, Manel; Tabernero, Josep; Ramón y Cajal, Santiago; Kloor, Matthias; Gebert, Johannes; Mariadason, John M.; Schwartz, Simo; Aaltonen, Lauri A.; Mooseker, Mark S.; Arango, Diego

    2012-01-01

    The loss of the epithelial architecture and cell polarity/differentiation is known to be important during the tumorigenic process. Here we demonstrate that the brush border protein Myosin Ia (MYO1A) is important for polarization and differentiation of colon cancer cells and is frequently inactivated in colorectal tumors by genetic and epigenetic mechanisms. MYO1A frame-shift mutations were observed in 32% (37 of 116) of the colorectal tumors with microsatellite instability analyzed, and evidence of promoter methylation was observed in a significant proportion of colon cancer cell lines and primary colorectal tumors. The loss of polarization/differentiation resulting from MYO1A inactivation is associated with higher tumor growth in soft agar and in a xenograft model. In addition, the progression of genetically and carcinogen-initiated intestinal tumors was significantly accelerated in Myo1a knockout mice compared with Myo1a wild-type animals. Moreover, MYO1A tumor expression was found to be an independent prognostic factor for colorectal cancer patients. Patients with low MYO1A tumor protein levels had significantly shorter disease-free and overall survival compared with patients with high tumoral MYO1A (logrank test P = 0.004 and P = 0.009, respectively). The median time-to-disease recurrence in patients with low MYO1A was 1 y, compared with >9 y in the group of patients with high MYO1A. These results identify MYO1A as a unique tumor-suppressor gene in colorectal cancer and demonstrate that the loss of structural brush border proteins involved in cell polarity are important for tumor development. PMID:22307608

  19. NDRG2 is a candidate tumor-suppressor for oral squamous-cell carcinoma

    SciTech Connect

    Furuta, Hiroshi; Kondo, Yuudai; Nakahata, Shingo; Hamasaki, Makoto; Sakoda, Sumio; Morishita, Kazuhiro

    2010-01-22

    Oral cancer is one of the most common cancers worldwide, and squamous-cell carcinoma (OSCC) is the most common phenotype of oral cancer. Although patients with OSCC have poor survival rates and a high incidence of metastasis, the molecular mechanisms of OSCC development have not yet been elucidated. This study investigated whether N-myc downstream-regulated gene 2 (NDRG2) contributes to the carcinogenesis of OSCC, as NDRG2 is reported to be a candidate tumor-suppressor gene in a wide variety of cancers. The down-regulation of NDRG2 mRNA, which was dependent on promoter methylation, was seen in the majority of OSCC cases and in several cases of precancerous leukoplakia with dysplasia. Induction of NDRG2 expression in an HSC-3/OSCC cell line significantly inhibited cell proliferation and decreased colony formation ability on soft agar. The majority of OSCC cell lines showed an activation of PI3K/Akt signaling, and enforced expression of NDRG2 in HSC-3 cells decreased the level of phosphorylated Akt at Serine 473 (p-Akt). Immunohistochemical p-Akt staining was detected in 56.5% of the OSCC tumors, and 80.4% of the tumors were negative for NDRG2 staining. Moreover, positive p-Akt staining was inversely correlated with decreased NDRG2 expression in OSCC tumors with moderate to poor differentiation (p < 0.005). Therefore, NDRG2 is a candidate tumor-suppressor gene for OSCC development and probably contributes to the tumorigenesis of OSCC partly via the modulation of Akt signaling.

  20. Expression of the tumor suppressor genes NF2, 4.1B, and TSLC1 in canine meningiomas.

    PubMed

    Dickinson, P J; Surace, E I; Cambell, M; Higgins, R J; Leutenegger, C M; Bollen, A W; LeCouteur, R A; Gutmann, D H

    2009-09-01

    Meningiomas are common primary brain tumors in dogs; however, little is known about the molecular genetic mechanisms involved in their tumorigenesis. Several tumor suppressor genes have been implicated in meningioma pathogenesis in humans, including the neurofibromatosis 2 (NF2), protein 4.1B (4.1 B), and tumor suppressor in lung cancer-1 (TSLC1) genes. We investigated the expression of these tumor suppressor genes in a series of spontaneous canine meningiomas using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) (NF2; n = 25) and western blotting (NF2/merlin, 4.1B, TSLC1; n = 30). Decreased expression of 4.1B and TSLC1 expression on western blotting was seen in 6/30 (20%) and in 15/30 (50%) tumors, respectively, with 18/30 (60%) of meningiomas having decreased or absent expression of one or both proteins. NF2 gene expression assessed by western blotting and RT-PCR varied considerably between individual tumors. Complete loss of NF2 protein on western blotting was not seen, unlike 4.1B and TSLC1. Incidence of TSLC1 abnormalities was similar to that seen in human meningiomas, while perturbation of NF2 and 4.1B appeared to be less common than reported for human tumors. No association was observed between tumor grade, subtype, or location and tumor suppressor gene expression based on western blot or RT-PCR. These results suggest that loss of these tumor suppressor genes is a frequent occurrence in canine meningiomas and may be an early event in tumorigenesis in some cases. In addition, it is likely that other, as yet unidentified, genes play an important role in canine meningioma formation and growth.

  1. The tumor suppressor Rb critically regulates starvation-induced stress response in C. elegans.

    PubMed

    Cui, Mingxue; Cohen, Max L; Teng, Cindy; Han, Min

    2013-06-03

    How animals coordinate gene expression in response to starvation is an outstanding problem closely linked to aging, obesity, and cancer. Newly hatched Caenorhabditis elegans respond to food deprivation by halting development and promoting long-term survival (L1 diapause), thereby providing an excellent model for the study of starvation response. Through a genetic search, we have discovered that the tumor suppressor Rb critically promotes survival during L1 diapause and most likely does so by regulating the expression of genes in both insulin-IGF-1 signaling (IIS)-dependent and -independent pathways mainly in neurons and the intestine. Global gene expression analyses suggested that Rb maintains the "starvation-induced" transcriptome and represses the "refeeding-induced" transcriptome, including the repression of many pathogen-, toxin-, and oxidative-stress-inducible and metabolic genes, as well as the activation of many other stress-resistant genes, mitochondrial respiratory chain genes, and potential IIS receptor antagonists. Notably, the majority of genes dysregulated in starved L1 Rb(-) animals were not found to be dysregulated in fed conditions. Altogether, these findings identify Rb as a critical regulator of the starvation response and suggest a link between functions of tumor suppressors and starvation survival. These results may provide mechanistic insights into why cancer cells are often hypersensitive to starvation treatment.

  2. Tumor suppressor role of the CL2/DRO1/CCDC80 gene in thyroid carcinogenesis.

    PubMed

    Ferraro, Angelo; Schepis, Filippo; Leone, Vincenza; Federico, Antonella; Borbone, Eleonora; Pallante, Pierlorenzo; Berlingieri, Maria Teresa; Chiappetta, Gennaro; Monaco, Mario; Palmieri, Dario; Chiariotti, Lorenzo; Santoro, Massimo; Fusco, Alfredo

    2013-07-01

    Thyroid carcinoma is one of the most common malignancies of the endocrine system, and, despite the high frequency of oncogene activation in thyroid neoplastic lesions, the tumor suppressor genes involved in thyroid carcinogenesis remain unidentified. Our previous data implicated a link between the CL2/CCDC80 gene and thyroid cancer. The objective of the study was to examine the expression of the CL2/CCDC80 gene in human thyroid carcinomas in the attempt to determine whether it plays a role in thyroid carcinogenesis. We evaluated the expression of CL2/CCDC80 in a large number of thyroid neoplastic tissue samples differing in degree of malignancy. We also investigated the effects of its restoration in 2 human thyroid carcinoma cell lines characterized by very low levels of CL2/CCDC80 expression. CL2/CCDC80 expression was much lower in almost all the thyroid carcinomas analyzed than in normal thyroid tissues and was lowest in follicular variants of papillary carcinomas. Loss of heterozygosity partially accounted for CL2/CCDC80 down-regulation in thyroid carcinoma samples. Restoration of CL2/CCDC80 expression in the 2 human thyroid anaplastic carcinoma cell lines resulted in a higher susceptibility to apoptosis and suppression of the malignant phenotype. CL2/CCDC80 expression positively regulated the expression of E-cadherin, thereby halting cancer progression. These results indicate that CL2/CCDC80 is a putative tumor suppressor gene in thyroid carcinogenesis.

  3. LKB1 Tumor Suppressor: Therapeutic Opportunities Knock when LKB1 Is Inactivated

    PubMed Central

    Zhou, Wei; Zhang, Jun; Marcus, Adam I.

    2014-01-01

    LKB1 is commonly thought of as a tumor suppressor gene because its hereditary mutation is responsible for a cancer syndrome, and somatic inactivation of LKB1 is found in non-small cell lung cancer, melanoma, and cervical cancers. However, unlike other tumor suppressors whose main function is to either suppress cell proliferation or promote cell death, one of the functions of LKB1-regulated AMPK signaling is to suppress cell proliferation in order to promote cell survival under energetic stress conditions. This unique, pro-survival function of LKB1 has led to the discovery of reagents, such as phenformin, that specifically exploit the vulnerability of LKB1-null cells in their defect in sensing energetic stress. Such targeted agents represent a novel treatment strategy because they induce cell killing when LKB1 is absent. This review article summarizes various vulnerabilities of LKB1-mutant cells that have been reported in the literature and discusses the potential of using existing or developing novel reagents to target cancer cells with defective LKB1. PMID:25679014

  4. The LATS2 tumor suppressor inhibits SREBP and suppresses hepatic cholesterol accumulation.

    PubMed

    Aylon, Yael; Gershoni, Anat; Rotkopf, Ron; Biton, Inbal E; Porat, Ziv; Koh, Anna P; Sun, Xiaochen; Lee, Youngmin; Fiel, Maria-Isabel; Hoshida, Yujin; Friedman, Scott L; Johnson, Randy L; Oren, Moshe

    2016-04-01

    The Hippo signaling pathway is a major regulator of organ size. In the liver, Hippo pathway deregulation promotes hyperplasia and hepatocellular carcinoma primarily through hyperactivation of its downstream effector, YAP. The LATS2 tumor suppressor is a core member of the Hippo pathway. A screen for LATS2-interacting proteins in liver-derived cells identified the transcription factor SREBP2, master regulator of cholesterol homeostasis. LATS2 down-regulation caused SREBP activation and accumulation of excessive cholesterol. Likewise, mice harboring liver-specific Lats2 conditional knockout (Lats2-CKO) displayed constitutive SREBP activation and overexpressed SREBP target genes and developed spontaneous fatty liver disease. Interestingly, the impact of LATS2 depletion on SREBP-mediated transcription was clearly distinct from that of YAP overexpression. When challenged with excess dietary cholesterol, Lats2-CKO mice manifested more severe liver damage than wild-type mice. Surprisingly, apoptosis, inflammation, and fibrosis were actually attenuated relative to wild-type mice, in association with impaired p53 activation. Subsequently, Lats2-CKO mice failed to recover effectively from cholesterol-induced damage upon return to a normal diet. Additionally, decreased LATS2 mRNA in association with increased SREBP target gene expression was observed in a subset of human nonalcoholic fatty liver disease cases. Together, these findings further highlight the tight links between tumor suppressors and metabolic homeostasis.

  5. Tumor Suppressor Genes within Common Fragile Sites Are Active Players in the DNA Damage Response

    PubMed Central

    Hazan, Idit; Hofmann, Thomas G.; Aqeilan, Rami I.

    2016-01-01

    The role of common fragile sites (CFSs) in cancer remains controversial. Two main views dominate the discussion: one suggests that CFS loci are hotspots of genomic instability leading to inactivation of genes encoded within them, while the other view proposes that CFSs are functional units and that loss of the encoded genes confers selective pressure, leading to cancer development. The latter view is supported by emerging evidence showing that expression of a given CFS is associated with genome integrity and that inactivation of CFS-resident tumor suppressor genes leads to dysregulation of the DNA damage response (DDR) and increased genomic instability. These two viewpoints of CFS function are not mutually exclusive but rather coexist; when breaks at CFSs are not repaired accurately, this can lead to deletions by which cells acquire growth advantage because of loss of tumor suppressor activities. Here, we review recent advances linking some CFS gene products with the DDR, genomic instability, and carcinogenesis and discuss how their inactivation might represent a selective advantage for cancer cells. PMID:27977694

  6. Histone deacetylase 3 inhibits new tumor suppressor gene DTWD1 in gastric cancer

    PubMed Central

    Ma, Yanning; Yue, Yongfang; Pan, Min; Sun, Jie; Chu, Jue; Lin, Xiaoying; Xu, Wenxia; Feng, Lifeng; Chen, Yan; Chen, Dingwei; Shin, Vivian Y; Wang, Xian; Jin, Hongchuan

    2015-01-01

    Cancer epigenetics plays an important role in the pathogenesis of many cancers including gastric cancer. Histone deacetylases (HDACs) emerge as exciting therapeutic targets for cancer treatment and prevention. In this study, we identified DTWD1 as one of the 122 genes upregulated after treatment of trichostatin A (TSA) in two gastric cancer cell lines. Moreover, DTWD1 was downregulated in gastric cancer cell lines and primary gastric carcinoma tissues. It was further identified as the new target of p53. Then we revealed that HDAC3 downregulated DTWD1 by disrupting the interaction of p53 with DTWD1 promoter. Furthermore, DTWD1 functioned as a tumor suppressor by downregulating cyclin B1 expression to inhibit proliferation. In summary, as the new p53 target gene, DTWD1 was downregulated in gastric cancer by HDAC3 and acted as a novel tumor suppressor gene. Specific inhibitors of HDAC3 might be a new approach for gastric cancer treatment by activating DTWD1 expression. PMID:25973305

  7. Tumor Suppressor Genes within Common Fragile Sites Are Active Players in the DNA Damage Response.

    PubMed

    Hazan, Idit; Hofmann, Thomas G; Aqeilan, Rami I

    2016-12-01

    The role of common fragile sites (CFSs) in cancer remains controversial. Two main views dominate the discussion: one suggests that CFS loci are hotspots of genomic instability leading to inactivation of genes encoded within them, while the other view proposes that CFSs are functional units and that loss of the encoded genes confers selective pressure, leading to cancer development. The latter view is supported by emerging evidence showing that expression of a given CFS is associated with genome integrity and that inactivation of CFS-resident tumor suppressor genes leads to dysregulation of the DNA damage response (DDR) and increased genomic instability. These two viewpoints of CFS function are not mutually exclusive but rather coexist; when breaks at CFSs are not repaired accurately, this can lead to deletions by which cells acquire growth advantage because of loss of tumor suppressor activities. Here, we review recent advances linking some CFS gene products with the DDR, genomic instability, and carcinogenesis and discuss how their inactivation might represent a selective advantage for cancer cells.

  8. DNA methylation determines nucleosome occupancy in the 5'-CpG islands of tumor suppressor genes.

    PubMed

    Portela, A; Liz, J; Nogales, V; Setién, F; Villanueva, A; Esteller, M

    2013-11-21

    Promoter CpG island hypermethylation of tumor suppressor genes is an epigenetic hallmark of human cancer commonly associated with nucleosome occupancy and the transcriptional silencing of the neighboring gene. Nucleosomes can determine the underlying DNA methylation status. Herein, we show that the opposite is also true: DNA methylation can determine nucleosome positioning. Using a cancer model and digital nucleosome positioning techniques, we demonstrate that the induction of DNA hypomethylation events by genetic (DNMT1/DNMT3B deficient cells) or drug (a DNA demethylating agent) approaches is associated with the eviction of nucleosomes from previously hypermethylated CpG islands of tumor suppressor genes. Most importantly, the establishment of a stable cell line that restores DNMT1/DNMT3B deficiency shows that nucleosomes reoccupy their positions in de novo methylated CpG islands. Finally, we extend these results to the genomic level, combining a DNA methylation microarray and the nucleosome positioning technique. Using this global approach, we observe the dependency of nucleosome occupancy upon the DNA methylation status. Thus, our results suggest that there is a close association between hypermethylated CpG islands and the presence of nucleosomes, such that each of these epigenetic mechanisms can determine the recruitment of the other.

  9. Sprouty1 is a candidate tumor-suppressor gene in medullary thyroid carcinoma.

    PubMed

    Macià, A; Gallel, P; Vaquero, M; Gou-Fabregas, M; Santacana, M; Maliszewska, A; Robledo, M; Gardiner, J R; Basson, M A; Matias-Guiu, X; Encinas, M

    2012-08-30

    Medullary thyroid carcinoma (MTC) is a malignancy derived from the calcitonin-producing C-cells of the thyroid gland. Oncogenic mutations of the Ret proto-oncogene are found in all heritable forms of MTC and roughly one half of the sporadic cases. However, several lines of evidence argue for the existence of additional genetic lesions necessary for the development of MTC. Sprouty (Spry) family of genes is composed of four members in mammals (Spry1-4). Some Spry family members have been proposed as candidate tumor-suppressor genes in a variety of cancerous pathologies. In this work, we show that targeted deletion of Spry1 causes C-cell hyperplasia, a precancerous lesion preceding MTC, in young adult mice. Expression of Spry1 restrains proliferation of the MTC-derived cell line, TT. Finally, we found that the Spry1 promoter is frequently methylated in MTC and that Spry1 expression is consequently decreased. These findings identify Spry1 as a candidate tumor-suppressor gene in MTC.

  10. Regulation of ornithine decarboxylase gene expression by the Wilms' tumor suppressor WT1.

    PubMed Central

    Moshier, J A; Skunca, M; Wu, W; Boppana, S M; Rauscher, F J; Dosescu, J

    1996-01-01

    The importance of ornithine decarboxylase (ODC) to cell proliferation is underscored by the complex array of cell-specific mechanisms invoked to regulate its synthesis and activity. Misregulation of ODC has severe negative consequences on normal cell function, including the acquisition of tumorigenic growth properties by cells overexpressing ODC. We hypothesize that ODC gene expression is a candidate target for the anti-proliferative function of certain tumor suppressors. Here we show that the Wilms' tumor suppressor WT1 binds to multiple sites within the human ODC promoter, as determined by DNase I protection and methylation interference assays. The expression of WT1 in transfected HCT 116, NIH/3T3 and HepG2 cells represses activity of the ODC promoter controlling expression of a luciferase reporter gene. In contrast WT1 expression enhances ODC promoter activity in SV40-transfected HepG2 cells. Both the extent of modulation of ODC gene expression and the mediating WT1 binding elements are cell specific. Constructs expressing WT1 deletion mutants implicate two regions required for repressor function, as well as an intrinsic activation domain. Understanding the regulation of ODC gene expression by WT1 may provide valuable insights into the roles of both WT1 and ODC in development and tumorigenesis. PMID:8604351

  11. Tumor-suppressor Genes, Cell Cycle Regulatory Checkpoints, and the Skin

    PubMed Central

    Velez, Ana Maria Abreu; Howard, Michael S.

    2015-01-01

    The cell cycle (or cell-division cycle) is a series of events that take place in a cell, leading to its division and duplication. Cell division requires cell cycle checkpoints (CPs) that are used by the cell to both monitor and regulate the progress of the cell cycle. Tumor-suppressor genes (TSGs) or antioncogenes are genes that protect the cell from a single event or multiple events leading to cancer. When these genes mutate, the cell can progress to a cancerous state. We aimed to perform a narrative review, based on evaluation of the manuscripts published in MEDLINE-indexed journals using the Medical Subject Headings (MeSH) terms “tumor suppressor's genes,” “skin,” and “cell cycle regulatory checkpoints.” We aimed to review the current concepts regarding TSGs, CPs, and their association with selected cutaneous diseases. It is important to take into account that in some cell cycle disorders, multiple genetic abnormalities may occur simultaneously. These abnormalities may include intrachromosomal insertions, unbalanced division products, recombinations, reciprocal deletions, and/or duplication of the inserted segments or genes; thus, these presentations usually involve several genes. Due to their complexity, these disorders require specialized expertise for proper diagnosis, counseling, personal and family support, and genetic studies. Alterations in the TSGs or CP regulators may occur in many benign skin proliferative disorders, neoplastic processes, and genodermatoses. PMID:26110128

  12. The Retinoblastoma (RB) Tumor Suppressor: Pushing Back against Genome Instability on Multiple Fronts

    PubMed Central

    Johnson, David G.

    2017-01-01

    The retinoblastoma (RB) tumor suppressor is known as a master regulator of the cell cycle. RB is mutated or functionally inactivated in the majority of human cancers. This transcriptional regulator exerts its function in cell cycle control through its interaction with the E2F family of transcription factors and with chromatin remodelers and modifiers that contribute to the repression of genes important for cell cycle progression. Over the years, studies have shown that RB participates in multiple processes in addition to cell cycle control. Indeed, RB is known to interact with over 200 different proteins and likely exists in multiple complexes. RB, in some cases, acts through its interaction with E2F1, other members of the pocket protein family (p107 and p130), and/or chromatin remodelers and modifiers. RB is a tumor suppressor with important chromatin regulatory functions that affect genomic stability. These functions include the role of RB in DNA repair, telomere maintenance, chromosome condensation and cohesion, and silencing of repetitive regions. In this review we will discuss recent advances in RB biology related to RB, partner proteins, and their non-transcriptional functions fighting back against genomic instability. PMID:28812991

  13. Newcomers to the WW Domain-Mediated Network of the Hippo Tumor Suppressor Pathway.

    PubMed

    Sudol, Marius

    2010-11-01

    The Hippo tumor suppressor pathway regulates the size of organs by controlling 2 opposing processes: proliferation and apoptosis. The pathway was originally defined in Drosophila, but it is well conserved in mammals. One of the unique features of Hippo signaling is the unusually wide occurrence of WW domains and its cognate PPxY ligand motifs within components of this pathway. Recently, it was proposed that the prevalence of WW domain-mediated complexes in the Hippo signaling pathway should facilitate its molecular analysis and help in the identification of new components of the Hippo-centered network. Indeed, several new members of the Hippo pathway, which form functional complexes with WW domains of YAP and TAZ effectors, were recently described. We focus here on 2 families of such proteins, angiomotins and SMADs, plus 1 regulatory factor, WBP-2, which together shed new light on the rapidly expanding Hippo network. Since the Hippo pathway acts as a tumor suppressor pathway, the complexes described here, which assemble on WW domains of YAP and TAZ, represent potential targets of cancer therapy.

  14. NNK, a tobacco-specific carcinogen, inhibits the expression of lysyl oxidase, a tumor suppressor.

    PubMed

    Cheng, Guang; Li, Jianmin; Zheng, Maoguen; Zhao, Yinzhi; Zhou, Jing; Li, Wande

    2014-12-23

    A tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is believed to contribute to the cancer burden in cigarette smokers. To evaluate NNK effects on the expression of lysyl oxidase (LOX), a tumor suppressor, we examined this enzyme at various levels in NNK-treated rat fetal lung fibroblasts (RFL6). Exposure of cells to NNK reduced levels of steady-states LOX mRNA and new transcript synthesis. NNK inhibited all LOX protein species in a dose-dependent manner. Although 300 µM NNK markedly decreased the level in the 46 kDa preproenzyme, under same conditions, there was no detectable amounts of the 50 kDa proenzyme and the 32 kDa mature enzyme suggesting NNK perturbing the LOX protein processing to its mature form. Moreover, NNK also suppressed LOX activities in conditioned media of treated cells. At the promoter level, NNK enhanced methylation of CpG, but decreased acetylation of histone H3 at the core promoter region of the LOX gene. These results indicated that transcriptional and translational processes of LOX are major targets for NNK. Thus, inactivation of tumor suppressor gene LOX may play a critical role in NNK carcinogenesis.

  15. EBNA1 binding and epigenetic regulation of gastrokine tumor suppressor genes in gastric carcinoma cells.

    PubMed

    Lu, Fang; Tempera, Italo; Lee, Hyunna T; Dewispelaere, Karen; Lieberman, Paul M

    2014-01-24

    Epstein-Barr Virus (EBV) latently infects ~10% of gastric carcinomas (GC). Epstein-Barr Nuclear Antigen 1 (EBNA1) is expressed in EBV-associated GC, and can bind host DNA, where it may impact cellular gene regulation. Here, we show that EBNA1 binds directly to DNA upstream of the divergently transcribed GC-specific tumor suppressor genes gastrokine 1 (GKN1) and gastrokine 2 (GKN2). We use ChIP-Seq, ChIP-qPCR, and EMSA to demonstrate that EBNA1 binds directly to the GKN1 and GKN2 promoter locus. We generate AGS-EBV, and AGS-EBNA1 cell lines to study the effects of EBNA1 on GKN1 and GKN2 mRNA expression with or without 5' azacytidine treatment. We show that gastrokine genes are transcriptionally silenced by DNA methylation. We also show that latent EBV infection further reduces GKN1 and GKN2 expression in AGS gastric carcinoma cells, and that siRNA depletion of EBNA1 partially alleviates this repression. However, ectopic expression of EBNA1 slightly increased GKN1 and GKN2 basal mRNA levels, but reduced their responsiveness to demethylating agent. These findings demonstrate that EBNA1 binds to the divergent promoter of the GKN1 and GKN2 genes in GC cells, and suggest that EBNA1 contributes to the complex transcriptional and epigenetic deregulation of the GKN1 and GKN2 tumor suppressor genes in EBV positive GC.

  16. EZH2 Inhibition Blocks Multiple Myeloma Cell Growth through Upregulation of Epithelial Tumor Suppressor Genes.

    PubMed

    Hernando, Henar; Gelato, Kathy A; Lesche, Ralf; Beckmann, Georg; Koehr, Silke; Otto, Saskia; Steigemann, Patrick; Stresemann, Carlo

    2016-02-01

    Multiple myeloma is a plasma cell malignancy characterized by marked heterogeneous genomic instability including frequent genetic alterations in epigenetic enzymes. In particular, the histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2) is overexpressed in multiple myeloma. EZH2 is the catalytic component of the polycomb repressive complex 2 (PRC2), a master transcriptional regulator of differentiation. EZH2 catalyzes methylation of lysine 27 on histone H3 and its deregulation in cancer has been reported to contribute to silencing of tumor suppressor genes, resulting in a more undifferentiated state, and thereby contributing to the multiple myeloma phenotype. In this study, we propose the use of EZH2 inhibitors as a new therapeutic approach for the treatment of multiple myeloma. We demonstrate that EZH2 inhibition causes a global reduction of H3K27me3 in multiple myeloma cells, promoting reexpression of EZH2-repressed tumor suppressor genes in a subset of cell lines. As a result of this transcriptional activation, multiple myeloma cells treated with EZH2 inhibitors become more adherent and less proliferative compared with untreated cells. The antitumor efficacy of EZH2 inhibitors is also confirmed in vivo in a multiple myeloma xenograft model in mice. Together, our data suggest that EZH2 inhibition may provide a new therapy for multiple myeloma treatment and a promising addition to current treatment options. Mol Cancer Ther; 15(2); 287-98. ©2015 AACR.

  17. The LATS2 tumor suppressor inhibits SREBP and suppresses hepatic cholesterol accumulation

    PubMed Central

    Aylon, Yael; Gershoni, Anat; Rotkopf, Ron; Biton, Inbal E.; Porat, Ziv; Koh, Anna P.; Sun, Xiaochen; Lee, Youngmin; Fiel, Maria-Isabel; Hoshida, Yujin; Friedman, Scott L.; Johnson, Randy L.; Oren, Moshe

    2016-01-01

    The Hippo signaling pathway is a major regulator of organ size. In the liver, Hippo pathway deregulation promotes hyperplasia and hepatocellular carcinoma primarily through hyperactivation of its downstream effector, YAP. The LATS2 tumor suppressor is a core member of the Hippo pathway. A screen for LATS2-interacting proteins in liver-derived cells identified the transcription factor SREBP2, master regulator of cholesterol homeostasis. LATS2 down-regulation caused SREBP activation and accumulation of excessive cholesterol. Likewise, mice harboring liver-specific Lats2 conditional knockout (Lats2-CKO) displayed constitutive SREBP activation and overexpressed SREBP target genes and developed spontaneous fatty liver disease. Interestingly, the impact of LATS2 depletion on SREBP-mediated transcription was clearly distinct from that of YAP overexpression. When challenged with excess dietary cholesterol, Lats2-CKO mice manifested more severe liver damage than wild-type mice. Surprisingly, apoptosis, inflammation, and fibrosis were actually attenuated relative to wild-type mice, in association with impaired p53 activation. Subsequently, Lats2-CKO mice failed to recover effectively from cholesterol-induced damage upon return to a normal diet. Additionally, decreased LATS2 mRNA in association with increased SREBP target gene expression was observed in a subset of human nonalcoholic fatty liver disease cases. Together, these findings further highlight the tight links between tumor suppressors and metabolic homeostasis. PMID:27013235

  18. Tricyclic Guanidine Alkaloids from the Marine Sponge Acanthella cavernosa that Stabilize the Tumor Suppressor PDCD4

    PubMed Central

    Grkovic, Tanja; Blees, Johanna S.; Bayer, Magdalena M.; Colburn, Nancy H.; Thomas, Cheryl L.; Henrich, Curtis J.; Peach, Megan L.; McMahon, James B.; Schmid, Tobias; Gustafson, Kirk R.

    2014-01-01

    A cell-based high-throughput screen that assessed the cellular stability of a tumor suppressor protein PDCD4 (Programmed cell death 4) was used to identify a new guanidine-containing marine alkaloid mirabilin K (3), as well as the known compounds mirabilin G (1) and netamine M (2). The structures of these tricyclic guanidine alkaloids were established from extensive spectroscopic analyses. Compounds 1 and 2 inhibited cellular degradation of PDCD4 with EC50 values of 1.8 μg/mL and 2.8 μg/mL, respectively. Mirabilin G (1) and netamine M (2) are the first marine natural products reported to stabilize PDCD4 under tumor promoting conditions. PMID:25196934

  19. Tricyclic guanidine alkaloids from the marine sponge Acanthella cavernosa that stabilize the tumor suppressor PDCD4.

    PubMed

    Grkovic, Tanja; Blees, Johanna S; Bayer, Magdalena M; Colburn, Nancy H; Thomas, Cheryl L; Henrich, Curtis J; Peach, Megan L; McMahon, James B; Schmid, Tobias; Gustafson, Kirk R

    2014-08-21

    A cell-based high-throughput screen that assessed the cellular stability of a tumor suppressor protein PDCD4 (Programmed cell death 4) was used to identify a new guanidine-containing marine alkaloid mirabilin K (3), as well as the known compounds mirabilin G (1) and netamine M (2). The structures of these tricyclic guanidine alkaloids were established from extensive spectroscopic analyses. Compounds 1 and 2 inhibited cellular degradation of PDCD4 with EC50 values of 1.8 μg/mL and 2.8 μg/mL, respectively. Mirabilin G (1) and netamine M (2) are the first marine natural products reported to stabilize PDCD4 under tumor promoting conditions.

  20. Gastrokines: stomach-specific proteins with putative homeostatic and tumor suppressor roles.

    PubMed

    Menheniott, Trevelyan R; Kurklu, Bayzar; Giraud, Andrew S

    2013-01-15

    During the past decade, a new family of stomach-specific proteins has been recognized. Known as "gastrokines" (GKNs), these secreted proteins are products of gastric mucus-producing cell lineages. GKNs are highly conserved in physical structure, and emerging data point to convergent functions in the modulation of gastric mucosal homeostasis and inflammation. While GKNs are highly prevalent in the normal stomach, frequent loss of GKN expression in gastric cancers, coupled with established antiproliferative activity, suggests putative tumor suppressor roles. Conversely, ectopic expression of GKNs in reparative lesions of Crohn's disease alludes to additional activity in epithelial wound healing and/or repair. Modes of action remain unsolved, but the recent demonstration of a GKN2-trefoil factor 1 heterodimer implicates functional interplay with trefoil factors. This review aims to provide a historical account of GKN biology and encapsulate the rapidly accumulating evidence supporting roles in gastric epithelial homeostasis and tumor suppression.

  1. MicroRNA-106b regulates the tumor suppressor RUNX3 in laryngeal carcinoma cells.

    PubMed

    Xu, Ying; Wang, Kai; Gao, Wei; Zhang, Chunming; Huang, Fuhui; Wen, Shuxin; Wang, Binquan

    2013-10-01

    Our study focuses on a set of laryngeal tumors that show reduced RUNX3 expression in the absence of transcriptional silencing of tumor suppressor gene RUNX3 by aberrant methylation of CpG islands. We report that the loss of expression of RUNX3 correlates with up-regulation of miR-106b in human laryngeal carcinoma tissue. The downregulation of RUNX3 is mediated by miR-106b through binding of its 3'UTR. Moreover, miR-106b can promote the proliferation and invasion of laryngeal carcinoma cells by directly targeting RUNX3, and RUXN3 knockdown can abolish this phenotype. These results shed a new insight into the mechanism of miRNA regulation in laryngeal carcinoma.

  2. Functional conservation of the human EXT1 tumor suppressor gene and its Drosophila homolog tout velu.

    PubMed

    Dasgupta, Ujjaini; Dixit, Bharat L; Rusch, Melissa; Selleck, Scott; The, Inge

    2007-08-01

    Heparan sulfate proteoglycans play a vital role in signaling of various growth factors in both Drosophila and vertebrates. In Drosophila, mutations in the tout velu (ttv) gene, a homolog of the mammalian EXT1 tumor suppressor gene, leads to abrogation of glycosaminoglycan (GAG) biosynthesis. This impairs distribution and signaling activities of various morphogens such as Hedgehog (Hh), Wingless (Wg), and Decapentaplegic (Dpp). Mutations in members of the exostosin (EXT) gene family lead to hereditary multiple exostosis in humans leading to bone outgrowths and tumors. In this study, we provide genetic and biochemical evidence that the human EXT1 (hEXT1) gene is conserved through species and can functionally complement the ttv mutation in Drosophila. The hEXT1 gene was able to rescue a ttv null mutant to adulthood and restore GAG biosynthesis.

  3. Tumor suppressor gene E-cadherin and its role in normal and malignant cells

    PubMed Central

    Pećina-Šlaus, Nives

    2003-01-01

    E-cadherin tumor suppressor genes are particularly active area of research in development and tumorigenesis. The calcium-dependent interactions among E-cadherin molecules are critical for the formation and maintenance of adherent junctions in areas of epithelial cell-cell contact. Loss of E-cadherin-mediated-adhesion characterises the transition from benign lesions to invasive, metastatic cancer. Nevertheless, there is evidence that E-cadherins may also play a role in the wnt signal transduction pathway, together with other key molecules involved in it, such as beta-catenins and adenomatous poliposis coli gene products. The structure and function of E-cadherin, gene and protein, in normal as well as in tumor cells are reviewed in this paper. PMID:14613514

  4. The putative tumor suppressor gene EphA7 is a novel BMI-1 target

    PubMed Central

    Jagemann, Lucas; Nolbrant, Sara; Leefa, Isabelle V.; Offen, Nils; Miharada, Kenichi; Lang, Stefan; Artner, Isabella; Nuber, Ulrike A.

    2016-01-01

    Bmi1 was originally identified as a gene that contributes to the development of mouse lymphoma by inhibiting MYC-induced apoptosis through repression of Ink4a and Arf. It codes for the Polycomb group protein BMI-1 and acts primarily as a transcriptional repressor via chromatin modifications. Although it binds to a large number of genomic regions, the direct BMI-1 target genes described so far do not explain the full spectrum of BMI-1-mediated effects. Here we identify the putative tumor suppressor gene EphA7 as a novel direct BMI-1 target in neural cells and lymphocytes. EphA7 silencing has been reported in several different human tumor types including lymphomas, and our data suggest BMI1 overexpression as a novel mechanism leading to EphA7 inactivation via H3K27 trimethylation and DNA methylation. PMID:27533460

  5. NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome

    PubMed Central

    Hölzel, Michael; Huang, Sidong; Koster, Jan; Øra, Ingrid; Lakeman, Arjan; Caron, Huib; Nijkamp, Wouter; Xie, Jing; Callens, Tom; Asgharzadeh, Shahab; Seeger, Robert C.; Messiaen, Ludwine; Versteeg, Rogier; Bernards, René

    2010-01-01

    Summary Retinoic acid (RA) induces differentiation of neuroblastoma cells in vitro and is used with variable success to treat aggressive forms of this disease. This variability in clinical response to RA is enigmatic, as no mutations in components of the RA signaling cascade have been found. Using a large-scale RNAi genetic screen, we identify crosstalk between the tumor suppressor NF1 and retinoic acid induced differentiation in neuroblastoma. Loss of NF1 activates RAS-MEK signaling, which in turn represses ZNF423, a critical transcriptional co-activator of the retinoic acid receptors. Neuroblastomas with low levels of both NF1 and ZNF423 have extremely poor outcome. We find NF1 mutations in neuroblastoma cell lines and in primary tumors. Inhibition of MEK signaling downstream of NF1 restores responsiveness to RA, suggesting a therapeutic strategy to overcome RA resistance in NF1 deficient neuroblastomas. PMID:20655465

  6. Inhibition of pluripotency networks by the Rb tumor suppressor restricts reprogramming and tumorigenesis.

    PubMed

    Kareta, Michael S; Gorges, Laura L; Hafeez, Sana; Benayoun, Bérénice A; Marro, Samuele; Zmoos, Anne-Flore; Cecchini, Matthew J; Spacek, Damek; Batista, Luis F Z; O'Brien, Megan; Ng, Yi-Han; Ang, Cheen Euong; Vaka, Dedeepya; Artandi, Steven E; Dick, Frederick A; Brunet, Anne; Sage, Julien; Wernig, Marius

    2015-01-08

    Mutations in the retinoblastoma tumor suppressor gene Rb are involved in many forms of human cancer. In this study, we investigated the early consequences of inactivating Rb in the context of cellular reprogramming. We found that Rb inactivation promotes the reprogramming of differentiated cells to a pluripotent state. Unexpectedly, this effect is cell cycle independent, and instead reflects direct binding of Rb to pluripotency genes, including Sox2 and Oct4, which leads to a repressed chromatin state. More broadly, this regulation of pluripotency networks and Sox2 in particular is critical for the initiation of tumors upon loss of Rb in mice. These studies therefore identify Rb as a global transcriptional repressor of pluripotency networks, providing a molecular basis for previous reports about its involvement in cell fate pliability, and implicate misregulation of pluripotency factors such as Sox2 in tumorigenesis related to loss of Rb function.

  7. Genome-Wide CRISPR Screen Identifies Regulators of Mitogen-Activated Protein Kinase as Suppressors of Liver Tumors in Mice.

    PubMed

    Song, Chun-Qing; Li, Yingxiang; Mou, Haiwei; Moore, Jill; Park, Angela; Pomyen, Yotsawat; Hough, Soren; Kennedy, Zachary; Fischer, Andrew; Yin, Hao; Anderson, Daniel G; Conte, Darryl; Zender, Lars; Wang, Xin Wei; Thorgeirsson, Snorri; Weng, Zhiping; Xue, Wen

    2017-04-01

    It has been a challenge to identify liver tumor suppressors or oncogenes due to the genetic heterogeneity of these tumors. We performed a genome-wide screen to identify suppressors of liver tumor formation in mice, using CRISPR-mediated genome editing. We performed a genome-wide CRISPR/Cas9-based knockout screen of P53-null mouse embryonic liver progenitor cells that overexpressed MYC. We infected p53(-/-);Myc;Cas9 hepatocytes with the mGeCKOa lentiviral library of 67,000 single-guide RNAs (sgRNAs), targeting 20,611 mouse genes, and transplanted the transduced cells subcutaneously into nude mice. Within 1 month, all the mice that received the sgRNA library developed subcutaneous tumors. We performed high-throughput sequencing of tumor DNA and identified sgRNAs increased at least 8-fold compared to the initial cell pool. To validate the top 10 candidate tumor suppressors from this screen, we collected data from patients with hepatocellular carcinoma (HCC) using the Cancer Genome Atlas and COSMIC databases. We used CRISPR to inactivate candidate tumor suppressor genes in p53(-/-);Myc;Cas9 cells and transplanted them subcutaneously into nude mice; tumor formation was monitored and tumors were analyzed by histology and immunohistochemistry. Mice with liver-specific disruption of p53 were given hydrodynamic tail-vein injections of plasmids encoding Myc and sgRNA/Cas9 designed to disrupt candidate tumor suppressors; growth of tumors and metastases was monitored. We compared gene expression profiles of liver cells with vs without tumor suppressor gene disrupted by sgRNA/Cas9. Genes found to be up-regulated after tumor suppressor loss were examined in liver cancer cell lines; their expression was knocked down using small hairpin RNAs, and tumor growth was examined in nude mice. Effects of the MEK inhibitors AZD6244, U0126, and trametinib, or the multi-kinase inhibitor sorafenib, were examined in human and mouse HCC cell lines. We identified 4 candidate liver tumor

  8. mTOR masters monocytic myeloid-derived suppressor cells in mice with allografts or tumors

    PubMed Central

    Wu, Tingting; Zhao, Yang; Wang, Hao; Li, yang; Shao, Lijuan; Wang, Ruoyu; Lu, Jun; Yang, Zhongzhou; Wang, Junjie; Zhao, Yong

    2016-01-01

    CD11b+ Gr1+ myeloid-derived suppressor cells (MDSCs) play critical roles in controlling the processes of tumors, infections, autoimmunity and graft rejection. Immunosuppressive drug rapamycin (RPM), targeting on the key cellular metabolism molecule mTOR, is currently used in clinics to treat patients with allo-grafts, autoimmune diseases and tumors. However, the effect of RPM on MDSCs has not been studied. RPM significantly decreases the cell number and the immunosuppressive ability on T cells of CD11b+ Ly6Chigh monocytic MDSCs (M-MDSCs) in both allo-grafts-transplanted and tumor-bearing mice respectively. Mice with a myeloid-specific deletion of mTOR have poor M-MDSCs after grafting with allo-skin tissue or a tumor. Grafting of allo-skin or tumors significantly activates glycolysis pathways in myeloid precursor cells in bone marrow, which is inhibited by RPM or mTOR deletion. 2-deoxyglucose (2-DG), an inhibitor of the glycolytic pathway, inhibits M-MDSC differentiation from precursors, while enhancing glycolysis by metformin significantly rescues the RPM-caused deficiency of M-MDSCs. Therefore, we offer evidence supporting that mTOR is an intrinsic factor essential for the differentiation and immunosuppressive function of M-MDSCs and that these metabolism-relevant medicines may impact MDSCs-mediated immunosuppression or immune tolerance induction, which is of considerable clinical importance in treating graft rejection, autoimmune diseases and cancers. PMID:26833095

  9. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma.

    PubMed Central

    Herman, J G; Latif, F; Weng, Y; Lerman, M I; Zbar, B; Liu, S; Samid, D; Duan, D S; Gnarra, J R; Linehan, W M

    1994-01-01

    Mutational inactivation and allelic loss of the von Hippel-Lindau (VHL) gene appear to be causal events for the majority of spontaneous clear-cell renal carcinomas. We now show that hypermethylation of a normally unmethylated CpG island in the 5' region provides another potentially important mechanism for inactivation of the VHL gene in a significant portion of these cancers. This hypermethylation was found in 5 of 26 (19%) tumors examined. Four of these had lost one copy of VHL while one retained two heavily methylated alleles. Four of the tumors with VHL hypermethylation had no detectable mutations, whereas one had a missense mutation in addition to hypermethylation of the single retained allele. As would be predicted for the consequence of methylation in this 5' CpG island, none of the 5 tumors expressed the VHL gene. In contrast, normal kidney and all tumors examined with inactivating VHL gene mutations but no CpG island methylation had expression. In a renal cell culture line, treatment with 5-aza-2'-deoxycytidine resulted in reexpression of the VHL gene. These findings suggest that aberrant methylation of CpG islands may participate in the tumor-suppressor gene inactivations which initiate or cause progression of common human cancers. Images PMID:7937876

  10. An identity crisis for fps/fes: oncogene or tumor suppressor?

    PubMed

    Sangrar, Waheed; Zirgnibl, Ralph A; Gao, Yan; Muller, William J; Jia, Zongchao; Greer, Peter A

    2005-05-01

    Fps/Fes proteins were among the first members of the protein tyrosine kinase family to be characterized as dominant-acting oncoproteins. Addition of retroviral GAG sequences or other experimentally induced mutations activated the latent transforming potential of Fps/Fes. However, activating mutations in fps/fes had not been found in human tumors until recently, when mutational analysis of a panel of colorectal cancers identified four somatic mutations in sequences encoding the Fps/Fes kinase domain. Here, we report biochemical and theoretical structural analysis demonstrating that three of these mutations result in inactivation, not activation, of Fps/Fes, whereas the fourth mutation compromised in vivo activity. These results did not concur with a classic dominant-acting oncogenic role for fps/fes involving activating somatic mutations but instead raised the possibility that inactivating fps/fes mutations might promote tumor progression in vivo. Consistent with this, we observed that tumor onset in a mouse model of breast epithelial cancer occurred earlier in mice targeted with either null or kinase-inactivating fps/fes mutations. Furthermore, a fps/fes transgene restored normal tumor onset kinetics in targeted fps/fes null mice. These data suggest a novel and unexpected tumor suppressor role for Fps/Fes in epithelial cells.

  11. Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers.

    PubMed

    Olsen, Sarah Naomi; Wronski, Ania; Castaño, Zafira; Dake, Benjamin; Malone, Clare; De Raedt, Thomas; Enos, Miriam; DeRose, Yoko S; Zhou, Wenhui; Guerra, Stephanie; Loda, Massimo; Welm, Alana; Partridge, Ann H; McAllister, Sandra S; Kuperwasser, Charlotte; Cichowski, Karen

    2017-02-01

    Luminal breast cancers are typically estrogen receptor-positive and generally have the best prognosis. However, a subset of luminal tumors, namely luminal B cancers, frequently metastasize and recur. Unfortunately, the causal events that drive their progression are unknown, and therefore it is difficult to identify individuals who are likely to relapse and should receive escalated treatment. Here, we identify a bifunctional RasGAP tumor suppressor whose expression is lost in almost 50% of luminal B tumors. Moreover, we show that two RasGAP genes are concomitantly suppressed in the most aggressive luminal malignancies. Importantly, these genes cooperatively regulate two major oncogenic pathways, RAS and NF-κB, through distinct domains, and when inactivated drive the metastasis of luminal tumors in vivo Finally, although the cooperative effects on RAS drive invasion, NF-κB activation triggers epithelial-to-mesenchymal transition and is required for metastasis. Collectively, these studies reveal important mechanistic insight into the pathogenesis of luminal B tumors and provide functionally relevant prognostic biomarkers that may guide treatment decisions.

  12. Rnd3 in Cancer: A Review of the Evidence for Tumor Promoter or Suppressor.

    PubMed

    Paysan, Lisa; Piquet, Léo; Saltel, Frédéric; Moreau, Violaine

    2016-11-01

    Rho-GTPases are members of the Ras superfamily of small GTPases and are general modulators of important cellular processes in tumor biology such as migration and proliferation. Among these proteins, Rnd3/RhoE, an atypical Rho-GTPase devoid of GTP hydrolytic activity, has recently been studied for its putative role in tumorigenesis. Indeed, Rnd3 is implicated in processes, such as proliferation and migration, whose deregulation is linked to cancer development and metastasis. The aim of this review is to provide an overview of the data surrounding Rnd3 deregulation in cancers, its origin, and consequences. Presented here is a comprehensive account of the expression status and biological output obtained in prostate, liver, stomach, colon, lung, and brain cancers as well as in melanoma and squamous cell carcinoma. Although there appears to be no general consensus about Rnd3 expression in cancers as this protein is differently altered according to the tumor context, these alterations overwhelmingly favor a protumorigenic role. Thus, depending on the tumor type, it may behave either as a tumor suppressor or as a tumor promoter. Importantly, the deregulation of Rnd3, in most cases, is linked to patient poor outcome.

  13. The p53 tumor suppressor protein protects against chemotherapeutic stress and apoptosis in human medulloblastoma cells

    PubMed Central

    Parasido, Erika; Tricoli, Lucas; Sivakumar, Angiela; Mikhaiel, John P.; Yenugonda, Venkata; Rodriguez, Olga C.; Karam, Sana D.; Rood, Brian R.; Avantaggiati, Maria Laura; Albanese, Chris

    2015-01-01

    Medulloblastoma (MB), a primitive neuroectodermal tumor, is the most common malignant childhood brain tumor and remains incurable in about a third of patients. Currently, survivors carry a significant burden of late treatment effects. The p53 tumor suppressor protein plays a crucial role in influencing cell survival in response to cellular stress and while the p53 pathway is considered a key determinant of anti-tumor responses in many tumors, its role in cell survival in MB is much less well defined. Herein, we report that the experimental drug VMY-1-103 acts through induction of a partial DNA damage-like response as well induction of non-survival autophagy. Surprisingly, the genetic or chemical silencing of p53 significantly enhanced the cytotoxic effects of both VMY and the DNA damaging drug, doxorubicin. The inhibition of p53 in the presence of VMY revealed increased late stage apoptosis, increased DNA fragmentation and increased expression of genes involved in apoptosis, including CAPN12 and TRPM8, p63, p73, BIK, EndoG, CIDEB, P27Kip1 and P21cip1. These data provide the groundwork for additional studies on VMY as a therapeutic drug and support further investigations into the intriguing possibility that targeting p53 function may be an effective means of enhancing clinical outcomes in MB. PMID:26540407

  14. mTOR masters monocytic myeloid-derived suppressor cells in mice with allografts or tumors.

    PubMed

    Wu, Tingting; Zhao, Yang; Wang, Hao; Li, Yang; Shao, Lijuan; Wang, Ruoyu; Lu, Jun; Yang, Zhongzhou; Wang, Junjie; Zhao, Yong

    2016-02-01

    CD11b(+) Gr1(+) myeloid-derived suppressor cells (MDSCs) play critical roles in controlling the processes of tumors, infections, autoimmunity and graft rejection. Immunosuppressive drug rapamycin (RPM), targeting on the key cellular metabolism molecule mTOR, is currently used in clinics to treat patients with allo-grafts, autoimmune diseases and tumors. However, the effect of RPM on MDSCs has not been studied. RPM significantly decreases the cell number and the immunosuppressive ability on T cells of CD11b(+) Ly6C(high) monocytic MDSCs (M-MDSCs) in both allo-grafts-transplanted and tumor-bearing mice respectively. Mice with a myeloid-specific deletion of mTOR have poor M-MDSCs after grafting with allo-skin tissue or a tumor. Grafting of allo-skin or tumors significantly activates glycolysis pathways in myeloid precursor cells in bone marrow, which is inhibited by RPM or mTOR deletion. 2-deoxyglucose (2-DG), an inhibitor of the glycolytic pathway, inhibits M-MDSC differentiation from precursors, while enhancing glycolysis by metformin significantly rescues the RPM-caused deficiency of M-MDSCs. Therefore, we offer evidence supporting that mTOR is an intrinsic factor essential for the differentiation and immunosuppressive function of M-MDSCs and that these metabolism-relevant medicines may impact MDSCs-mediated immunosuppression or immune tolerance induction, which is of considerable clinical importance in treating graft rejection, autoimmune diseases and cancers.

  15. Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages.

    PubMed

    Ugel, Stefano; De Sanctis, Francesco; Mandruzzato, Susanna; Bronte, Vincenzo

    2015-09-01

    The generation of an inflammatory environment is favorable and often decisive for the growth of both primary tumors and metastases. Tumor cells either express membrane molecules or release tumor-derived soluble factors able to alter myelopoiesis. Tumor-reprogrammed myeloid cells not only create a tolerogenic environment by blocking T cell functions and proliferation, but also directly drive tumor growth by promoting cancer stemness, angiogenesis, stroma deposition, epithelial-to-mesenchymal transition, and metastasis formation. In this Review, we discuss the interplay between immunosuppressive and protumoral myeloid cells and detail their immune-regulatory mechanisms, the molecular pathways involved in their differentiation, as well as their potential role as prognostic and diagnostic biomarkers and prospective targets for innovative approaches to treat tumor-bearing hosts.

  16. Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages

    PubMed Central

    Ugel, Stefano; De Sanctis, Francesco; Mandruzzato, Susanna; Bronte, Vincenzo

    2015-01-01

    The generation of an inflammatory environment is favorable and often decisive for the growth of both primary tumors and metastases. Tumor cells either express membrane molecules or release tumor-derived soluble factors able to alter myelopoiesis. Tumor-reprogrammed myeloid cells not only create a tolerogenic environment by blocking T cell functions and proliferation, but also directly drive tumor growth by promoting cancer stemness, angiogenesis, stroma deposition, epithelial-to-mesenchymal transition, and metastasis formation. In this Review, we discuss the interplay between immunosuppressive and protumoral myeloid cells and detail their immune-regulatory mechanisms, the molecular pathways involved in their differentiation, as well as their potential role as prognostic and diagnostic biomarkers and prospective targets for innovative approaches to treat tumor-bearing hosts. PMID:26325033

  17. Compositional features are potentially involved in the regulation of gene expression of tumor suppressor genes in human tissues.

    PubMed

    Hajjari, Mohammadreza; Khoshnevisan, Atefeh; Behmanesh, Mehrdad

    2014-12-15

    Different mechanisms regulate the expression level of tissue specific genes in human. Here we report some compositional features such as codon usage bias, amino acid usage bias, codon frequency, and base composition which may be potentially related to mRNA amount of tissue specific tumor suppressor genes. Our findings support the possibility that structural elements in gene and protein may play an important role in the regulation of tumor suppressor genes, development, and tumorigenesis. The data presented here can open broad vistas in the understanding and treatment of a variety of human malignancies.

  18. Circulating and Tumor-Infiltrating Myeloid-Derived Suppressor Cells in Patients with Colorectal Carcinoma

    PubMed Central

    Wu, Liangliang; Zhang, Meng; Li, Wei; Ding, Jianhua; Zhu, Jun; Wei, Huafeng; Zhao, Ke

    2013-01-01

    Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of myeloid cells that suppress T cell immunity in tumor-bearing hosts. In patients with colon cancer, MDSCs have recently been described as Lin−/lowHLA-DR−CD11b+CD33+ cells correlating with cancer stage, metastasis and chemotherapy response. To learn in more detail the dynamic change and clinical relevance of circulating and tumor-infiltrating Lin−/lowHLA-DR−CD11b+CD33+ MDSC in colorectal cancer, we harvested the blood from 64 patients with varying stage of colorectal cancer and tumor and matched paraneoplastic tissues from 5 patients with advanced colorectal cancer, subjected them to multicolor flow cytometric analysis of percentage, absolute number and phenotype of MDSC and finally characterized their immunosuppressive functions. Our results demonstrate that peripheral blood from colorectal cancer patients contains markedly increased percentage and absolute number of Lin−/lowHLA-DR−CD11b+CD33+ MDSCs compared with healthy individuals, and this increase is closely correlated with clinical cancer stage and tumor metastasis but not primary tumor size and serum concentrations of cancer biomarker. A similar increase of MDSCs was also observed in the tumor tissues. Phenotyping MDSCs shows that they express high CD13 and CD39, low CD115, CD117, CD124 and PD-L1, and devoid of CD14, CD15 and CD66b, reminiscent of precursor myeloid cells. MDSCs from cancer patients but not healthy donors have the immunosuppressive activity and were able to inhibit in vitro autologous T-cell proliferation. Collectively, this study substantiates the presence of increased immunosuppressive circulating and tumor-resident Lin−/lowHLA-DR−CD11b+CD33+ MDSCs in patients with colorectal cancers correlating with cancer stage and metastasis, and suggests that pharmacologic blockade of MDSCs should be considered in future clinical trials. PMID:23437326

  19. Evidence that selenium binding protein 1 is a tumor suppressor in prostate cancer.

    PubMed

    Ansong, Emmanuel; Ying, Qi; Ekoue, Dede N; Deaton, Ryan; Hall, Andrew R; Kajdacsy-Balla, Andre; Yang, Wancai; Gann, Peter H; Diamond, Alan M

    2015-01-01

    Selenium-Binding Protein 1 (SBP1, SELENBP1, hSP56) is a selenium-associated protein shown to be at lower levels in tumors, and its lower levels are frequently predictive of a poor clinical outcome. Distinguishing indolent from aggressive prostate cancer is a major challenge in disease management. Associations between SBP1 levels, tumor grade, and disease recurrence following prostatectomy were investigated by duplex immunofluorescence imaging using a tissue microarray containing tissue from 202 prostate cancer patients who experienced biochemical (PSA) recurrence after prostatectomy and 202 matched control patients whose cancer did not recur. Samples were matched by age, ethnicity, pathological stage and Gleason grade, and images were quantified using the Vectra multispectral imaging system. Fluorescent labels were targeted for SBP1 and cytokeratins 8/18 to restrict scoring to tumor cells, and cell-by-cell quantification of SBP1 in the nucleus and cytoplasm was performed. Nuclear SBP1 levels and the nuclear to cytoplasm ratio were inversely associated with tumor grade using linear regression analysis. Following classification of samples into quartiles based on the SBP1 levels among controls, tumors in the lowest quartile were more than twice as likely to recur compared to those in any other quartile. Inducible ectopic SBP1 expression reduced the ability of HCT-116 human tumor cells to grow in soft agar, a measure of transformation, without affecting proliferation. Cells expressing SBP1 also demonstrated a robust induction in the phosphorylation of the p53 tumor suppressor at serine 15. These data indicate that loss of SBP1 may play an independent contributing role in prostate cancer progression and its levels might be useful in distinguishing indolent from aggressive disease.

  20. Evidence That Selenium Binding Protein 1 Is a Tumor Suppressor in Prostate Cancer

    PubMed Central

    Ansong, Emmanuel; Ying, Qi; Ekoue, Dede N.; Deaton, Ryan; Hall, Andrew R.; Kajdacsy-Balla, Andre; Yang, Wancai; Gann, Peter H.; Diamond, Alan M.

    2015-01-01

    Selenium-Binding Protein 1 (SBP1, SELENBP1, hSP56) is a selenium-associated protein shown to be at lower levels in tumors, and its lower levels are frequently predictive of a poor clinical outcome. Distinguishing indolent from aggressive prostate cancer is a major challenge in disease management. Associations between SBP1 levels, tumor grade, and disease recurrence following prostatectomy were investigated by duplex immunofluorescence imaging using a tissue microarray containing tissue from 202 prostate cancer patients who experienced biochemical (PSA) recurrence after prostatectomy and 202 matched control patients whose cancer did not recur. Samples were matched by age, ethnicity, pathological stage and Gleason grade, and images were quantified using the Vectra multispectral imaging system. Fluorescent labels were targeted for SBP1 and cytokeratins 8/18 to restrict scoring to tumor cells, and cell-by-cell quantification of SBP1 in the nucleus and cytoplasm was performed. Nuclear SBP1 levels and the nuclear to cytoplasm ratio were inversely associated with tumor grade using linear regression analysis. Following classification of samples into quartiles based on the SBP1 levels among controls, tumors in the lowest quartile were more than twice as likely to recur compared to those in any other quartile. Inducible ectopic SBP1 expression reduced the ability of HCT-116 human tumor cells to grow in soft agar, a measure of transformation, without affecting proliferation. Cells expressing SBP1 also demonstrated a robust induction in the phosphorylation of the p53 tumor suppressor at serine 15. These data indicate that loss of SBP1 may play an independent contributing role in prostate cancer progression and its levels might be useful in distinguishing indolent from aggressive disease. PMID:25993660

  1. ECRG4 is a candidate tumor suppressor gene frequently hypermethylated in colorectal carcinoma and glioma

    PubMed Central

    2009-01-01

    Background Cancer cells display widespread changes in DNA methylation that may lead to genetic instability by global hypomethylation and aberrant silencing of tumor suppressor genes by focal hypermethylation. In turn, altered DNA methylation patterns have been used to identify putative tumor suppressor genes. Methods In a methylation screening approach, we identified ECRG4 as a differentially methylated gene. We analyzed different cancer cells for ECRG4 promoter methylation by COBRA and bisulfite sequencing. Gene expression analysis was carried out by semi-quantitative RT-PCR. The ECRG4 coding region was cloned and transfected into colorectal carcinoma cells. Cell growth was assessed by MTT and BrdU assays. ECRG4 localization was analyzed by fluorescence microscopy and Western blotting after transfection of an ECRG4-eGFP fusion gene. Results We found a high frequency of ECRG4 promoter methylation in various cancer cell lines. Remarkably, aberrant methylation of ECRG4 was also found in primary human tumor tissues, including samples from colorectal carcinoma and from malignant gliomas. ECRG4 hypermethylation associated strongly with transcriptional silencing and its expression could be re-activated in vitro by demethylating treatment with 5-aza-2'-deoxycytidine. Overexpression of ECRG4 in colorectal carcinoma cells led to a significant decrease in cell growth. In transfected cells, ECRG4 protein was detectable within the Golgi secretion machinery as well as in the culture medium. Conclusions ECRG4 is silenced via promoter hypermethylation in different types of human cancer cells. Its gene product may act as inhibitor of cell proliferation in colorectal carcinoma cells and may play a role as extracellular signaling molecule. PMID:20017917

  2. Interleukin-2 regulates the expression of the tumor suppressor Interleukin-24 in melanoma cells

    PubMed Central

    Jen, Emily Y.; Poindexter, Nancy J.; Farnsworth, Elizabeth S.; Grimm, Elizabeth A.

    2011-01-01

    Melanoma is notoriously resistant to chemotherapy, but variable responses to biotherapies, including the IFNs and IL-2, provide intriguing avenues for further study. Systemic IL-2 treatment has provided significant clinical benefit in a minority of metastatic melanoma patients, leading to long term survival in a few cases. We hypothesize that one previously unidentified mechanism of effective IL-2 therapy is through direct upregulation of the tumor suppressor IL-24 in melanoma tumor cells resulting in growth suppression. In this study five melanoma cell lines were treated with high dose recombinant human IL-2. Three (A375, WM1341, WM793) showed statistically significant increases in IL-24 protein; two (WM35, MeWo) remained negative for IL-24 message and protein. This increase was abolished by preincubating with anti-IL-2 antibody or blocking with antibodies against the IL-2 receptor chains. These IL-2 responsive melanoma cell lines expressed IL-2Rβ and γ mRNA. The IL-2Rβγ complex was functional, as measured by IL-2-induced STAT activation as well as IL-15 signaling through its shared receptor complex. IL-24 upregulation was observed in response to either IL-2 or IL-15. Cell growth was significantly decreased by treatment of IL-24 positive cells with IL-2 or IL-15, while no effect was seen in negative cells. Incubating the IL-24 inducible-cells with anti-IL-24 antibody as well as transfecting with IL-24 siRNA effectively reversed the growth suppression seen with IL-2. Thus, we have shown that one mechanism of clinically effective IL-2 therapy may be the direct action of IL-2 on a biologically distinct subset of melanoma cells leading to upregulation of the tumor suppressor IL-24. PMID:22027907

  3. The tumor suppressor HHEX inhibits axon growth when prematurely expressed in developing central nervous system neurons.

    PubMed

    Simpson, Matthew T; Venkatesh, Ishwariya; Callif, Ben L; Thiel, Laura K; Coley, Denise M; Winsor, Kristen N; Wang, Zimei; Kramer, Audra A; Lerch, Jessica K; Blackmore, Murray G

    2015-09-01

    Neurons in the embryonic and peripheral nervous system respond to injury by activating transcriptional programs supportive of axon growth, ultimately resulting in functional recovery. In contrast, neurons in the adult central nervous system (CNS) possess a limited capacity to regenerate axons after injury, fundamentally constraining repair. Activating pro-regenerative gene expression in CNS neurons is a promising therapeutic approach, but progress is hampered by incomplete knowledge of the relevant transcription factors. An emerging hypothesis is that factors implicated in cellular growth and motility outside the nervous system may also control axon growth in neurons. We therefore tested sixty-nine transcription factors, previously identified as possessing tumor suppressive or oncogenic properties in non-neuronal cells, in assays of neurite outgrowth. This screen identified YAP1 and E2F1 as enhancers of neurite outgrowth, and PITX1, RBM14, ZBTB16, and HHEX as inhibitors. Follow-up experiments are focused on the tumor suppressor HHEX, one of the strongest growth inhibitors. HHEX is widely expressed in adult CNS neurons, including corticospinal tract neurons after spinal injury, but is present only in trace amounts in immature cortical neurons and adult peripheral neurons. HHEX overexpression in early postnatal cortical neurons reduced both initial axonogenesis and the rate of axon elongation, and domain deletion analysis strongly implicated transcriptional repression as the underlying mechanism. These findings suggest a role for HHEX in restricting axon growth in the developing CNS, and substantiate the hypothesis that previously identified oncogenes and tumor suppressors can play conserved roles in axon extension. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. The tumor suppressor HHEX inhibits axon growth when prematurely expressed in developing central nervous system neurons

    PubMed Central

    Simpson, Matthew T; Venkatesh, Ishwariya; Callif, Ben L; Thiel, Laura K; Coley, Denise M; Winsor, Kristen N; Wang, Zimei; Kramer, Audra A; Lerch, Jessica K; Blackmore, Murray G

    2015-01-01

    Neurons in the embryonic and peripheral nervous system respond to injury by activating transcriptional programs supportive of axon growth, ultimately resulting in functional recovery. In contrast, neurons in the adult central nervous system (CNS) possess a limited capacity to regenerate axons after injury, fundamentally constraining repair. Activating pro-regenerative gene expression in CNS neurons is a promising therapeutic approach, but progress is hampered by incomplete knowledge of the relevant transcription factors. An emerging hypothesis is that factors implicated in cellular growth and motility outside the nervous system may also control axon growth in neurons. We therefore tested sixty-nine transcription factors, previously identified as possessing tumor suppressive or oncogenic properties in non-neuronal cells, in assays of neurite outgrowth. This screen identified YAP1 and E2F1 as enhancers of neurite outgrowth, and PITX1, RBM14, ZBTB16, and HHEX as inhibitors. Follow-up experiments focused on the tumor suppressor HHEX, one of the strongest growth inhibitors. HHEX is widely expressed in adult CNS neurons, including corticospinal tract neurons after spinal injury, but is present in only trace amounts in immature cortical neurons and adult peripheral neurons. HHEX overexpression in early postnatal cortical neurons reduced both initial axonogenesis and the rate of axon elongation, and domain deletion analysis strongly implicated transcriptional repression as the underlying mechanism. These findings suggest a role for HHEX in restricting axon growth in the developing CNS, and substantiate the hypothesis that previously identified oncogenes and tumor suppressors can play conserved roles in axon extension. PMID:26306672

  5. The WWOX tumor suppressor is essential for postnatal survival and normal bone metabolism.

    PubMed

    Aqeilan, Rami I; Hassan, Mohammad Q; de Bruin, Alain; Hagan, John P; Volinia, Stefano; Palumbo, Titziana; Hussain, Sadiq; Lee, Suk-Hee; Gaur, Tripti; Stein, Gary S; Lian, Jane B; Croce, Carlo M

    2008-08-01

    The WW domain-containing oxidoreductase (WWOX) gene encodes a tumor suppressor. We have previously shown that targeted ablation of the Wwox gene in mouse increases the incidence of spontaneous and chemically induced tumors. To investigate WWOX function in vivo, we examined Wwox-deficient (Wwox(-/-)) mice for phenotypical abnormalities. Wwox(-/-) mice are significantly reduced in size, die at the age of 2-3 weeks, and suffer a metabolic disorder that affects the skeleton. Wwox(-/-) mice exhibit a delay in bone formation from a cell autonomous defect in differentiation beginning at the mineralization stage shown in calvarial osteoblasts ex vivo and supported by significantly decreased bone formation parameters in Wwox(-/-) mice by microcomputed tomography analyses. Wwox(-/-) mice develop metabolic bone disease, as a consequence of reduced serum calcium, hypoproteinuria, and hypoglycemia leading to increased osteoclast activity and bone resorption. Interestingly, we find WWOX physically associates with RUNX2, the principal transcriptional regulator of osteoblast differentiation, and on osteocalcin chromatin. We show WWOX functionally suppresses RUNX2 transactivation ability in osteoblasts. In breast cancer MDA-MB-242 cells that lack endogenous WWOX protein, restoration of WWOX expression inhibited Runx2 and RUNX2 target genes related to metastasis. Affymetrix mRNA profiling revealed common gene targets in multiple tissues. In Wwox(-/-) mice, genes related to nucleosome assembly and cell growth genes were down-regulated, and negative regulators of skeletal metabolism exhibited increased expression. Our results demonstrate an essential requirement for the WWOX tumor suppressor in postnatal survival, growth, and metabolism and suggest a central role for WWOX in regulation of bone tissue formation.

  6. Structural investigation of nucleophosmin interaction with the tumor suppressor Fbw7γ.

    PubMed

    Di Matteo, A; Franceschini, M; Paiardini, A; Grottesi, A; Chiarella, S; Rocchio, S; Di Natale, C; Marasco, D; Vitagliano, L; Travaglini-Allocatelli, C; Federici, L

    2017-09-18

    Nucleophosmin (NPM1) is a multifunctional nucleolar protein implicated in ribogenesis, centrosome duplication, cell cycle control, regulation of DNA repair and apoptotic response to stress stimuli. The majority of these functions are played through the interactions with a variety of protein partners. NPM1 is frequently overexpressed in solid tumors of different histological origin. Furthermore NPM1 is the most frequently mutated protein in acute myeloid leukemia (AML) patients. Mutations map to the C-terminal domain and lead to the aberrant and stable localization of the protein in the cytoplasm of leukemic blasts. Among NPM1 protein partners, a pivotal role is played by the tumor suppressor Fbw7γ, an E3-ubiquitin ligase that degrades oncoproteins like c-MYC, cyclin E, Notch and c-jun. In AML with NPM1 mutations, Fbw7γ is degraded following its abnormal cytosolic delocalization by mutated NPM1. This mechanism also applies to other tumor suppressors and it has been suggested that it may play a key role in leukemogenesis. Here we analyse the interaction between NPM1 and Fbw7γ, by identifying the protein surfaces implicated in recognition and key aminoacids involved. Based on the results of computational methods, we propose a structural model for the interaction, which is substantiated by experimental findings on several site-directed mutants. We also extend the analysis to two other NPM1 partners (HIV Tat and CENP-W) and conclude that NPM1 uses the same molecular surface as a platform for recognizing different protein partners. We suggest that this region of NPM1 may be targeted for cancer treatment.

  7. Peperomin E reactivates silenced tumor suppressor genes in lung cancer cells by inhibition of DNA methyltransferase.

    PubMed

    Wang, Xin-Zhi; Cheng, Ying; Wang, Kui-Long; Liu, Rui; Yang, Xiao-Lin; Wen, Hong-Mei; Chai, Chuan; Liang, Jing-Yu; Wu, Hao

    2016-10-01

    Advanced lung cancer has poor prognosis owing to its low sensitivity to current chemotherapy agents. Therefore, discovery of new therapeutic agents is urgently needed. In this study, we investigated the antitumor effects of peperomin E, a secolignan isolated from Peperomia dindygulensis, a frequently used Chinese folk medicine for lung cancer treatment. The results indicate that peperomin E has antiproliferative effects, promoting apoptosis and cell cycle arrest in non-small-cell lung cancer (NSCLC) cell lines in a dose-dependent manner, while showing lower toxicity against normal human lung epidermal cells. Peperomin E inhibited tumor growth in A549 xenograft BALB/c nude mice without significant secondary adverse effects, indicating that it may be safely used to treat NSCLC. Furthermore, the mechanisms underlying the anticancer effects of peperomin E have been investigated. Using an in silico target fishing method, we observed that peperomin E directly interacts with the active domain of DNA methyltransferase 1 (DNMT1), potentially affecting its genome methylation activity. Subsequent experiments verified that peperomin E decreased DNMT1 activity and expression, thereby decreasing global methylation and reactivating the epigenetically silenced tumor suppressor genes including RASSF1A, APC, RUNX3, and p16INK4, which in turn activates their mediated pro-apoptotic and cell cycle regulatory signaling pathways in lung cancer cells. The observations herein report for the first time that peperomin E is a potential chemotherapeutic agent for NSCLC. The anticancer effects of peperomin E may be partly attributable to its ability to demethylate and reactivate methylation-silenced tumor suppressor genes through direct inhibition of the activity and expression of DNMT1.

  8. SOX30, a novel epigenetic silenced tumor suppressor, promotes tumor cell apoptosis by transcriptional activating p53 in lung cancer

    PubMed Central

    Han, F; Liu, W; Jiang, X; Shi, X; Yin, L; Ao, L; Cui, Z; Li, Y; Huang, C; Cao, J; Liu, J

    2015-01-01

    Although members of SOX family have been well documented for their essential roles in embryonic development, cell proliferation and disease, the functional role and molecular mechanism of SOX30 in cancer are largely unexplored. Here, we first identified SRY-box containing gene 30 (SOX30) as a novel preferentially methylated gene using genome-wide methylation screening. SOX30 hypermethylation was detected in 100% of lung cancer cell lines (9/9) and 70.83% (85/120) of primary lung tumor tissues compared with none (0/20) of normal and 8.0% (2/25) of peri-tumoral lung tissues (P<0.01). SOX30 was expressed in normal and peri-tumoral lung tissues in which SOX30 was unmethylated, but was silenced or downregulated in lung cancer cell lines and primary lung tumor tissues harboring a hypermethylated SOX30. De-methylation experiments further confirmed that silence of SOX30 was regulated by its hypermethylation. Ectopic expression of SOX30 induces cancer cell apoptosis with inhibiting proliferation in vitro and represses tumor formation in vivo, whereas knockdown of SOX30 demonstrates a reversed effect both in vitro and in vivo. At the molecular level, the antitumorigenic effect of SOX30 is mediated by directly binding to CACTTTG (+115 to +121) of p53 promoter region and activating p53 transcription, suggesting that SOX30 is a novel transcriptional activating factor of p53. Indeed, blockade of p53 attenuates the tumor inhibition of SOX30. Overall, these findings demonstrate that SOX30 is a novel epigenetic silenced tumor suppressor acting through direct regulation of p53 transcription and expression. This study provides novel insights on the mechanism of tumorigenesis in lung cancer. PMID:25435374

  9. The retinoblastoma tumor suppressor gene, the exception that proves the rule

    PubMed Central

    Goodrich, David W.

    2009-01-01

    The retinoblastoma tumor suppressor gene (Rb1) is centrally important in cancer research. Mutational inactivation of Rb1 causes the pediatric cancer retinoblastoma, while deregulation of the pathway in which it functions is common in most types of human cancer. The Rb1 encoded protein (pRb) is well known as a general cell cycle regulator, and this activity is centrally important for pRb-mediated tumor suppression. The main focus of this review, however, is on more recent evidence demonstrating the existence of additional, cell type specific pRb functions in cellular differentiation and survival. These additional functions are relevant to carcinogenesis suggesting that the net effect of Rb1 loss on the behavior of resulting tumors is highly dependent on biological context. The molecular mechanisms underlying pRb functions are based on the cellular proteins it interacts with and the functional consequences of those interactions. Better insight into pRb-mediated tumor suppression and clinical exploitation of pRb as a therapeutic target will require a global view of the complex, interdependent network of pocket protein complexes that function simultaneously within given tissues. PMID:16936742

  10. How the other half lives, the amino-terminal domain of the retinoblastoma tumor suppressor protein.

    PubMed

    Goodrich, David W

    2003-11-01

    The retinoblastoma tumor suppressor gene (RB1) is currently the only known gene whose mutation is necessary and sufficient for the development of a human cancer. Mutation or deregulation of RB1 is observed so frequently in other tumor types that compromising RB1 function may be a prerequisite for malignant transformation. Identifying the molecular mechanisms that provide the basis for RB1-mediated tumor suppression has become an important goal in the quest to understand and treat cancer. The lion's share of research on these mechanisms has focused on the carboxy-terminal half of the RB1 encoded protein (pRB). This focus is with good reason since this part of the protein, now called the "large pocket," is required for most of its known activities identified in vitro and in vivo. Large pocket mediated mechanisms alone, however, cannot account for all observed properties of pRB. The thesis presented here is that the relatively uncharacterized amino-terminal half of the protein makes important contributions to pRB-mediated tumor suppression. The goals of this review are to summarize evidence indicating that an amino-terminal structural domain is important for pRB function and to suggest a general hypothesis as to how this domain can be integrated with current models of pRB function.

  11. Tumor suppressor p53 negatively regulates glycolysis stimulated by hypoxia through its target RRAD

    PubMed Central

    Wu, Rui; Liang, Yingjian; Lin, Meihua; Liu, Jia; Chan, Chang S.; Hu, Wenwei; Feng, Zhaohui

    2014-01-01

    Cancer cells display enhanced glycolysis to meet their energetic and biosynthetic demands even under normal oxygen concentrations. Recent studies have revealed that tumor suppressor p53 represses glycolysis under normoxia as a novel mechanism for tumor suppression. As the common microenvironmental stress for tumors, hypoxia drives the metabolic switch from the oxidative phosphorylation to glycolysis, which is crucial for survival and proliferation of cancer cells under hypoxia. The p53's role and mechanism in regulating glycolysis under hypoxia is poorly understood. Here, we found that p53 represses hypoxia-stimulated glycolysis in cancer cells through RRAD, a newly-identified p53 target. RRAD expression is frequently decreased in lung cancer. Ectopic expression of RRAD greatly reduces glycolysis whereas knockdown of RRAD promotes glycolysis in lung cancer cells. Furthermore, RRAD represses glycolysis mainly through inhibition of GLUT1 translocation to the plasma membrane. Under hypoxic conditions, p53 induces RRAD, which in turn inhibits the translocation of GLUT1 and represses glycolysis in lung cancer cells. Blocking RRAD by siRNA greatly abolishes p53's function in repressing glycolysis under hypoxia. Taken together, our results revealed an important role and mechanism of p53 in antagonizing the stimulating effect of hypoxia on glycolysis, which contributes to p53's function in tumor suppression. PMID:25114038

  12. Tumor suppressor p53 negatively regulates glycolysis stimulated by hypoxia through its target RRAD.

    PubMed

    Zhang, Cen; Liu, Juan; Wu, Rui; Liang, Yingjian; Lin, Meihua; Liu, Jia; Chan, Chang S; Hu, Wenwei; Feng, Zhaohui

    2014-07-30

    Cancer cells display enhanced glycolysis to meet their energetic and biosynthetic demands even under normal oxygen concentrations. Recent studies have revealed that tumor suppressor p53 represses glycolysis under normoxia as a novel mechanism for tumor suppression. As a common microenvironmental stress for tumors, hypoxia drives the metabolic switch from the oxidative phosphorylation to glycolysis, which is crucial for survival and proliferation of cancer cells under hypoxia. The p53's role and mechanism in regulating glycolysis under hypoxia is poorly understood. Here, we found that p53 represses hypoxia-stimulated glycolysis in cancer cells through RRAD, a newly-identified p53 target. RRAD expression is frequently decreased in lung cancer. Ectopic expression of RRAD greatly reduces glycolysis whereas knockdown of RRAD promotes glycolysis in lung cancer cells. Furthermore, RRAD represses glycolysis mainly through inhibition of GLUT1 translocation to the plasma membrane. Under hypoxic conditions, p53 induces RRAD, which in turn inhibits the translocation of GLUT1 and represses glycolysis in lung cancer cells. Blocking RRAD by siRNA greatly abolishes p53's function in repressing glycolysis under hypoxia. Taken together, our results revealed an important role and mechanism of p53 in antagonizing the stimulating effect of hypoxia on glycolysis, which contributes to p53's function in tumor suppression.

  13. Tumor Suppressor WWOX inhibits osteosarcoma metastasis by modulating RUNX2 function.

    PubMed

    Del Mare, Sara; Aqeilan, Rami I

    2015-08-10

    Osteosarcoma (OS) is among the most frequently occurring primary bone tumors, primarily affecting adolescents and young adults. This malignant osteoid forming tumor is characterized by its metastatic potential, mainly to lungs. We recently demonstrated that WW domain-containing oxidoreductase (WWOX) is frequently inactivated in human OS and that WWOX restoration in WWOX-negative OS cells suppresses tumorigenicity. Of note, WWOX levels are reduced in paired OS samples of post-treatment metastastectomies as compared to pre-treatment biopsies suggesting that decreased WWOX levels are associated with a more aggressive phenotype at the metastatic site. Nevertheless, little is known about WWOX function in OS metastasis. Here, we investigated the role of tumor suppressor WWOX in suppressing pulmonary OS metastasis both in vitro and in vivo. We demonstrated that ectopic expression of WWOX in OS cells, HOS and LM-7, inhibits OS invasion and cell migration in vitro. Furthermore, WWOX expression reduced tumor burden in vivo and inhibited metastases' seeding and colonization. Mechanistically, WWOX function is associated with reduced levels of RUNX2 metastatic target genes implicated in adhesion and motility. Our results suggest that WWOX plays a critical role in determining the aggressive phenotype of OS, and its expression could be an attractive therapeutic target to combat this devastating adolescent disease.

  14. Tumor Suppressor WWOX inhibits osteosarcoma metastasis by modulating RUNX2 function

    PubMed Central

    Del Mare, Sara; Aqeilan, Rami I.

    2015-01-01

    Osteosarcoma (OS) is among the most frequently occurring primary bone tumors, primarily affecting adolescents and young adults. This malignant osteoid forming tumor is characterized by its metastatic potential, mainly to lungs. We recently demonstrated that WW domain-containing oxidoreductase (WWOX) is frequently inactivated in human OS and that WWOX restoration in WWOX-negative OS cells suppresses tumorigenicity. Of note, WWOX levels are reduced in paired OS samples of post-treatment metastastectomies as compared to pre-treatment biopsies suggesting that decreased WWOX levels are associated with a more aggressive phenotype at the metastatic site. Nevertheless, little is known about WWOX function in OS metastasis. Here, we investigated the role of tumor suppressor WWOX in suppressing pulmonary OS metastasis both in vitro and in vivo. We demonstrated that ectopic expression of WWOX in OS cells, HOS and LM-7, inhibits OS invasion and cell migration in vitro. Furthermore, WWOX expression reduced tumor burden in vivo and inhibited metastases’ seeding and colonization. Mechanistically, WWOX function is associated with reduced levels of RUNX2 metastatic target genes implicated in adhesion and motility. Our results suggest that WWOX plays a critical role in determining the aggressive phenotype of OS, and its expression could be an attractive therapeutic target to combat this devastating adolescent disease. PMID:26256646

  15. Inactivation of tumor suppressor gene pten in early and advanced gallbladder cancer.

    PubMed

    Roa, Iván; de Toro, Gonzalo; Fernández, Fernanda; Game, Anakaren; Muñoz, Sergio; de Aretxabala, Xabier; Javle, Milind

    2015-08-21

    PTEN is a tumor suppressor gene that regulates the PTEN/PI3k/AKT/mTOR pathway, which is frequently altered in human cancers including gallbladder cancer (GBC). To determine the frequency of PTEN expression in GBC and to establish its relation to clinical and morphological parameters and survival in GBC. The immunohistochemical expression of PTEN was studied in 108 GBC. All the cases included areas of non-tumor mucosa adjacent to the tumor. The group was comprised of 108 patients, 91 women (84.3%) and 17 men (15.7%) with an average age of 65.2 years (SD ± 12.3 years). Thirty-five cases (33%) were early carcinomas (EC) and the remaining 73 (67%) were advanced cases (AC). All the internal controls were positive (moderate or intense in 96.3%). Only in three AC (4.1%) was there a complete absence of PTEN immunohistochemical expression. There were no significant differences in relation between PTEN expression and tumor infiltration or degree of differentiation. The three patients with PTEN inactivation died before 10 months; however, the other patients with AC had a survival of 53% at 10 months. Loss of PTEN expression was observed in 4.1% of the advanced GBC. All the patients with this alteration died before 10 months. PTEN inactivation could be a rare event, but with a poor prognosis in advanced GBC.

  16. gld-1, a tumor suppressor gene required for oocyte development in Caenorhabditis elegans

    SciTech Connect

    Francis, R.; Schedl, T.; Barton, M.K.; Kimble, J.

    1995-02-01

    We have characterized 31 mutations in the gld-1 (defective in germline development) gene of Caenorhabditis elegans. In gld-1 (null) hermaphrodites, oogenesis is abolished and a germline tumor forms where oocyte development would normally occur. By contrast, gld-1 (null) males are unaffected. The hermaphrodite germline tumor appears to derive from germ cells that enter the meiotic pathway normally but then exit pachytene and return to the mitotic cycle. Certain gld-1 partial loss-of-function mutations also abolish oogenesis, but germ cells arrest in pachytene rather than returning to mitosis. Our results indicate that gld-1 is a tumor suppressor gene required for oocyte development. The tumorous phenotype suggests that gld-1(+) may function to negatively regulate proliferation during meiotic prophase and/or act to direct progression through meiotic prophase. We also show that gld-1(+) has an additional nonessential role in germline sex determination: promotion of hermaphrodite spermatogenesis. This function of gld-1 is inferred from a haplo-insufficient phenotype and from the properties of gain-of-function gld-1 mutations that cause alterations in the sexual identity of germ cells. 69 refs., 10 figs., 8 tabs.

  17. BRAF-activated LncRNA functions as a tumor suppressor in papillary thyroid cancer

    PubMed Central

    Guo, Kai; Ma, Ben; Cao, Yi-Ming; Xiang, Jun; Lu, Zhong-Wu; Zhu, Yong-Xue; Li, Duan-Shu; Ji, Qing-Hai

    2017-01-01

    Long non-coding RNAs (lncRNAs) participate in cancer cell tumorigenesis, cell cycle control, migration, proliferation, apoptosis, metastasis and drug resistance. The BRAF-activated non-coding RNA (BANCR) functions as both an oncogene and a tumor suppressor. Here, we investigated BANCR's role in papillary thyroid carcinoma (PTC) by assessing BANCR levels in PTC and matched normal thyroid epithelial tissues from 92 patients using qRT-PCR. We also used lentiviral vectors to establish PTC cell lines to investigate the effects of BANCR overexpression on cancer cell proliferation, apoptosis, migration and invasion. Our results indicate BANCR levels are lower in PTC tumor tissues than control tissues. Decreased BANCR levels correlate with tumor size, the presence of multifocal lesions and advanced PTC stage. BANCR overexpression reduced PTC cell proliferation and promoted apoptosis, which inhibited metastasis. It also inactivated ERK1/2 and p38, and this effect was enhanced by treatment with the MEK inhibitor U0126. Finally, BANCR overexpression dramatically inhibited tumor growth from PTC cells in xenograft mouse models. These results suggest BANCR inhibits tumorigenesis in PTC and that BANCR levels may be used as a novel prognostic marker. PMID:27462868

  18. microRNA-622 acts as a tumor suppressor in hepatocellular carcinoma

    PubMed Central

    Song, Wei-Hua; Feng, Xiao-Jun; Gong, Shao-Juan; Chen, Jian-Ming; Wang, Shou-Mei; Xing, Dong-Juan; Zhu, Ming-Hua; Zhang, Shu-Hui; Xu, Ai-Min

    2015-01-01

    microRNAs (miRNAs) are important regulators of tumor development and progression. In this study, we aimed to explore the expression and role of miR-622 in hepatocellular carcinoma (HCC). We found that miR-622 was significantly downregulated in human HCC specimens compared to adjacent noncancerous liver tissues. miR-622 downregulation was significantly associated with aggressive parameters and poor prognosis in HCC. Enforced expression of miR-622 significantly decreased the proliferation and colony formation and induced apoptosis of HCC cells. In vivo studies demonstrated that miR-622 overexpression retarded the growth of HCC xenograft tumors. Bioinformatic analysis and luciferase reporter assays revealed that miR-622 directly targeted the 3′-untranslated region (UTR) of mitogen-activated protein 4 kinase 4 (MAP4K4) mRNA. Ectopic expression of miR-622 led to a significant reduction of MAP4K4 expression in HCC cells and xenograft tumors. Overexpression of MAP4K4 partially restored cell proliferation and colony formation and reversed the induction of apoptosis in miR-622-overexpressing HCC cells. Inhibition of JNK and NF-κB signaling phenocopied the anticancer effects of miR-622 on HCC cells. Taken together, miR-622 acts as a tumor suppressor in HCC and restoration of miR-622 may provide therapeutic benefits in the treatment of HCC. PMID:26467022

  19. Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias.

    PubMed

    Dunford, Andrew; Weinstock, David M; Savova, Virginia; Schumacher, Steven E; Cleary, John P; Yoda, Akinori; Sullivan, Timothy J; Hess, Julian M; Gimelbrant, Alexander A; Beroukhim, Rameen; Lawrence, Michael S; Getz, Gad; Lane, Andrew A

    2017-01-01

    There is a striking and unexplained male predominance across many cancer types. A subset of X-chromosome genes can escape X-inactivation, which would protect females from complete functional loss by a single mutation. To identify putative 'escape from X-inactivation tumor-suppressor' (EXITS) genes, we examined somatic alterations from >4,100 cancers across 21 tumor types for sex bias. Six of 783 non-pseudoautosomal region (PAR) X-chromosome genes (ATRX, CNKSR2, DDX3X, KDM5C, KDM6A, and MAGEC3) harbored loss-of-function mutations more frequently in males (based on a false discovery rate < 0.1), in comparison to zero of 18,055 autosomal and PAR genes (Fisher's exact P < 0.0001). Male-biased mutations in genes that escape X-inactivation were observed in combined analysis across many cancers and in several individual tumor types, suggesting a generalized phenomenon. We conclude that biallelic expression of EXITS genes in females explains a portion of the reduced cancer incidence in females as compared to males across a variety of tumor types.

  20. Demethylating agent decitabine disrupts tumor-induced immune tolerance by depleting myeloid-derived suppressor cells.

    PubMed

    Zhou, Jihao; Yao, Yushi; Shen, Qi; Li, Guoqiang; Hu, Lina; Zhang, Xinyou

    2017-08-01

    The immunoregulatory effect of demethylating agent decitabine (DAC) has been recognized recently. However, little is known about its impact on immune tolerance. In this study, we aimed to determine the impact of DAC on the immune tolerance induced by tumor cells. The effects of DAC on immune cells in vivo were measured by flow cytometry. Myeloid-derived suppressor cells (MDSCs) were sorted using magnetic beads and cultured in vitro. The mixed lymphocyte reaction was used to determine the immunoregulatory effect of DAC in vitro. An adoptive transfusion mouse model was established to evaluate the effect in vivo. We found that DAC treatment significantly depleted MDSCs in vivo by inducing MDSCs apoptosis. When given at a low dose, the immune effector cells were less affected by the treatment, except for MDSCs. The mixed lymphocyte reaction in vitro showed that T-cell responses were enhanced when MDSCs were depleted. Supplementation of MDSCs would attenuate this T-cell activation effect. Using an adoptive transfusion mouse model, we further demonstrated in vivo that DAC treatment could induce autologous anti-tumor immune response by depleting MDSCs. This study is the first to illustrate DAC's immunoregulatory effect on immune tolerance. The disruption of immune tolerance is due to MDSCs depletion that induces an autologous immune response in vivo. By depleting MDSCs, DAC treatment removes one of the obstacles affecting anti-tumor immune activation and warrants further experimental and clinical studies to explore its potential utility in combination with various anti-tumor immunotherapies in the future.

  1. Gld-1, a Tumor Suppressor Gene Required for Oocyte Development in Caenorhabditis Elegans

    PubMed Central

    Francis, R.; Barton, M. K.; Kimble, J.; Schedl, T.

    1995-01-01

    We have characterized 31 mutations in the gld-1 (defective in germline development) gene of Caenorhabditis elegans. In gld-1(null) hermaphrodites, oogenesis is abolished and a germline tumor forms where oocyte development would normally occur. By contrast, gld-1(null) males are unaffected. The hermaphrodite germline tumor appears to derive from germ cells that enter the meiotic pathway normally but then exit pachytene and return to the mitotic cycle. Certain gld-1 partial loss-of-function mutations also abolish oogenesis, but germ cells arrest in pachytene rather than returning to mitosis. Our results indicate that gld-1 is a tumor suppressor gene required for oocyte development. The tumorous phenotype suggests that gld-1(+) may function to negatively regulate proliferation during meiotic prophase and/or act to direct progression through meiotic prophase. We also show that gld-1(+) has an additional nonessential role in germline sex determination: promotion of hermaphrodite spermatogenesis. This function of gld-1 is inferred from a haplo-insufficient phenotype and from the properties of gain-of-function gld-1 mutations that cause alterations in the sexual identity of germ cells. PMID:7713419

  2. Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155

    PubMed Central

    Chang, Suhwan; Wang, Rui-Hong; Akagi, Keiko; Kim, Kyung-Ae; Martin, Betty K; Cavallone, Luca; Haines, Diana C; Basik, Mark; Mai, Phuong; Poggi, Elizabeth; Isaacs, Claudine; Looi, Lai M; Mun, Kein S; Greene, Mark H; Byers, Stephen W; Teo, Soo H; Deng, Chu-Xia; Sharan, Shyam K

    2012-01-01

    BRCA1, a well-known tumor suppressor with multiple interacting partners, is predicted to have diverse biological functions. However, so far its only well-established role is in the repair of damaged DNA and cell cycle regulation. In this regard, the etiopathological study of low-penetrant variants of BRCA1 provides an opportunity to uncover its other physiologically important functions. Using this rationale, we studied the R1699Q variant of BRCA1, a potentially moderate-risk variant, and found that it does not impair DNA damage repair but abrogates the repression of microRNA-155 (miR-155), a bona fide oncomir. Mechanistically, we found that BRCA1 epigenetically represses miR-155 expression via its association with HDAC2, which deacetylates histones H2A and H3 on the miR-155 promoter. We show that overexpression of miR-155 accelerates whereas the knockdown of miR-155 attenuates the growth of tumor cell lines in vivo. Our findings demonstrate a new mode of tumor suppression by BRCA1 and suggest that miR-155 is a potential therapeutic target for BRCA1-deficient tumors. PMID:21946536

  3. Tumor Suppressor Function of the SEMA3B Gene in Human Lung and Renal Cancers

    PubMed Central

    Senchenko, Vera N.; Pronina, Irina V.; Khodyrev, Dmitry S.; Kudryavtseva, Anna V.; Krasnov, George S.; Gerashchenko, Ganna V.; Chashchina, Larisa I.; Kazubskaya, Tatiana P.; Kondratieva, Tatiana T.; Lerman, Michael I.; Angeloni, Debora; Braga, Eleonora A.; Kashuba, Vladimir I.

    2015-01-01

    The SEMA3B gene is located in the 3p21.3 LUCA region, which is frequently affected in different types of cancer. The objective of our study was to expand our knowledge of the SEMA3B gene as a tumor suppressor and the mechanisms of its inactivation. In this study, several experimental approaches were used: tumor growth analyses and apoptosis assays in vitro and in SCID mice, expression and methylation assays and other. With the use of the small cell lung cancer cell line U2020 we confirmed the function of SEMA3B as a tumor suppressor, and showed that the suppression can be realized through the induction of apoptosis and, possibly, associated with the inhibition of angiogenesis. In addition, for the first time, high methylation frequencies have been observed in both intronic (32-39%) and promoter (44-52%) CpG-islands in 38 non-small cell lung carcinomas, including 16 squamous cell carcinomas (SCC) and 22 adenocarcinomas (ADC), and in 83 clear cell renal cell carcinomas (ccRCC). Correlations between the methylation frequencies of the promoter and the intronic CpG-islands of SEMA3B with tumor stage and grade have been revealed for SCC, ADC and ccRCC. The association between the decrease of the SEMA3B mRNA level and hypermethylation of the promoter and the intronic CpG-islands has been estimated in renal primary tumors (P < 0.01). Using qPCR, we observed on the average 10- and 14-fold decrease of the SEMA3B mRNA level in SCC and ADC, respectively, and a 4-fold decrease in ccRCC. The frequency of this effect was high in both lung (92-95%) and renal (84%) tumor samples. Moreover, we showed a clear difference (P < 0.05) of the SEMA3B relative mRNA levels in ADC with and without lymph node metastases. We conclude that aberrant expression and methylation of SEMA3B could be suggested as markers of lung and renal cancer progression. PMID:25961819

  4. Tumor Suppressor Function of the SEMA3B Gene in Human Lung and Renal Cancers.

    PubMed

    Loginov, Vitaly I; Dmitriev, Alexey A; Senchenko, Vera N; Pronina, Irina V; Khodyrev, Dmitry S; Kudryavtseva, Anna V; Krasnov, George S; Gerashchenko, Ganna V; Chashchina, Larisa I; Kazubskaya, Tatiana P; Kondratieva, Tatiana T; Lerman, Michael I; Angeloni, Debora; Braga, Eleonora A; Kashuba, Vladimir I

    2015-01-01

    The SEMA3B gene is located in the 3p21.3 LUCA region, which is frequently affected in different types of cancer. The objective of our study was to expand our knowledge of the SEMA3B gene as a tumor suppressor and the mechanisms of its inactivation. In this study, several experimental approaches were used: tumor growth analyses and apoptosis assays in vitro and in SCID mice, expression and methylation assays and other. With the use of the small cell lung cancer cell line U2020 we confirmed the function of SEMA3B as a tumor suppressor, and showed that the suppression can be realized through the induction of apoptosis and, possibly, associated with the inhibition of angiogenesis. In addition, for the first time, high methylation frequencies have been observed in both intronic (32-39%) and promoter (44-52%) CpG-islands in 38 non-small cell lung carcinomas, including 16 squamous cell carcinomas (SCC) and 22 adenocarcinomas (ADC), and in 83 clear cell renal cell carcinomas (ccRCC). Correlations between the methylation frequencies of the promoter and the intronic CpG-islands of SEMA3B with tumor stage and grade have been revealed for SCC, ADC and ccRCC. The association between the decrease of the SEMA3B mRNA level and hypermethylation of the promoter and the intronic CpG-islands has been estimated in renal primary tumors (P < 0.01). Using qPCR, we observed on the average 10- and 14-fold decrease of the SEMA3B mRNA level in SCC and ADC, respectively, and a 4-fold decrease in ccRCC. The frequency of this effect was high in both lung (92-95%) and renal (84%) tumor samples. Moreover, we showed a clear difference (P < 0.05) of the SEMA3B relative mRNA levels in ADC with and without lymph node metastases. We conclude that aberrant expression and methylation of SEMA3B could be suggested as markers of lung and renal cancer progression.

  5. Lowered Expression of Tumor Suppressor Candidate MYO1C Stimulates Cell Proliferation, Suppresses Cell Adhesion and Activates AKT

    PubMed Central

    Visuttijai, Kittichate; Pettersson, Jennifer; Mehrbani Azar, Yashar; van den Bout, Iman; Örndal, Charlotte; Marcickiewicz, Janusz; Nilsson, Staffan; Hörnquist, Michael; Olsson, Björn; Ejeskär, Katarina

    2016-01-01

    Myosin-1C (MYO1C) is a tumor suppressor candidate located in a region of recurrent losses distal to TP53. Myo1c can tightly and specifically bind to PIP2, the substrate of Phosphoinositide 3-kinase (PI3K), and to Rictor, suggesting a role for MYO1C in the PI3K pathway. This study was designed to examine MYO1C expression status in a panel of well-stratified endometrial carcinomas as well as to assess the biological significance of MYO1C as a tumor suppressor in vitro. We found a significant correlation between the tumor stage and lowered expression of MYO1C in endometrial carcinoma samples. In cell transfection experiments, we found a negative correlation between MYO1C expression and cell proliferation, and MYO1C silencing resulted in diminished cell migration and adhesion. Cells expressing excess of MYO1C had low basal level of phosphorylated protein kinase B (PKB, a.k.a. AKT) and cells with knocked down MYO1C expression showed a quicker phosphorylated AKT (pAKT) response in reaction to serum stimulation. Taken together the present study gives further evidence for tumor suppressor activity of MYO1C and suggests MYO1C mediates its tumor suppressor function through inhibition of PI3K pathway and its involvement in loss of contact inhibition. PMID:27716847

  6. Identification of a third protein 4.1 tumor suppressor, protein 4.1R, in meningioma pathogenesis

    SciTech Connect

    Robb, Victoria A.; Li, Wen; Gascard, Philippe; Perry, Arie; Mohandas, Narla; Gutmann, David H.

    2003-06-11

    Meningiomas are common tumors of the central nervous system, however, the mechanisms under lying their pathogenesis are largely undefined. Two members of the Protein 4.1 super family, the neuro fibromatosis 2 (NF2) gene product (merlin/schwannomin) and Protein 4.1B have been implicated as meningioma tumor suppressors. In this report, we demonstrate that another Protein 4.1 family member, Protein 4.1R, also functions as a meningioma tumor suppressor. Based on the assignment of the Protein 4.1R gene to chromosome 1p32-36, a common region of deletion observed in meningiomas, we analyzed Protein 4.1R expression in meningioma cell lines and surgical tumor specimens. We observed loss of Protein 4.1R protein expression in two meningioma cell lines (IOMM-Lee, CH157-MN) by Western blotting as well as in 6 of 15 sporadic meningioma as by immuno histo chemistry (IHC). Analysis of a subset of these sporadic meningiomas by fluorescent in situ hybridization (FISH) with a Protein 4.1R specific probe demonstrated 100 percent concordance with the IHC results. In support of a meningioma tumor suppressor function, over expression of Protein 4.1R resulted in suppression of IOMM-Lee and CH157MN cell proliferation. Similar to the Protein 4.1B and merlin meningioma tumor suppressors, Protein 4.1R localization in the membrane fraction increased significantly under conditions of growth arrest in vitro. Lastly, Protein 4.1R interacted with some known merlin/Protein 4.1B interactors such as CD44 and bII-spectrin, but did not associate with the Protein 4.1B interactors 14-3-3 and PRMT3 or the merlin binding proteins SCHIP-1 and HRS. Collectively, these results suggest that Protein 4.1R functions as an important tumor suppressor important in the molecular pathogenesis of meningioma.

  7. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis | Center for Cancer Research

    Cancer.gov

    We demonstrate a novel tumor-promoting role of myeloid immune suppressor Gr+CD11b+ cells, which are evident in cancer patients and tumor-bearing animals. These cells constitute approximately 5% of total cells in tumors. Tumors coinjected with Gr+CD11b+ cells exhibited increased vascular density, vascular maturation, and decreased necrosis. These immune cells produce high levels of MMP9. Deletion of MMP9 in these cells completely abolishes their tumor-promoting ability. Gr+CD11b+ cells were also found to directly incorporate into tumor endothelium.

  8. [Correlation of size of the primary tumor and axillary node status with the p53 tumor suppressor gene in carcinoma of the breast].

    PubMed

    Topić, Brano; Stanković, N; Savjak, D; Grbić, S

    2002-01-01

    Correlation of standard pathomorphological prognostic parameters, primary tumor size and axillary nodal status with new prognostic factor in breast carcinoma: tumor suppressor gene p53 was analyzed. The studied sample included 65 women who underwent surgery for breast carcinoma at the Surgical Clinic of Clinical Center Banja Luka, from January 1st 1997 till January 1st 1999. Statistical data analysis was performed and correlation of prognostic factors was determined. The majority of authors in this field agree that the primary tumor size and axillary nodal status are the two most important prognostic factors. These factors are the best predictors of prognosis and survival of women who had the tumor and were operated on. Tumor markers were immunohistochemically determined in the last ten years and, according to the majority of authors, are still considered the additional or relative prognostic factors in breast carcinoma. Their prognostic value and significance increase almost daily. Most frequently determined tumor markers are bcl-2, pS2, Ki-67 and p53. There was a positive, directly proportional relationship between primary tumor size and tumor suppressor gene p53, but there was no positive correlation between the axillary nodal status and tumor suppressor gene p53. Significance of determination of new tumor markers as the prognostic factors was emphasized. These markers represent a powerful tool in the early detection and prevention of breast carcinoma.

  9. Differential Splicing of Oncogenes and Tumor Suppressor Genes in African- and Caucasian-American Populations: Contributing Factor in Prostate Cancer Disparities

    DTIC Science & Technology

    2015-10-01

    15. SUBJECT TERMS prostate cancer , cancer health disparities, alternative splicing, African American, European American, oncogenes, tumor suppressor...Prostate cancer , cancer health disparities, alternative RNA splicing, African American, European American, oncogenes, tumor suppressor genes...that alternative splicing in kinases can affect the sensitivity these signaling proteins to cancer therapeutic agents. Our findings raise the issue

  10. ME-10TUMOR MICROENVIRONMENT INFILTRATING MYELOID DERIVED SUPPRESSOR CELLS INHIBIT ANTI-TUMOR T CELL RESPONSES

    PubMed Central

    Kamran, Neha; Ayala, Mariela; Li, Youping; Assi, Hikmat; Candolfi, Marianela; Dzaman, Marta; Lowenstein, Pedro; Castro, Maria

    2014-01-01

    MDSCs represent a population of immature myeloid cells at various stages of differentiation that inhibit anti-tumor T cell-mediated responses. We demonstrate the accumulation of MDSCs in GL26 induced glioma and B16 melanoma bearing mice. Absolute numbers of Ly-6G+ (Gr-1high) MDSCs showed a 200 fold increase within the tumor microenvironment (TME) 28 days post-tumor implantation. The numbers of Ly-6C+ (Gr-1low) MDSCs also showed a similar trend within the TME. While this massive influx of MDSCs was noted within intracranial tumors, MDSC levels did not increase in the dLNs, spleen or bone marrow (BM) of intracranial tumor bearing mice. MDSCs numbers were significantly elevated in the blood of GL26 intracranial tumor bearing mice at 28 days. Mice bearing B16 tumors in the flank showed a ∼5 fold increased influx of Ly-6G+ MDSCs while the Ly6C+ MDSCs increased marginally by 1.1 fold within the tumor mass. Levels of circulating MDSCs also increased by ∼10 fold, while the levels of splenic MDSCs did not change. While both Ly-6G+ and Ly6C+ MDSCs isolated from the brain TME of GL26 intracranial tumor bearing mice inhibited antigen-specific T cell proliferation, Ly6C+ MDSC were found to be more efficient. Ly6G+ or Ly6C+ MDSCs from the bone marrow of intracranial tumor bearing mice failed to suppress antigen-specific T cell proliferation. Splenic and bone marrow MDSCs from naïve mice also did not inhibit antigen-specific T cell proliferation suggesting that TME derived factors may activate MDSCs to exert their immune-suppressive properties. Microarray analysis of glioma cell lines showed elevated levels of CXCL1 mRNA and splenic MDSCs from GL26 tumor mice showed upregulation of the CXCR2 mRNA. Preliminary experiments indicate that CXCR2 signaling mediates MDSC chemotaxis. Overall, our data suggests that strategies that inhibit MDSC recruitment to the TME and/or block their activity could enhance the T cell mediated tumor clearance.

  11. The ARF Tumor Suppressor Regulates Bone Remodeling and Osteosarcoma Development in Mice

    PubMed Central

    Harding, John C.; Deng, Hongju; Shea, Lauren K.; Eagleton, Mark C.; Niewiesk, Stefan; Lairmore, Michael D.; Piwnica-Worms, David; Rosol, Thomas J.; Weber, Jason D.; Ratner, Lee; Weilbaecher, Katherine N.

    2010-01-01

    The ARF tumor suppressor regulates p53 as well as basic developmental processes independent of p53, including osteoclast activation, by controlling ribosomal biogenesis. Here we provide evidence that ARF is a master regulator of bone remodeling and osteosarcoma (OS) development in mice. Arf-/- mice displayed increased osteoblast (OB) and osteoclast (OC) activity with a significant net increase in trabecular bone volume. The long bones of Arf-/- mice had increased expression of OB genes while Arf-/- OB showed enhanced differentiation in vitro. Mice transgenic for the Tax oncogene develop lymphocytic tumors with associated osteolytic lesions, while Tax+Arf-/- mice uniformly developed spontaneous OS by 7 months of age. Tax+Arf-/- tumors were well differentiated OS characterized by an abundance of new bone with OC recruitment, expressed OB markers and displayed intact levels of p53 mRNA and reduced Rb transcript levels. Cell lines established from OS recapitulated characteristics of the primary tumor, including the expression of mature OB markers and ability to form mineralized tumors when transplanted. Loss of heterozygosity in OS tumors arising in Tax+Arf+/- mice emphasized the necessity of ARF-loss in OS development. Hypothesizing that inhibition of ARF-regulated bone remodeling would repress development of OS, we demonstrated that treatment of Tax+Arf-/- mice with zoledronic acid, a bisphosphonate inhibitor of OC activity and repressor of bone turnover, prevented or delayed the onset of OS. These data describe a novel role for ARF as a regulator of bone remodeling through effects on both OB and OC. Finally, these data underscore the potential of targeting bone remodeling as adjuvant therapy or in patients with genetic predispositions to prevent the development of OS. PMID:21209895

  12. CFTR is a tumor suppressor gene in murine and human intestinal cancer

    PubMed Central

    Than, BLN; Linnekamp, JF; Starr, TK; Largaespada, DA; Rod, A; Zhang, Y; Bruner, V; Abrahante, J; Schumann, A; Luczak, T; Niemczyk, A; O’Sullivan, MG; Medema, JP; Fijneman, RJA; Meijer, GA; Van den Broek, E; Hodges, CA; Scott, PM; Vermeulen, L; Cormier, RT

    2016-01-01

    CFTR, the cystic fibrosis (CF) gene, encodes for the CFTR protein that plays an essential role in anion regulation and tissue homeostasis of various epithelia. In the gastrointestinal (GI) tract CFTR promotes chloride and bicarbonate secretion, playing an essential role in ion and acid–base homeostasis. Cftr has been identified as a candidate driver gene for colorectal cancer (CRC) in several Sleeping Beauty DNA transposon-based forward genetic screens in mice. Further, recent epidemiological and clinical studies indicate that CF patients are at high risk for developing tumors in the colon. To investigate the effects of CFTR dysregulation on GI cancer, we generated ApcMin mice that carried an intestinal-specific knockout of Cftr. Our results indicate that Cftr is a tumor suppressor gene in the intestinal tract as Cftr mutant mice developed significantly more tumors in the colon and the entire small intestine. In Apc+/+ mice aged to ~ 1 year, Cftr deficiency alone caused the development of intestinal tumors in >60% of mice. Colon organoid formation was significantly increased in organoids created from Cftr mutant mice compared with wild-type controls, suggesting a potential role of Cftr in regulating the intestinal stem cell compartment. Microarray data from the Cftr-deficient colon and the small intestine identified dysregulated genes that belong to groups of immune response, ion channel, intestinal stem cell and other growth signaling regulators. These associated clusters of genes were confirmed by pathway analysis using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA). We also conducted RNA Seq analysis of tumors from Apc+/+ Cftr knockout mice and identified sets of genes dysregulated in tumors including altered Wnt β-catenin target genes. Finally we analyzed expression of CFTR in early stage human CRC patients stratified by risk of recurrence and found that loss of expression of CFTR was significantly associated with poor disease

  13. CFTR is a tumor suppressor gene in murine and human intestinal cancer.

    PubMed

    Than, B L N; Linnekamp, J F; Starr, T K; Largaespada, D A; Rod, A; Zhang, Y; Bruner, V; Abrahante, J; Schumann, A; Luczak, T; Niemczyk, A; O'Sullivan, M G; Medema, J P; Fijneman, R J A; Meijer, G A; Van den Broek, E; Hodges, C A; Scott, P M; Vermeulen, L; Cormier, R T

    2016-08-11

    CFTR, the cystic fibrosis (CF) gene, encodes for the CFTR protein that plays an essential role in anion regulation and tissue homeostasis of various epithelia. In the gastrointestinal (GI) tract CFTR promotes chloride and bicarbonate secretion, playing an essential role in ion and acid-base homeostasis. Cftr has been identified as a candidate driver gene for colorectal cancer (CRC) in several Sleeping Beauty DNA transposon-based forward genetic screens in mice. Further, recent epidemiological and clinical studies indicate that CF patients are at high risk for developing tumors in the colon. To investigate the effects of CFTR dysregulation on GI cancer, we generated Apc(Min) mice that carried an intestinal-specific knockout of Cftr. Our results indicate that Cftr is a tumor suppressor gene in the intestinal tract as Cftr mutant mice developed significantly more tumors in the colon and the entire small intestine. In Apc(+/+) mice aged to ~1 year, Cftr deficiency alone caused the development of intestinal tumors in >60% of mice. Colon organoid formation was significantly increased in organoids created from Cftr mutant mice compared with wild-type controls, suggesting a potential role of Cftr in regulating the intestinal stem cell compartment. Microarray data from the Cftr-deficient colon and the small intestine identified dysregulated genes that belong to groups of immune response, ion channel, intestinal stem cell and other growth signaling regulators. These associated clusters of genes were confirmed by pathway analysis using Ingenuity Pathway Analysis and gene set enrichment analysis (GSEA). We also conducted RNA Seq analysis of tumors from Apc(+/+) Cftr knockout mice and identified sets of genes dysregulated in tumors including altered Wnt β-catenin target genes. Finally we analyzed expression of CFTR in early stage human CRC patients stratified by risk of recurrence and found that loss of expression of CFTR was significantly associated with poor disease

  14. Selective Retention of an Inactive Allele of the DKK2 Tumor Suppressor Gene in Hepatocellular Carcinoma

    PubMed Central

    Lin, Yung-Feng; Li, Ling-Hui; Lin, Chih-Hung; Tsou, Mei-Hua; Chuang, Ming-Tai Kiffer; Wu, Keh-Ming; Liao, Tsai-Lien; Li, Jian-Chiuan; Wang, Wei-Jie; Tomita, Angela; Tomita, Beverly; Huang, Shiu-Feng; Tsai, Shih-Feng

    2016-01-01

    In an effort to identify the functional alleles associated with hepatocellular carcinoma (HCC), we investigated 152 genes found in the 4q21-25 region that exhibited loss of heterozygosity (LOH). A total of 2,293 pairs of primers were designed for 1,449 exonic and upstream promoter regions to amplify and sequence 76.8–114 Mb on human chromosome 4. Based on the results from analyzing 12 HCC patients and 12 healthy human controls, we discovered 1,574 sequence variations. Among the 99 variants associated with HCC (p < 0.05), four are from the Dickkopf 2 (DKK2) gene: three in the promoter region (g.-967A>T, g.-923C>A, and g.-441T>G) and one in the 5’UTR (c.550T>C). To verify the results, we expanded the subject cohort to 47 HCC cases and 88 healthy controls for conducting haplotype analysis. Eight haplotypes were detected in the non-tumor liver tissue samples, but one major haplotype (TAGC) was found in the tumor tissue samples. Using a reporter assay, this HCC-associated allele registered the lowest level of promoter activity among all the tested haplotype sequences. Retention of this allele in LOH was associated with reduced DKK2 transcription in the HCC tumor tissues. In HuH-7 cells, DKK2 functioned in the Wnt/β-catenin signaling pathway, as an antagonist of Wnt3a, in a dose-dependent manner that inhibited Wnt3a-induced cell proliferation. Taken together, the genotyping and functional findings are consistent with the hypothesis that DKK2 is a tumor suppressor; by selectively retaining a transcriptionally inactive DKK2 allele, the reduction of DKK2 function results in unchecked Wnt/β-catenin signaling, contributing to HCC oncogenesis. Thus our study reveals a new mechanism through which a tumor suppressor gene in a LOH region loses its function by allelic selection. PMID:27203079

  15. Tumor suppressor Menin acts as a corepressor of LXRα to inhibit hepatic lipogenesis.

    PubMed

    Cheng, Peng; Li, Gang; Yang, Sheng Sheng; Liu, Rui; Jin, Gang; Zhou, Xu Yu; Hu, Xian Gui

    2015-10-07

    Menin, encoded by the MEN1 gene, was initially identified as a tumor suppressor for endocrine neoplasia. Our previous report showed that Menin enhances PPARα transactivity preventing triglyceride accumulation in the liver. Here, we further explore the role of Menin in liver steatosis. Transient transfection assays demonstrate that Menin inhibits the transcriptional activity of nuclear receptor liver X receptor α (LXRα). Accordingly, Menin overexpression results in reduced expression of LXRα target genes, such as lipogenic enzymes including SREBP-1c, FASN and SCD-1. Co-immunoprecipitation assays revealed physical interaction between Menin and LXRα. Collectively, our data suggest that Menin acts as a novel corepressor of LXRα and functions as a negative regulator of hepatic lipogenesis. Copyright © 2015. Published by Elsevier B.V.

  16. Identification of the von Hippel-Lindau disease tumor suppressor gene

    SciTech Connect

    Latif, F.; Masahiro Yao; Orcutt, L.; Kuzmin, I.; Fangwei Zhou; Zbar, B.; Lerman, M.I.; Dean, M. ); Tory, K.; Fuhmei Duh; Stackhouse, T.; Modi, W.; Geil, L.; Schmidt, L.; Hua Li; Ming Hui Wei; Fan Chen; Glavac, D. National Cancer Inst., Frederick, MD ); Gnarra, J.; Walther, M.M.; Yongkai Weng; Duan, D.S.R.; Linehan, W.M.; Glenn, G.; Choyke, P. ); Richards, F.M.; Crossey, P.A.; Ferguson-Smith, M.A.; Maher, E.R. ); Paslier D. Le; Chumakov, I.; Cohen, D. ); Chinault, A.C. )

    1993-05-28

    A gene discovered by positional cloning has been identified as the von Hippel-Lindau (VHL) disease tumor suppressor gene. A restriction fragment encompassing the gene showed rearrangements in 28 of 221 VHL kindreds. Eighteen of these rearrangements were due to deletions in the candidate gene, including three large nonoverlapping deletions. Intragenic mutations were detected in cell lines derived from VHL patients and from sporadic renal cell carcinomas. The VHL gene is evolutionarily conserved and encodes two widely expressed transcripts of approximately 6 and 6.5 kilobases. The partial sequence of the inferred gene product shows no homology to other proteins, except for an acidic repeat domain found in the procyclic surface membrane glycoprotein of Trypanosoma brucei. 17 refs., 4 figs. 1 tab.

  17. Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells*

    PubMed Central

    Abu-Remaileh, Muhannad; Joy-Dodson, Emma; Schueler-Furman, Ora; Aqeilan, Rami I.

    2015-01-01

    WW domain-containing oxidoreductase (WWOX), originally marked as a likely tumor suppressor gene, has over the years become recognized for its role in a much wider range of cellular activities. Phenotypic effects displayed in animal studies, along with resolution of WWOX's architecture, fold, and binding partners, point to the protein's multifaceted biological functions. Results from a series of complementary experiments seem to indicate WWOX's involvement in metabolic regulation. More recently, clinical studies involving cases of severe encephalopathy suggest that WWOX also plays a part in controlling CNS development, further expanding our understanding of the breadth and complexity of WWOX behavior. Here we present a short overview of the various approaches taken to study this dynamic gene, emphasizing the most recent findings regarding WWOX's metabolic- and CNS-associated functions and their underlying molecular basis. PMID:26499798

  18. NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas

    PubMed Central

    Yu, Yinhua; Xu, Fengji; Peng, Hongqi; Fang, Xianjun; Zhao, Shulei; Li, Yang; Cuevas, Bruce; Kuo, Wen-Lin; Gray, Joe W.; Siciliano, Michael; Mills, Gordon B.; Bast, Robert C.

    1999-01-01

    Using differential display PCR, we have identified a gene [NOEY2, ARHI (designation by the Human Gene Nomenclature Committee)] with high homology to ras and rap that is expressed consistently in normal ovarian and breast epithelial cells but not in ovarian and breast cancers. Reexpression of NOEY2 through transfection suppresses clonogenic growth of breast and ovarian cancer cells. Growth suppression was associated with down-regulation of the cyclin D1 promoter activity and induction of p21WAF1/CIP1. In an effort to identify mechanisms leading to NOEY2 silencing in cancer, we found that the gene is expressed monoallelically and is imprinted maternally. Loss of heterozygosity of the gene was detected in 41% of ovarian and breast cancers. In most of cancer samples with loss of heterozygosity, the nonimprinted functional allele was deleted. Thus, NOEY2 appears to be a putative imprinted tumor suppressor gene whose function is abrogated in ovarian and breast cancers. PMID:9874798

  19. The Regulatory Mechanisms of Tumor Suppressor P16INK4A and Relevance to Cancer†

    PubMed Central

    Li, Junan; Poi, Ming Jye; Tsai, Ming-Daw

    2011-01-01

    P16INK4A (also known as P16 and MTS1), a protein consisting exclusively of four ankyrin repeats, is recognized as a tumor suppressor mainly due to the prevalence of genetic inactivation of the p16INK4A (or CDKN2A) gene in virtually all types of human cancers. However, it has also been shown that elevated expression (up-regulation) of P16 is involved in cellular senescence, aging, and cancer progression, indicating that the regulation of P16 is critical for its function. Here, we discuss the regulatory mechanisms of P16 function at the DNA level, the transcription level, and the posttranscriptional level, as well as their implications in the structure-function relationship of P16 and in human cancers. PMID:21619050

  20. Analysis of tumor suppressor genes based on gene ontology and the KEGG pathway.

    PubMed

    Yang, Jing; Chen, Lei; Kong, Xiangyin; Huang, Tao; Cai, Yu-Dong

    2014-01-01

    Cancer is a serious disease that causes many deaths every year. We urgently need to design effective treatments to cure this disease. Tumor suppressor genes (TSGs) are a type of gene that can protect cells from becoming cancerous. In view of this, correct identification of TSGs is an alternative method for identifying effective cancer therapies. In this study, we performed gene ontology (GO) and pathway enrichment analysis of the TSGs and non-TSGs. Some popular feature selection methods, including minimum redundancy maximum relevance (mRMR) and incremental feature selection (IFS), were employed to analyze the enrichment features. Accordingly, some GO terms and KEGG pathways, such as biological adhesion, cell cycle control, genomic stability maintenance and cell death regulation, were extracted, which are important factors for identifying TSGs. We hope these findings can help in building effective prediction methods for identifying TSGs and thereby, promoting the discovery of effective cancer treatments.

  1. Regulation of Notch signaling and endocytosis by the Lgl neoplastic tumor suppressor

    PubMed Central

    Portela, Marta; Parsons, Linda M; Grzeschik, Nicola A; Richardson, Helena E

    2015-01-01

    The evolutionarily conserved neoplastic tumor suppressor protein, Lethal (2) giant larvae (Lgl), plays roles in cell polarity and tissue growth via regulation of the Hippo pathway. In our recent study, we showed that in the developing Drosophila eye epithelium, depletion of Lgl leads to increased ligand-dependent Notch signaling. lgl mutant tissue also exhibits an accumulation of early endosomes, recycling endosomes, early-multivesicular body markers and acidic vesicles. We showed that elevated Notch signaling in lgl− tissue can be rescued by feeding larvae the vesicle de-acidifying drug chloroquine, revealing that Lgl attenuates Notch signaling by limiting vesicle acidification. Strikingly, chloroquine also rescued the lgl− overgrowth phenotype, suggesting that the Hippo pathway defects were also rescued. In this extraview, we provide additional data on the regulation of Notch signaling and endocytosis by Lgl, and discuss possible mechanisms by which Lgl depletion contributes to signaling pathway defects and tumorigenesis. PMID:25789785

  2. Retinoblastoma tumor suppressor functions shared by stem cell and cancer cell strategies

    PubMed Central

    Kohno, Susumu; Kitajima, Shunsuke; Sasaki, Nobunari; Takahashi, Chiaki

    2016-01-01

    Carcinogenic transformation of somatic cells resembles nuclear reprogramming toward the generation of pluripotent stem cells. These events share eternal escape from cellular senescence, continuous self-renewal in limited but certain population of cells, and refractoriness to terminal differentiation while maintaining the potential to differentiate into cells of one or multiple lineages. As represented by several oncogenes those appeared to be first keys to pluripotency, carcinogenesis and nuclear reprogramming seem to share a number of core mechanisms. The retinoblastoma tumor suppressor product retinoblastoma (RB) seems to be critically involved in both events in highly complicated manners. However, disentangling such complicated interactions has enabled us to better understand how stem cell strategies are shared by cancer cells. This review covers recent findings on RB functions related to stem cells and stem cell-like behaviors of cancer cells. PMID:27114748

  3. Conditional inactivation of the mouse Wwox tumor suppressor gene recapitulates the null phenotype†

    PubMed Central

    Abdeen, Suhaib K.; Mare, Sara Del; Hussain, Sadeeq; Remaileh, Muhannad Abu; Salah, Zaidoun; Hagan, John; Rawahneh, Maysoon; Pu, Xin-an; Russell, Stacey; Stein, Janet L.; Stein, Gary S.; Lian, Jane B.; Aqeilan, Rami I.

    2013-01-01

    WW domain-containing oxidoreductase (WWOX) is highly conserved in both humans and murine. WWOX spans the second most common human chromosomal fragile site, FRA16D, and is commonly inactivated in multiple human cancers. Modeling WWOX inactivation in mice revealed a complex phenotype including postnatal lethality, defects in bone metabolism and steroidogenesis and tumor suppressor function resulting in osteosarcomas. For better understanding of WWOX roles in different tissues at distinct stages of development and in pathological conditions, Wwox conditional knockout mice were generated in which loxp sites flank exon 1 in the Wwox allele. We demonstrated that Cre-mediated recombination using EIIA-Cre, a Cre line expressed in germline, results in postnatal lethality by age of three weeks and decreased bone mineralization resembling total ablation of WWOX as in conventional null mice. This animal model will be useful to study distinct roles of WWOX in multiple tissues at different ages. PMID:23254685

  4. Pleiotropic Functions of Tumor Suppressor WWOX in Normal and Cancer Cells.

    PubMed

    Abu-Remaileh, Muhannad; Joy-Dodson, Emma; Schueler-Furman, Ora; Aqeilan, Rami I

    2015-12-25

    WW domain-containing oxidoreductase (WWOX), originally marked as a likely tumor suppressor gene, has over the years become recognized for its role in a much wider range of cellular activities. Phenotypic effects displayed in animal studies, along with resolution of WWOX's architecture, fold, and binding partners, point to the protein's multifaceted biological functions. Results from a series of complementary experiments seem to indicate WWOX's involvement in metabolic regulation. More recently, clinical studies involving cases of severe encephalopathy suggest that WWOX also plays a part in controlling CNS development, further expanding our understanding of the breadth and complexity of WWOX behavior. Here we present a short overview of the various approaches taken to study this dynamic gene, emphasizing the most recent findings regarding WWOX's metabolic- and CNS-associated functions and their underlying molecular basis.

  5. The tumor suppressor WW domain-containing oxidoreductase modulates cell metabolism

    PubMed Central

    Abu-Remaileh, Muhannad

    2015-01-01

    The WW domain-containing oxidoreductase (WWOX) encodes a tumor suppressor that is frequently altered in cancer. WWOX binds several proteins and thus is postulated to be involved in a variety of cellular processes. Interestingly, Wwox-knockout mice develop normally in utero but succumb to hypoglycemia and other metabolic defects early in life resulting in their death by 3–4 weeks of age. Cumulative evidence has linked WWOX with cellular metabolism including steroid metabolism, high-density lipoprotein cholesterol (HDL-C) metabolism, bone metabolism and, more recently, glucose metabolism. In this review, we discuss these evolving functions for WWOX and how its deletion affects cellular metabolism and neoplastic progression. PMID:25491415

  6. Tumor suppressor WWOX binds to ΔNp63α and sensitizes cancer cells to chemotherapy.

    PubMed

    Salah, Z; Bar-mag, T; Kohn, Y; Pichiorri, F; Palumbo, T; Melino, G; Aqeilan, R I

    2013-01-31

    The WWOX tumor suppressor is a WW domain-containing protein. Its function in the cell has been shown to be mediated, in part, by interacting with its partners through its first WW (WW1) domain. Here, we demonstrated that WWOX via WW1 domain interacts with p53 homolog, ΔNp63α. This protein-protein interaction stabilizes ΔNp63α, through antagonizing function of the E3 ubiquitin ligase ITCH, inhibits nuclear translocation of ΔNp63α into the nucleus and suppresses ΔNp63α transactivation function. Additionally, we found that this functional crosstalk reverses cancer cells resistance to cisplatin, mediated by ΔNp63α, and consequently renders these cells more sensitive to undergo apoptosis. These findings suggest a functional crosstalk between WWOX and ΔNp63α in tumorigenesis.

  7. Tumor suppressor WWOX binds to ΔNp63α and sensitizes cancer cells to chemotherapy

    PubMed Central

    Salah, Z; Bar-mag, T; Kohn, Y; Pichiorri, F; Palumbo, T; Melino, G; Aqeilan, R I

    2013-01-01

    The WWOX tumor suppressor is a WW domain-containing protein. Its function in the cell has been shown to be mediated, in part, by interacting with its partners through its first WW (WW1) domain. Here, we demonstrated that WWOX via WW1 domain interacts with p53 homolog, ΔNp63α. This protein–protein interaction stabilizes ΔNp63α, through antagonizing function of the E3 ubiquitin ligase ITCH, inhibits nuclear translocation of ΔNp63α into the nucleus and suppresses ΔNp63α transactivation function. Additionally, we found that this functional crosstalk reverses cancer cells resistance to cisplatin, mediated by ΔNp63α, and consequently renders these cells more sensitive to undergo apoptosis. These findings suggest a functional crosstalk between WWOX and ΔNp63α in tumorigenesis. PMID:23370280

  8. Conditional inactivation of the mouse Wwox tumor suppressor gene recapitulates the null phenotype.

    PubMed

    Abdeen, Suhaib K; Del Mare, Sara; Hussain, Sadeeq; Abu-Remaileh, Muhannad; Salah, Zaidoun; Hagan, John; Rawahneh, Maysoon; Pu, Xin-An; Russell, Stacey; Stein, Janet L; Stein, Gary S; Lian, Jane B; Aqeilan, Rami I

    2013-07-01

    WW domain-containing oxidoreductase (WWOX) is highly conserved in both human and murine. WWOX spans the second most common human chromosomal fragile site, FRA16D, and is commonly inactivated in multiple human cancers. Modeling WWOX inactivation in mice revealed a complex phenotype including postnatal lethality, defects in bone metabolism and steroidogenesis and tumor suppressor function resulting in osteosarcomas. For better understanding of WWOX roles in different tissues at distinct stages of development and in pathological conditions, Wwox conditional knockout mice were generated in which loxp sites flank exon 1 in the Wwox allele. We demonstrated that Cre-mediated recombination using EIIA-Cre, a Cre line expressed in germline, results in postnatal lethality by age of 3 weeks and decreased bone mineralization resembling total ablation of WWOX as in conventional null mice. This animal model will be useful to study distinct roles of WWOX in multiple tissues at different ages.

  9. p53 isoforms - a conspiracy to kidnap p53 tumor suppressor activity?

    PubMed

    Marcel, V; Hainaut, P

    2009-02-01

    For 25 years, the p53 tumor suppressor protein was considered the only protein expressed by the (TP53) gene. However, in several studies the existence of p53 alternative transcripts in mouse and human cells has been documented, while their expression patterns and functions remained a mystery. Since 2002, several groups have identified and described the existence of up to 10 p53 isoforms and have demonstrated their roles in modulation of p53 suppressive activity. It is now clear that the patterns of p53 expression are much more complex than previously recognized and that these isoforms have the potential to act either synergistically or antagonistically, depending on their structure and mechanism of production. This review focuses on the different ways to produce p53 isoforms, on their specific properties, on their effect on p53 suppressive activity as well as on their implication in a new potential mechanism involved in p53 deregulation in cancer.

  10. Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to cancer.

    PubMed

    Li, Junan; Poi, Ming Jye; Tsai, Ming-Daw

    2011-06-28

    P16(INK4A) (also known as P16 and MTS1), a protein consisting exclusively of four ankyrin repeats, is recognized as a tumor suppressor mainly because of the prevalence of genetic inactivation of the p16(INK4A) (or CDKN2A) gene in virtually all types of human cancers. However, it has also been shown that an elevated level of expression (upregulation) of P16 is involved in cellular senescence, aging, and cancer progression, indicating that the regulation of P16 is critical for its function. Here, we discuss the regulatory mechanisms of P16 function at the DNA level, the transcription level, and the posttranscriptional level, as well as their implications for the structure-function relationship of P16 and for human cancers.

  11. Somatic Single-hits Inactivate the X-linked Tumor Suppressor FOXP3 in the Prostate

    PubMed Central

    Wang, Lizhong; Liu, Runhua; Li, Weiquan; Chen, Chong; Katoh, Hiroto; Chen, Guo-Yun; McNally, Beth; Lin, Lin; Zhou, Penghui; Zuo, Tao; Cooney, Kathleen A.; Liu, Yang; Zheng, Pan

    2009-01-01

    Despite clear epidemiological and genetic evidence for X-linked prostate cancer risk, all prostate cancer genes identified are autosomal. Here we report somatic inactivating mutations and deletion of the X-linked FOXP3 gene residing at Xp11.23 in human prostate cancer. Lineage-specific ablation of FoxP3 in the mouse prostate epithelial cells leads to prostate hyperplasia and prostate intraepithelial neoplasia. In both normal and malignant prostate tissues, FOXP3 is both necessary and sufficient to transcriptionally repress cMYC, the most commonly over-expressed oncogene in prostate cancer as well as among the aggregates of other cancers. FOXP3 is an X-linked prostate tumor suppressor in the male. Since the male has only one X chromosome, our data represents a paradigm of “single-genetic-hit” inactivation-mediated carcinogenesis. PMID:19800578

  12. The tumor suppressor PTEN and the PDK1 kinase regulate formation of the columnar neural epithelium.

    PubMed

    Grego-Bessa, Joaquim; Bloomekatz, Joshua; Castel, Pau; Omelchenko, Tatiana; Baselga, José; Anderson, Kathryn V

    2016-01-26

    Epithelial morphogenesis and stability are essential for normal development and organ homeostasis. The mouse neural plate is a cuboidal epithelium that remodels into a columnar pseudostratified epithelium over the course of 24 hr. Here we show that the transition to a columnar epithelium fails in mutant embryos that lack the tumor suppressor PTEN, although proliferation, patterning and apical-basal polarity markers are normal in the mutants. The Pten phenotype is mimicked by constitutive activation of PI3 kinase and is rescued by the removal of PDK1 (PDPK1), but does not depend on the downstream kinases AKT and mTORC1. High resolution imaging shows that PTEN is required for stabilization of planar cell packing in the neural plate and for the formation of stable apical-basal microtubule arrays. The data suggest that appropriate levels of membrane-associated PDPK1 are required for stabilization of apical junctions, which promotes cell elongation, during epithelial morphogenesis.

  13. Expression of the human tumor suppressor p53 induces cell death in Pichia pastoris.

    PubMed

    Abdelmoula-Souissi, Salma; Mabrouk, Imed; Gargouri, Ali; Mokdad-Gargouri, Raja

    2012-02-01

    The human tumor suppressor p53 is known as guardian of genome because of its involvement in many signals related to cell life or death. In this work, we report that human p53 induces cell death in the yeast Pichia pastoris. We showed a growth inhibition effect, which increased with the p53 protein expression level in recombinant Mut(s) (methanol utilization slow) strain of Pichia. However, no effect of p53 was observed in recombinant strain of Mut(+) (methanol utilization plus) phenotype. Interestingly, human p53 induces cell death in recombinant strains Mut(s) with characteristic markers of apoptosis such as DNA fragmentation, exposure of phosphatidylserine, and reactive oxygen species generation. Taken together, our results strongly suggest that human p53 is biologically active in this heterologous context. Thus, we propose that P. pastoris could be a useful tool to better understand the biological function of human p53.

  14. Discovery of novel tumor suppressor p53 response elements using information theory

    PubMed Central

    Lyakhov, Ilya G.; Krishnamachari, Annangarachari; Schneider, Thomas D.

    2008-01-01

    An accurate method for locating genes under tumor suppressor p53 control that is based on a well-established mathematical theory and built using naturally occurring, experimentally proven p53 sites is essential in understanding the complete p53 network. We used a molecular information theory approach to create a flexible model for p53 binding. By searching around transcription start sites in human chromosomes 1 and 2, we predicted 16 novel p53 binding sites and experimentally demonstrated that 15 of the 16 (94%) sites were bound by p53. Some were also bound by the related proteins p63 and p73. Thirteen of the adjacent genes were controlled by at least one of the proteins. Eleven of the 16 sites (69%) had not been identified previously. This molecular information theory approach can be extended to any genetic system to predict new sites for DNA-binding proteins. PMID:18495754

  15. Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53

    PubMed Central

    Yoon, Kyoung Wan; Byun, Sanguine; Kwon, Eunjeong; Hwang, So-Young; Chu, Kiki; Hiraki, Masatsugu; Jo, Seung-Hee; Weins, Astrid; Hakroush, Samy; Cebulla, Angelika; Sykes, David B.; Greka, Anna; Mundel, Peter; Fisher, David E.; Mandinova, Anna; Lee, Sam W.

    2016-01-01

    The inefficient clearance of dying cells can lead to abnormal immune responses, such as unresolved inflammation and autoimmune conditions. We show that tumor suppressor p53 controls signaling-mediated phagocytosis of apoptotic cells through its target, Death Domain1α (DD1α), which suggests that p53 promotes both the proapoptotic pathway and postapoptotic events. DD1α appears to function as an engulfment ligand or receptor that engages in homophilic intermolecular interaction at intercellular junctions of apoptotic cells and macrophages, unlike other typical scavenger receptors that recognize phosphatidylserine on the surface of dead cells. DD1α-deficient mice showed in vivo defects in clearing dying cells, which led to multiple organ damage indicative of immune dysfunction. p53-induced expression of DD1α thus prevents persistence of cell corpses and ensures efficient generation of precise immune responses. PMID:26228159

  16. Frequent Attenuation of the WWOX Tumor Suppressor in Osteosarcoma is Associated with Increased Tumorigenicity and Aberrant RUNX2 Expression

    PubMed Central

    Kurek, Kyle; Del Mare, Sara; Salah, Zaidoun; Abdeen, Suhaib; Sadiq, Hussain; Lee, Sukhee; Gaudio, Eugenio; Zanesi, Nicola; Jones, Kevin B.; DeYoung, Barry; Amir, Gail; Gebhardt, Mark; Warman, Matthew; Stein, Gary S.; Stein, Janet L.; Lian, Jane B.; Aqeilan, Rami I.

    2011-01-01

    The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor that is deleted or attenuated in most human tumors. Wwox-deficient mice develop osteosarcoma (OS), an aggressive bone tumor with poor prognosis that often metastasizes to lung. On the basis of these observations, we examined the status of WWOX in human OS specimens and cell lines. In human OS clinical samples, WWOX expression was absent or reduced in 58% of tumors examined (P< 0.0001). Compared to the primary tumors, WWOX levels frequently increased in tumors resected following chemotherapy. In contrast, tumor metastases to lung often exhibited reduced WWOX levels, relative to the primary tumor. In human OS cell lines having reduced WWOX expression, ectopic expression of WWOX inhibited proliferation and attenuated invasion in vitro, and suppressed tumorgenicity in nude mice. Expression of WWOX was associated with reduced RUNX2 expression in OS cell lines, whereas Runx2 levels were elevated in femurs of Wwox-deficient mice. Furthermore, WWOX reconstitution in HOS cells was associated with downregulation of RUNX2 levels and RUNX2 target genes, consistent with the ability of WWOX to suppress RUNX2 transactivation activity. In clinical samples, RUNX2 was expressed in the majority of primary tumors and undetectable in most tumors resected following chemotherapy, whereas most metastases were RUNX2 positive. Our results deepen the evidence of a tumor suppressor role for WWOX in OS, furthering its prognostic and therapeutic significance in this disease. PMID:20530675

  17. Frequent attenuation of the WWOX tumor suppressor in osteosarcoma is associated with increased tumorigenicity and aberrant RUNX2 expression.

    PubMed

    Kurek, Kyle C; Del Mare, Sara; Salah, Zaidoun; Abdeen, Suhaib; Sadiq, Hussain; Lee, Suk-Hee; Gaudio, Eugenio; Zanesi, Nicola; Jones, Kevin B; DeYoung, Barry; Amir, Gail; Gebhardt, Mark; Warman, Matthew; Stein, Gary S; Stein, Janet L; Lian, Jane B; Aqeilan, Rami I

    2010-07-01

    The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor that is deleted or attenuated in most human tumors. Wwox-deficient mice develop osteosarcoma (OS), an aggressive bone tumor with poor prognosis that often metastasizes to lung. On the basis of these observations, we examined the status of WWOX in human OS specimens and cell lines. In human OS clinical samples, WWOX expression was absent or reduced in 58% of tumors examined (P < 0.0001). Compared with the primary tumors, WWOX levels frequently increased in tumors resected following chemotherapy. In contrast, tumor metastases to lung often exhibited reduced WWOX levels relative to the primary tumor. In human OS cell lines having reduced WWOX expression, ectopic expression of WWOX inhibited proliferation and attenuated invasion in vitro, and suppressed tumorigenicity in nude mice. Expression of WWOX was associated with reduced RUNX2 expression in OS cell lines, whereas RUNX2 levels were elevated in femurs of Wwox-deficient mice. Furthermore, WWOX reconstitution in HOS cells was associated with downregulation of RUNX2 levels and RUNX2 target genes, consistent with the ability of WWOX to suppress RUNX2 transactivation activity. In clinical samples, RUNX2 was expressed in the majority of primary tumors and undetectable in most tumors resected following chemotherapy, whereas most metastases were RUNX2 positive. Our results deepen the evidence of a tumor suppressor role for WWOX in OS, furthering its prognostic and therapeutic significance in this disease.

  18. TSGene 2.0: an updated literature-based knowledgebase for tumor suppressor genes.

    PubMed

    Zhao, Min; Kim, Pora; Mitra, Ramkrishna; Zhao, Junfei; Zhao, Zhongming

    2016-01-04

    Tumor suppressor genes (TSGs) are a major type of gatekeeper genes in the cell growth. A knowledgebase with the systematic collection and curation of TSGs in multiple cancer types is critically important for further studying their biological functions as well as for developing therapeutic strategies. Since its development in 2012, the Tumor Suppressor Gene database (TSGene), has become a popular resource in the cancer research community. Here, we reported the TSGene version 2.0, which has substantial updates of contents (e.g. up-to-date literature and pan-cancer genomic data collection and curation), data types (noncoding RNAs and protein-coding genes) and content accessibility. Specifically, the current TSGene 2.0 contains 1217 human TSGs (1018 protein-coding and 199 non-coding genes) curated from over 9000 articles. Additionally, TSGene 2.0 provides thousands of expression and mutation patterns derived from pan-cancer data of The Cancer Genome Atlas. A new web interface is available at http://bioinfo.mc.vanderbilt.edu/TSGene/. Systematic analyses of 199 non-coding TSGs provide numerous cancer-specific non-coding mutational events for further screening and clinical use. Intriguingly, we identified 49 protein-coding TSGs that were consistently down-regulated in 11 cancer types. In summary, TSGene 2.0, which is the only available database for TSGs, provides the most updated TSGs and their features in pan-cancer. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  19. PTEN functions as a melanoma tumor suppressor by promoting host immune response.

    PubMed

    Dong, Y; Richards, J-Ae; Gupta, R; Aung, P P; Emley, A; Kluger, Y; Dogra, S K; Mahalingam, M; Wajapeyee, N

    2014-09-18

    Cancer cells acquire several traits that allow for their survival and progression, including the ability to evade the host immune response. However, the mechanisms by which cancer cells evade host immune responses remain largely elusive. Here we study the phenomena of immune evasion in malignant melanoma cells. We find that the tumor suppressor phosphatase and tensin homolog (PTEN) is an important regulator of the host immune response against melanoma cells. Mechanistically, PTEN represses the expression of immunosuppressive cytokines by blocking the phosphatidylinositide 3-kinase (PI3K) pathway. In melanoma cells lacking PTEN, signal transducer and activator of transcription 3 activates the transcription of immunosuppressive cytokines in a PI3K-dependent manner. Furthermore, conditioned media from PTEN-deficient, patient-derived short-term melanoma cultures and established melanoma cell lines blocked the production of the interleukin-12 (IL-12) in human monocyte-derived dendritic cells. Inhibition of IL-12 production was rescued by restoring PTEN or using neutralizing antibodies against the immunosuppressive cytokines. Furthermore, we report that PTEN, as an alternative mechanism to promote the host immune response against cancer cells, represses the expression of programmed cell death 1 ligand, a known repressor of the host immune response. Finally, to establish the clinical significance of our results, we analyzed malignant melanoma patient samples with or without brisk host responses. These analyses confirmed that PTEN loss is associated with a higher percentage of malignant melanoma samples with non-brisk host responses compared with samples with brisk host responses. Collectively, these results establish that PTEN functions as a melanoma tumor suppressor in part by regulating the host immune response against melanoma cells and highlight the importance of assessing PTEN status before recruiting melanoma patients for immunotherapies.

  20. Generation and Characterization of Mice Carrying a Conditional Allele of the Wwox Tumor Suppressor Gene

    PubMed Central

    Ludes-Meyers, John H.; Kil, Hyunsuk; Parker-Thornburg, Jan; Kusewitt, Donna F.; Bedford, Mark T.; Aldaz, C. Marcelo

    2009-01-01

    WWOX, the gene that spans the second most common human chromosomal fragile site, FRA16D, is inactivated in multiple human cancers and behaves as a suppressor of tumor growth. Since we are interested in understanding WWOX function in both normal and cancer tissues we generated mice harboring a conditional Wwox allele by flanking Exon 1 of the Wwox gene with LoxP sites. Wwox knockout (KO) mice were developed by breeding with transgenic mice carrying the Cre-recombinase gene under the control of the adenovirus EIIA promoter. We found that Wwox KO mice suffered from severe metabolic defect(s) resulting in growth retardation and all mice died by 3 wk of age. All Wwox KO mice displayed significant hypocapnia suggesting a state of metabolic acidosis. This finding and the known high expression of Wwox in kidney tubules suggest a role for Wwox in acid/base balance. Importantly, Wwox KO mice displayed histopathological and hematological signs of impaired hematopoeisis, leukopenia, and splenic atrophy. Impaired hematopoeisis can also be a contributing factor to metabolic acidosis and death. Hypoglycemia and hypocalcemia was also observed affecting the KO mice. In addition, bone metabolic defects were evident in Wwox KO mice. Bones were smaller and thinner having reduced bone volume as a consequence of a defect in mineralization. No evidence of spontaneous neoplasia was observed in Wwox KO mice. We have generated a new mouse model to inactivate the Wwox tumor suppressor gene conditionally. This will greatly facilitate the functional analysis of Wwox in adult mice and will allow investigating neoplastic transformation in specific target tissues. PMID:19936220

  1. Epstein-Barr virus down-regulates tumor suppressor DOK1 expression.

    PubMed

    Siouda, Maha; Frecha, Cecilia; Accardi, Rosita; Yue, Jiping; Cuenin, Cyrille; Gruffat, Henri; Manet, Evelyne; Herceg, Zdenko; Sylla, Bakary S; Tommasino, Massimo

    2014-05-01

    The DOK1 tumor suppressor gene encodes an adapter protein that acts as a negative regulator of several signaling pathways. We have previously reported that DOK1 expression is up-regulated upon cellular stress, via the transcription factor E2F1, and down-regulated in a variety of human malignancies due to aberrant hypermethylation of its promoter. Here we show that Epstein Barr virus (EBV) infection of primary human B-cells leads to the down-regulation of DOK1 gene expression via the viral oncoprotein LMP1. LMP1 alone induces recruitment to the DOK1 promoter of at least two independent inhibitory complexes, one containing E2F1/pRB/DNMT1 and another containing at least EZH2. These events result in tri-methylation of histone H3 at lysine 27 (H3K27me3) of the DOK1 promoter and gene expression silencing. We also present evidence that the presence of additional EBV proteins leads to further repression of DOK1 expression with an additional mechanism. Indeed, EBV infection of B-cells induces DNA methylation at the DOK1 promoter region including the E2F1 responsive elements that, in turn, lose the ability to interact with E2F complexes. Treatment of EBV-infected B-cell-lines with the methyl-transferase inhibitor 5-aza-2'-deoxycytidine rescues DOK1 expression. In summary, our data show the deregulation of DOK1 gene expression by EBV and provide novel insights into the regulation of the DOK1 tumor suppressor in viral-related carcinogenesis.

  2. Epstein-Barr Virus Down-Regulates Tumor Suppressor DOK1 Expression

    PubMed Central

    Siouda, Maha; Frecha, Cecilia; Accardi, Rosita; Yue, Jiping; Cuenin, Cyrille; Gruffat, Henri; Manet, Evelyne; Herceg, Zdenko; Sylla, Bakary S.; Tommasino, Massimo

    2014-01-01

    The DOK1 tumor suppressor gene encodes an adapter protein that acts as a negative regulator of several signaling pathways. We have previously reported that DOK1 expression is up-regulated upon cellular stress, via the transcription factor E2F1, and down-regulated in a variety of human malignancies due to aberrant hypermethylation of its promoter. Here we show that Epstein Barr virus (EBV) infection of primary human B-cells leads to the down-regulation of DOK1 gene expression via the viral oncoprotein LMP1. LMP1 alone induces recruitment to the DOK1 promoter of at least two independent inhibitory complexes, one containing E2F1/pRB/DNMT1 and another containing at least EZH2. These events result in tri-methylation of histone H3 at lysine 27 (H3K27me3) of the DOK1 promoter and gene expression silencing. We also present evidence that the presence of additional EBV proteins leads to further repression of DOK1 expression with an additional mechanism. Indeed, EBV infection of B-cells induces DNA methylation at the DOK1 promoter region including the E2F1 responsive elements that, in turn, lose the ability to interact with E2F complexes. Treatment of EBV-infected B-cell-lines with the methyl-transferase inhibitor 5-aza-2′-deoxycytidine rescues DOK1 expression. In summary, our data show the deregulation of DOK1 gene expression by EBV and provide novel insights into the regulation of the DOK1 tumor suppressor in viral-related carcinogenesis. PMID:24809689

  3. Methylation of tumor suppressor genes is related with copy number aberrations in breast cancer

    PubMed Central

    Murria, Rosa; Palanca, Sarai; de Juan, Inmaculada; Egoavil, Cecilia; Alenda, Cristina; García-Casado, Zaida; Juan, María J; Sánchez, Ana B; Santaballa, Ana; Chirivella, Isabel; Segura, Ángel; Hervás, David; Llop, Marta; Barragán, Eva; Bolufer, Pascual

    2015-01-01

    This study investigates the relationship of promoter methylation in tumor suppressor genes with copy-number aberrations (CNA) and with tumor markers in breast cancer (BCs). The study includes 98 formalin fixed paraffin-embedded BCs in which promoter methylation of 24 tumour suppressor genes were assessed by Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA), CNA of 20 BC related genes by MLPA and ER, PR, HER2, CK5/6, CK18, EGFR, Cadherin-E, P53, Ki-67 and PARP expression by immunohistochemistry (IHC). Cluster analysis classed BCs in two groups according to promoter methylation percentage: the highly-methylated group (16 BCs), containing mostly hyper-methylated genes, and the sparsely-methylated group (82 BCs) with hypo-methylated genes. ATM, CDKN2A, VHL, CHFR and CDKN2B showed the greatest differences in the mean methylation percentage between these groups. We found no relationship of the IHC parameters or pathological features with methylation status, except for Catherin-E (p = 0.008). However the highly methylated BCs showed higher CNA proportion than the sparsely methylated BCs (p < 0.001, OR = 1.62; IC 95% [1.26, 2.07]). CDC6, MAPT, MED1, PRMD14 and AURKA showed the major differences in the CNA percentage between the two groups, exceeding the 22%. Methylation in RASSF1, CASP8, DAPK1 and GSTP1 conferred the highest probability of harboring CNA. Our results show a new link between promoter methylation and CNA giving support to the importance of methylation events to establish new BCs subtypes. Our findings may be also of relevance in personalized therapy assessment, which could benefit the hyper methylated BC patients group. PMID:25628946

  4. From tamoxifen to dendrogenin A: The discovery of a mammalian tumor suppressor and cholesterol metabolite.

    PubMed

    Silvente-Poirot, Sandrine; de Medina, Philippe; Record, Michel; Poirot, Marc

    2016-11-01

    Tamoxifen (Tam) was developed as a ligand and modulator of estrogen receptor α (ERα) and is one of the main drugs used globally for the hormonotherapy of breast cancers. Besides ERα, Tam also binds with high affinity to the microsomal antiestrogen binding site (AEBS). The AEBS is a hetero-oligomeric proteinaceous complex with cholesterol-5,6-epoxide hydrolase (ChEH) activity that is associated with an intracellular histamine (HA) binding site. The enzymatic activities of the ChEH subunits control developmental programs in mammals and transform cholesterol-5,6-epoxides (5,6-EC) into cholestane-3β,5α,6β-triol. Inhibition of the ChEH activity by pharmacological agents such as Tam induce cancer cell re-differentiation through the accumulation of 5,6-EC. A few years ago, the putative chemical reactivity of the 5,6-EC epoxide group towards nucleophiles led our group to hypothesize that 5,6-EC could react with HA that was co-localized at the AEBS to give a new molecule involved in cell differentiation. This hypothesis was chemically tested and the conjugation of 5,6α-EC: with HA was found possible but only under catalytic conditions. It gave a stereo-selective single product of transformation which was named dendrogenin A (DDA). DDA was found to display potent cancer cell differentiation and anticancer properties in vitro and in vivo, suggesting that it was a tumor suppressor metabolite. The presence of DDA was then established in several mammalian tissues, providing the first evidence of a steroidal alkaloid metabolite in mammals. The discovery of DDA highlights a new metabolic pathway in mammals which lies at the crossroads of cholesterol and histamine metabolism and produces this tumor suppressor metabolite. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  5. EBNA1 binding and epigenetic regulation of gastrokine tumor suppressor genes in gastric carcinoma cells

    PubMed Central

    2014-01-01

    Background Epstein-Barr Virus (EBV) latently infects ~10% of gastric carcinomas (GC). Epstein-Barr Nuclear Antigen 1 (EBNA1) is expressed in EBV-associated GC, and can bind host DNA, where it may impact cellular gene regulation. Here, we show that EBNA1 binds directly to DNA upstream of the divergently transcribed GC-specific tumor suppressor genes gastrokine 1 (GKN1) and gastrokine 2 (GKN2). Methods We use ChIP-Seq, ChIP-qPCR, and EMSA to demonstrate that EBNA1 binds directly to the GKN1 and GKN2 promoter locus. We generate AGS-EBV, and AGS-EBNA1 cell lines to study the effects of EBNA1 on GKN1 and GKN2 mRNA expression with or without 5′ azacytidine treatment. Results We show that gastrokine genes are transcriptionally silenced by DNA methylation. We also show that latent EBV infection further reduces GKN1 and GKN2 expression in AGS gastric carcinoma cells, and that siRNA depletion of EBNA1 partially alleviates this repression. However, ectopic expression of EBNA1 slightly increased GKN1 and GKN2 basal mRNA levels, but reduced their responsiveness to demethylating agent. Conclusions These findings demonstrate that EBNA1 binds to the divergent promoter of the GKN1 and GKN2 genes in GC cells, and suggest that EBNA1 contributes to the complex transcriptional and epigenetic deregulation of the GKN1 and GKN2 tumor suppressor genes in EBV positive GC. PMID:24460791

  6. Tumor suppressor microRNAs are downregulated in myelodysplastic syndrome with spliceosome mutations

    PubMed Central

    Aslan, Derya; Garde, Christian; Nygaard, Mette Katrine; Helbo, Alexandra Søgaard; Dimopoulos, Konstantinos; Hansen, Jakob Werner; Severinsen, Marianne Tang; Treppendahl, Marianne Bach; Sjø, Lene Dissing; Grønbæk, Kirsten; Kristensen, Lasse Sommer

    2016-01-01

    Spliceosome mutations are frequently observed in patients with myelodysplastic syndromes (MDS). However, it is largely unknown how these mutations contribute to the disease. MicroRNAs (miRNAs) are small noncoding RNAs, which have been implicated in most human cancers due to their role in post transcriptional gene regulation. The aim of this study was to analyze the impact of spliceosome mutations on the expression of miRNAs in a cohort of 34 MDS patients. In total, the expression of 76 miRNAs, including mirtrons and splice site overlapping miRNAs, was accurately quantified using reverse transcriptase quantitative PCR. The majority of the studied miRNAs have previously been implicated in MDS. Stably expressed miRNA genes for normalization of the data were identified using GeNorm and NormFinder algorithms. High-resolution melting assays covering all mutational hotspots within SF3B1, SRSF2, and U2AF1 (U2AF35) were developed, and all detected mutations were confirmed by Sanger sequencing. Overall, canonical miRNAs were downregulated in spliceosome mutated samples compared to wild-type (P = 0.002), and samples from spliceosome mutated patients clustered together in hierarchical cluster analyses. Among the most downregulated miRNAs were several tumor-suppressor miRNAs, including several let-7 family members, miR-423, and miR-103a. Finally, we observed that the predicted targets of the most downregulated miRNAs were involved in apoptosis, hematopoiesis, and acute myeloid leukemia among other cancer- and metabolic pathways. Our data indicate that spliceosome mutations may play an important role in MDS pathophysiology by affecting the expression of tumor suppressor miRNA genes involved in the development and progression of MDS. PMID:26848861

  7. PLK1 is a binding partner and a negative regulator of FOXO3 tumor suppressor

    PubMed Central

    Bucur, Octavian; Stancu, Andreea Lucia; Muraru, Maria Sinziana; Melet, Armelle; Petrescu, Stefana Maria; Khosravi-Far, Roya

    2015-01-01

    FOXO family members (FOXOs: FOXO1, FOXO3, FOXO4 and FOXO6) are important transcription factors and tumor suppressors controlling cell homeostasis and cell fate. They are characterized by an extraordinary functional diversity, being involved in regulation of cell cycle, proliferation, apoptosis, DNA damage response, oxidative detoxification, cell differentiation and stem cell maintenance, cell metabolism, angiogenesis, cardiac and other organ’s development, aging, and other critical cellular processes. FOXOs are tightly regulated by reversible phosphorylation, ubiquitination, acetylation and methylation. Interestingly, the known kinases phosphorylate only a small percentage of the known or predicted FOXOs phosphorylation sites, suggesting that additional kinases that phosphorylate and control FOXOs activity exist. In order to identify novel regulators of FOXO3, we have employed a proteomics screening strategy. Using HeLa cancer cell line and a Tandem Affinity Purification followed by Mass Spectrometry analysis, we identified several proteins as binding partners of FOXO3. Noteworthy, Polo Like Kinase 1 (PLK1) proto-oncogene was one of the identified FOXO3 binding partners. PLK1 plays a critical role during cell cycle (G2-M transition and all phases of mitosis) and in maintenance of genomic stability. Our experimental results presented in this manuscript demonstrate that FOXO3 and PLK1 exist in a molecular complex through most of the phases of the cell cycle, with a higher occurrence in the G2-M cell cycle phases. PLK1 induces translocation of FOXO3 from the nucleus to the cytoplasm and suppresses FOXO3 activity, measured by the decrease in the pro-apoptotic Bim protein levels and in the cell cycle inhibitor protein p27. Furthermore, PLK1 can directly phosphorylate FOXO3 in an in vitro kinase assay. These results present the discovery of PLK1 proto-oncogene as a binding partner and a negative regulator of FOXO3 tumor suppressor. PMID:26280018

  8. PLK1 is a binding partner and a negative regulator of FOXO3 tumor suppressor.

    PubMed

    Bucur, Octavian; Stancu, Andreea Lucia; Muraru, Maria Sinziana; Melet, Armelle; Petrescu, Stefana Maria; Khosravi-Far, Roya

    2014-01-01

    FOXO family members (FOXOs: FOXO1, FOXO3, FOXO4 and FOXO6) are important transcription factors and tumor suppressors controlling cell homeostasis and cell fate. They are characterized by an extraordinary functional diversity, being involved in regulation of cell cycle, proliferation, apoptosis, DNA damage response, oxidative detoxification, cell differentiation and stem cell maintenance, cell metabolism, angiogenesis, cardiac and other organ's development, aging, and other critical cellular processes. FOXOs are tightly regulated by reversible phosphorylation, ubiquitination, acetylation and methylation. Interestingly, the known kinases phosphorylate only a small percentage of the known or predicted FOXOs phosphorylation sites, suggesting that additional kinases that phosphorylate and control FOXOs activity exist. In order to identify novel regulators of FOXO3, we have employed a proteomics screening strategy. Using HeLa cancer cell line and a Tandem Affinity Purification followed by Mass Spectrometry analysis, we identified several proteins as binding partners of FOXO3. Noteworthy, Polo Like Kinase 1 (PLK1) proto-oncogene was one of the identified FOXO3 binding partners. PLK1 plays a critical role during cell cycle (G2-M transition and all phases of mitosis) and in maintenance of genomic stability. Our experimental results presented in this manuscript demonstrate that FOXO3 and PLK1 exist in a molecular complex through most of the phases of the cell cycle, with a higher occurrence in the G2-M cell cycle phases. PLK1 induces translocation of FOXO3 from the nucleus to the cytoplasm and suppresses FOXO3 activity, measured by the decrease in the pro-apoptotic Bim protein levels and in the cell cycle inhibitor protein p27. Furthermore, PLK1 can directly phosphorylate FOXO3 in an in vitro kinase assay. These results present the discovery of PLK1 proto-oncogene as a binding partner and a negative regulator of FOXO3 tumor suppressor.

  9. The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein

    PubMed Central

    Chen, Muhan; Nowak, Dawid G.; Narula, Navneet; Watrud, Kaitlin; Herzka, Tali M.; Zheng, Wu; Ebbesen, Saya H.; Wang, Victoria M.Y.; Nasar, Abu; Cordon-Cardo, Carlos; Wilkinson, John E.; Powers, Scott; Sordella, Raffaella; Altorki, Nasser K.; Stiles, Brendon M.

    2017-01-01

    Phosphatase and tensin homologue (PTEN) protein levels are critical for tumor suppression. However, the search for a recurrent cancer-associated gene alteration that causes PTEN degradation has remained futile. In this study, we show that Importin-11 (Ipo11) is a transport receptor for PTEN that is required to physically separate PTEN from elements of the PTEN degradation machinery. Mechanistically, we find that the E2 ubiquitin-conjugating enzyme and IPO11 cargo, UBE2E1, is a limiting factor for PTEN degradation. Using in vitro and in vivo gene-targeting methods, we show that Ipo11 loss results in degradation of Pten, lung adenocarcinoma, and neoplasia in mouse prostate with aberrantly high levels of Ube2e1 in the cytoplasm. These findings explain the correlation between loss of IPO11 and PTEN protein in human lung tumors. Furthermore, we find that IPO11 status predicts disease recurrence and progression to metastasis in patients choosing radical prostatectomy. Thus, our data introduce the IPO11 gene as a tumor-suppressor locus, which is of special importance in cancers that still retain at least one intact PTEN allele. PMID:28193700

  10. The Tumor Suppressor hTid1 Inhibits STAT5b Activity via Functional Interaction*

    PubMed Central

    Dhennin-Duthille, Isabelle; Nyga, Rémy; Yahiaoui, Saliha; Gouilleux-Gruart, Valérie; Régnier, Aline; Lassoued, Kaïss; Gouilleux, Fabrice

    2011-01-01

    STAT5a and -5b (signal transducers and activators of transcription 5a and 5b) proteins play an essential role in hematopoietic cell proliferation and survival and are frequently constitutively active in hematologic neoplasms and solid tumors. Because STAT5a and STAT5b differ mainly in the carboxyl-terminal transactivation domain, we sought to identify new proteins that bind specifically to this domain by using a bacterial two-hybrid screening. We isolated hTid1, a human DnaJ protein that acts as a tumor suppressor in various solid tumors. hTid1 interacts specifically with STAT5b but not with STAT5a in hematopoietic cell lines. This interaction involves the cysteine-rich region of the hTid1 DnaJ domain. We also demonstrated that hTid1 negatively regulates the expression and transcriptional activity of STAT5b and suppresses the growth of hematopoietic cells transformed by an oncogenic form of STAT5b. Our findings define hTid1 as a novel partner and negative regulator of STAT5b. PMID:21106534

  11. Mechanism regulating reactive oxygen species in tumor induced myeloid-derived suppressor cells1

    PubMed Central

    Corzo, Cesar A.; Cotter, Matthew J.; Cheng, Pingyan; Cheng, Fendong; Kusmartsev, Sergei; Sotomayor, Eduardo; Padhya, Tapan; McCaffrey, Thomas V.; McCaffrey, Judith C.; Gabrilovich, Dmitry I.

    2010-01-01

    Myeloid-derived suppressor cells (MDSC) are a major component of the immune suppressive network described in cancer and many other pathological conditions. Recent studies have demonstrated that one of the major mechanisms of MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). However, the mechanism of this phenomenon remained unknown. In this study we observed a substantial up-regulation of ROS by MDSC in all of seven different tumor models and in patients with head and neck cancer. The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). MDSC from tumor-bearing mice had significantly higher expression of NOX2 subunits, primarily p47phox and gp91phox, compared to immature myeloid cells from tumor-free mice. Expression of NOX2 subunits in MDSC was controlled by the STAT3 transcription factor. In the absence of NOX2 activity, MDSC lost the ability to suppress T-cell responses and quickly differentiated into mature macrophages and dendritic cells. These findings expand our fundamental understanding of the biology of MDSC and may also open new opportunities for therapeutic regulation of these cells in cancer. PMID:19380816

  12. Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells.

    PubMed

    Corzo, Cesar A; Cotter, Matthew J; Cheng, Pingyan; Cheng, Fendong; Kusmartsev, Sergei; Sotomayor, Eduardo; Padhya, Tapan; McCaffrey, Thomas V; McCaffrey, Judith C; Gabrilovich, Dmitry I

    2009-05-01

    Myeloid-derived suppressor cells (MDSC) are a major component of the immune suppressive network described in cancer and many other pathological conditions. Recent studies have demonstrated that one of the major mechanisms of MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). However, the mechanism of this phenomenon remained unknown. In this study, we observed a substantial up-regulation of ROS by MDSC in all of seven different tumor models and in patients with head and neck cancer. The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). MDSC from tumor-bearing mice had significantly higher expression of NOX2 subunits, primarily p47(phox) and gp91(phox), compared with immature myeloid cells from tumor-free mice. Expression of NOX2 subunits in MDSC was controlled by the STAT3 transcription factor. In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. These findings expand our fundamental understanding of the biology of MDSC and may also open new opportunities for therapeutic regulation of these cells in cancer.

  13. Hypermethylation of p16 tumor-suppressor gene in ameloblastic carcinoma, ameloblastoma, and dental follicles.

    PubMed

    Khojasteh, Arash; Khodayari, Abbas; Rahimi, Farzaneh; Ghaderian, Mohamad Hossain; Jafarian, Mohamad; Nayebi, Alireza; Akbarzadeh Najar, Reza; Tabatabayipanah, Akram; Jahangirnia, Alireza

    2013-01-01

    The high rate of p16 gene alterations in malignant neoplasms suggests the important effect of this tumor-suppressor gene mutation on the malignant behavior of tumoral lesions. The present study investigated the possible methylation of the p16 tumor in ameloblastic carcinoma, ameloblastoma, and dental follicles. Eighteen samples of ameloblastic carcinoma, ameloblastoma, and dental follicles of mandibular impacted third molar were selected from available documents in the archives of the Department of Oral and Maxillofacial Pathology, Taleghani Hospital and the Department of Oral and Maxillofacial Pathology, Shahid Beheshti University of Medical Sciences, Tehran, Iran. After confirming the initial diagnosis, 6-μm sections were used for DNA extraction. A CpG island methylation of p16 was identified by polymerase chain reaction. Although CpG methylation of p16 was observed in all ameloblastic carcinoma samples, only 1 ameloblastoma specimen exhibited the mutation. The mutation was not detected in other ameloblastoma specimens or in any dental follicle sample. The p16 alteration might play a role in the malignant progression of ameloblastic carcinoma. It is worth mentioning that ameloblastoma can be further differentiated from ameloblastic carcinoma based on molecular observations. Copyright © 2013 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

  14. Evidence for a potential tumor suppressor role for the Na,K-ATPase ß1-subunit

    PubMed Central

    Inge, Landon J.; Rajasekaran, Sigrid A.; Yoshimoto, Koji; Mischel, Paul S.; McBride, William; Landaw, Elliot; Rajasekaran, Ayyappan K.

    2009-01-01

    Summary The Na,K-ATPase, consisting of two essential subunits (α, ß), plays a critical role in the regulation of ion homeostasis in mammalian cells. Recent studies indicate that reduced expression of the ß1 isoform (NaK-ß1) is commonly observed in carcinoma and is associated with events involved in cancer progression. In this study, we present evidence that repletion of NaK-ß1 in Moloney sarcoma virus-transformed Madin-Darby canine kidney cells (MSV-MDCK), a highly tumorigenic cell line, inhibits anchorage independent growth and suppresses tumor formation in immunocompromised mice. Additionally, using an in vitro cell-cell aggregation assay, we showed that cell aggregates of NaK-ß1 subunit expressing MSV-MDCK cells have reduced extracellular regulated kinase (ERK) 1/2 activity compared with parental MSV-MDCK cells. Finally, using immunohistochemistry and fully quantitative image analysis approaches, we showed that the levels of phosphorylated ERK 1/2 are inversely correlated to the NaK-ß1 levels in the tumors. These findings reveal for the first time that NaK-ß1 has a potential tumor-suppressor function in epithelial cells. PMID:18228203

  15. The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein.

    PubMed

    Chen, Muhan; Nowak, Dawid G; Narula, Navneet; Robinson, Brian; Watrud, Kaitlin; Ambrico, Alexandra; Herzka, Tali M; Zeeman, Martha E; Minderer, Matthias; Zheng, Wu; Ebbesen, Saya H; Plafker, Kendra S; Stahlhut, Carlos; Wang, Victoria M Y; Wills, Lorna; Nasar, Abu; Castillo-Martin, Mireia; Cordon-Cardo, Carlos; Wilkinson, John E; Powers, Scott; Sordella, Raffaella; Altorki, Nasser K; Mittal, Vivek; Stiles, Brendon M; Plafker, Scott M; Trotman, Lloyd C

    2017-03-06

    Phosphatase and tensin homologue (PTEN) protein levels are critical for tumor suppression. However, the search for a recurrent cancer-associated gene alteration that causes PTEN degradation has remained futile. In this study, we show that Importin-11 (Ipo11) is a transport receptor for PTEN that is required to physically separate PTEN from elements of the PTEN degradation machinery. Mechanistically, we find that the E2 ubiquitin-conjugating enzyme and IPO11 cargo, UBE2E1, is a limiting factor for PTEN degradation. Using in vitro and in vivo gene-targeting methods, we show that Ipo11 loss results in degradation of Pten, lung adenocarcinoma, and neoplasia in mouse prostate with aberrantly high levels of Ube2e1 in the cytoplasm. These findings explain the correlation between loss of IPO11 and PTEN protein in human lung tumors. Furthermore, we find that IPO11 status predicts disease recurrence and progression to metastasis in patients choosing radical prostatectomy. Thus, our data introduce the IPO11 gene as a tumor-suppressor locus, which is of special importance in cancers that still retain at least one intact PTEN allele.

  16. Role of the WWOX tumor suppressor gene in bone homeostasis and the pathogenesis of osteosarcoma

    PubMed Central

    Del Mare, Sara; Kurek, Kyle C; Stein, Gary S; Lian, Jane B; Aqeilan, Rami I

    2011-01-01

    Osteosarcoma is the most common primary bone malignancy in children with unknown etiology and often with poor clinical outcome. In recent years, a critical role has emerged for the WW domain-containing oxidoreductase (WWOX) in osteosarcoma and bone biology. WWOX is a tumor suppressor that is deleted or attenuated in most human tumors. Wwox-deficient mice develop osteosarcoma and a bone metabolic disease characterized by hypocalcemia and osteopenia. Studies of human osteosarcomas have revealed that the WWOX gene is deleted in 30% of cases and WWOX protein is absent or reduced in ∼60% of tumors. Further, WWOX levels are attenuated in the majority of osteosarcoma cells, in which ectopic expression is associated with reduced proliferation, migration, invasion and tumorigenicity. At the molecular level, WWOX associates with RUNX2 and suppresses its transcriptional activity in osteoblasts and in cancer cells. This review provides new insights on the current knowledge of the spectrum of WWOX activities and future directions for the role of WWOX in bone biology and osteosarcoma. PMID:21731849

  17. Role of the WWOX tumor suppressor gene in bone homeostasis and the pathogenesis of osteosarcoma.

    PubMed

    Del Mare, Sara; Kurek, Kyle C; Stein, Gary S; Lian, Jane B; Aqeilan, Rami I

    2011-01-01

    Osteosarcoma is the most common primary bone malignancy in children with unknown etiology and often with poor clinical outcome. In recent years, a critical role has emerged for the WW domain-containing oxidoreductase (WWOX) in osteosarcoma and bone biology. WWOX is a tumor suppressor that is deleted or attenuated in most human tumors. Wwox-deficient mice develop osteosarcoma and a bone metabolic disease characterized by hypocalcemia and osteopenia. Studies of human osteosarcomas have revealed that the WWOX gene is deleted in 30% of cases and WWOX protein is absent or reduced in ∼60% of tumors. Further, WWOX levels are attenuated in the majority of osteosarcoma cells, in which ectopic expression is associated with reduced proliferation, migration, invasion and tumorigenicity. At the molecular level, WWOX associates with RUNX2 and suppresses its transcriptional activity in osteoblasts and in cancer cells. This review provides new insights on the current knowledge of the spectrum of WWOX activities and future directions for the role of WWOX in bone biology and osteosarcoma.

  18. Tracheal development and the von Hippel-Lindau tumor suppressor homolog in Drosophila.

    PubMed

    Adryan, B; Decker, H J; Papas, T S; Hsu, T

    2000-06-01

    von Hippel-Lindau disease is a hereditary cancer syndrome. Mutations in the VHL tumor suppressor gene predispose individuals to highly vascularized tumors. However, VHL-deficient mice die in utero due to a lack of vascularization in the placenta. To resolve the contradiction, we cloned the Drosophila VHL homologue (d-VHL) and studied its function. It showed an overall 50% similarity to the human counterpart and 76% similarity in the crucial functional domain: the elongin C binding site. The putative d-VHL protein can bind Drosophila elongin C in vitro. During embryogenesis, d-VHL is expressed in the developing tracheal regions where tube outgrowth no longer occurs. Reduced d-VHL activity (using RNA interference methodology) caused breakage of the main vasculature accompanied by excessive looping of smaller branches, whereas over-expression caused a general lack of vasculature. Importantly, human VHL can induce the same gain-of-function phenotypes. VHL is likely involved in halting cell migration at the end of vascular tube outgrowth. Loss of VHL activity can therefore lead to disruption of major vasculature (as in the mouse embryo), which requires precise cell movement and tube fusion, or ectopic outgrowth from existing secondary vascular branches (as in the adult tumors). Oncogene (2000) 19, 2803 - 2811

  19. PU.1 is a potent tumor suppressor in classical Hodgkin lymphoma cells.

    PubMed

    Yuki, Hiromichi; Ueno, Shikiko; Tatetsu, Hiro; Niiro, Hiroaki; Iino, Tadafumi; Endo, Shinya; Kawano, Yawara; Komohara, Yoshihiro; Takeya, Motohiro; Hata, Hiroyuki; Okada, Seiji; Watanabe, Toshiki; Akashi, Koichi; Mitsuya, Hiroaki; Okuno, Yutaka

    2013-02-07

    PU.1 has previously been shown to be down-regulated in classical Hodgkin lymphoma (cHL) cells via promoter methylation. We performed bisulfite sequencing and proved that the promoter region and the -17 kb upstream regulatory element of the PU.1 gene were highly methylated. To evaluate whether down-regulation of PU.1 is essential for the growth of cHL cells, we conditionally expressed PU.1 in 2 cHL cell lines, L428 and KM-H2. Overexpression of PU.1 induced complete growth arrest and apoptosis in both cell lines. Furthermore, in a Hodgkin lymphoma tumor xenograft model using L428 and KM-H2 cell lines, overexpression of PU.1 led to tumor regression or stable disease. Lentiviral transduction of PU.1 into primary cHL cells also induced apoptosis. DNA microarray analysis revealed that among genes related to cell cycle and apoptosis, p21 (CDKN1A) was highly up-regulated in L428 cells after PU.1 induction. Stable knockdown of p21 rescued PU.1-induced growth arrest in L428 cells, suggesting that the growth arrest and apoptosis observed are at least partially dependent on p21 up-regulation. These data strongly suggest that PU.1 is a potent tumor suppressor in cHL and that induction of PU.1 with demethylation agents and/or histone deacetylase inhibitors is worth exploring as a possible therapeutic option for patients with cHL.

  20. Enhancement of the RAD51 Recombinase Activity by the Tumor Suppressor PALB2

    SciTech Connect

    Dray, Eloise; Etchin, Julia; Wiese, Claudia; Saro, Dorina; Williams, Gareth J.; Hammel, Michal; Yu, Xiong; Galkin, Vitold E.; Liu, Dongqing; Tsai, Miaw-Sheue; Sy, Shirley M-H.; Egelman, Edward; Chen, Junjie; Sung, Patrick; Schild, D.

    2010-08-24

    Homologous recombination mediated by the RAD51 recombinase helps eliminate chromosomal lesions, such as DNA double-stranded breaks induced by radiation or arising from injured DNA replication forks. The tumor suppressors BRCA2 and PALB2 act together to deliver RAD51 to chromosomal lesions to initiate repair. Here we document a new function of PALB2 in the enhancement of RAD51's ability to form the D-loop. We show that PALB2 binds DNA and physically interacts with RAD51. Importantly, while PALB2 alone stimulates D-loop formation, a cooperative effect is seen with RAD51AP1, an enhancer of RAD51. This stimulation stems from PALB2's ability to function with RAD51 and RAD51AP1 to assemble the synaptic complex. Our results help unveil a multi-faceted role of PALB2 in chromosome damage repair. Since PALB2 mutations can cause breast and other tumors or lead to Fanconi anemia, our findings are important for understanding the mechanism of tumor suppression in humans.

  1. PCR-RFLP to Detect Codon 248 Mutation in Exon 7 of "p53" Tumor Suppressor Gene

    ERIC Educational Resources Information Center

    Ouyang, Liming; Ge, Chongtao; Wu, Haizhen; Li, Suxia; Zhang, Huizhan

    2009-01-01

    Individual genome DNA was extracted fast from oral swab and followed up with PCR specific for codon 248 of "p53" tumor suppressor gene. "Msp"I restriction mapping showed the G-C mutation in codon 248, which closely relates to cancer susceptibility. Students learn the concepts, detection techniques, and research significance of point mutations or…

  2. LARG at chromosome 11q23 has functional characteristics of a tumor suppressor in human breast cancer

    SciTech Connect

    Ong, Danny C.T.; Rudduck, Christina; Chin, Koei; Kuo, Wen-Lin; Lie, Daniel K.H.; Chua, Constance L.M.; Wong, Chow Yin; Hong, Ga Sze; Gray, Joe; Lee, Ann S.G.

    2008-05-06

    Deletion of 11q23-q24 is frequent in a diverse variety of malignancies, including breast and colorectal carcinoma, implicating the presence of a tumor suppressor gene at that chromosomal region. We show here that LARG, from 11q23, has functional characteristics of a tumor suppressor. We examined a 6-Mb region on 11q23 by high-resolution deletion mapping, utilizing both loss of heterozygosity (LOH) analysis and microarray comparative genomic hybridization (CGH). LARG (also called ARHGEF12), identified from the analyzed region, was underexpressed in 34% of primary breast carcinomas and 80% of breast cancer cell lines including the MCF-7 line. Multiplex ligation-dependent probe amplification on 30 primary breast cancers and six breast cancer cell lines showed that LARG had the highest frequency of deletion compared to the BCSC-1 and TSLC1 genes, two known candidate tumor suppressor genes from 11q. In vitro analysis of breast cancer cell lines that underexpress LARG showed that LARG could be reactivated by trichostatin A, a histone deacetylase inhibitor, but not by 5-Aza-2{prime}-deoxycytidine, a demethylating agent. Bisulfite sequencing and quantitative high-throughput analysis of DNA methylation confirmed the lack of CpG island methylation in LARG in breast cancer. Restoration of LARG expression in MCF-7 cells by stable transfection resulted in reduced proliferation and colony formation, suggesting that LARG has functional characteristics of a tumor suppressor gene.

  3. PCR-RFLP to Detect Codon 248 Mutation in Exon 7 of "p53" Tumor Suppressor Gene

    ERIC Educational Resources Information Center

    Ouyang, Liming; Ge, Chongtao; Wu, Haizhen; Li, Suxia; Zhang, Huizhan

    2009-01-01

    Individual genome DNA was extracted fast from oral swab and followed up with PCR specific for codon 248 of "p53" tumor suppressor gene. "Msp"I restriction mapping showed the G-C mutation in codon 248, which closely relates to cancer susceptibility. Students learn the concepts, detection techniques, and research significance of point mutations or…

  4. The LKB1 tumor suppressor differentially affects anchorage independent growth of HPV positive cervical cancer cell lines

    SciTech Connect

    Mack, Hildegard I.D.; Munger, Karl

    2013-11-15

    Infection with high-risk human papillomaviruses is causally linked to cervical carcinogenesis. However, most lesions caused by high-risk HPV infections do not progress to cancer. Host cell mutations contribute to malignant progression but the molecular nature of such mutations is unknown. Based on a previous study that reported an association between liver kinase B1 (LKB1) tumor suppressor loss and poor outcome in cervical cancer, we sought to determine the molecular basis for this observation. LKB1-negative cervical and lung cancer cells were reconstituted with wild type or kinase defective LKB1 mutants and we examined the importance of LKB1 catalytic activity in known LKB1-regulated processes including inhibition of cell proliferation and elevated resistance to energy stress. Our studies revealed marked differences in the biological activities of two kinase defective LKB1 mutants in the various cell lines. Thus, our results suggest that LKB1 may be a cell-type specific tumor suppressor. - Highlights: • LKB1 is a tumor suppressor that is linked to Peutz-Jeghers syndrome. • Peutz-Jeghers syndrome patients have a high incidence of cervical cancer. • Cervical cancer is caused by HPV infections. • This study investigates LKB1 tumor suppressor activity in cervical cancer.

  5. Thioredoxin interacting protein (TXNIP) is a novel tumor suppressor in thyroid cancer

    PubMed Central

    2014-01-01

    Background Thyroid cancer is the most common endocrine malignancy, and many patients with metastatic differentiated thyroid cancer (DTC), poorly differentiated thyroid cancer (PDTC), and anaplastic thyroid cancer (ATC) fail to respond to conventional therapies, resulting in morbidity and mortality. Additional therapeutic targets and treatment options are needed for these patients. We recently reported that peroxisome proliferator-activated receptor gamma (PPARγ) is highly expressed in ATC and confers an aggressive phenotype when overexpressed in DTC cells. Methods Microarray analysis was used to identify downstream targets of PPARγ in ATC cells. Western blot analysis and immunohistochemistry (IHC) were used to assess thioredoxin interacting protein (TXNIP) expression in thyroid cancer cell lines and primary tumor specimens. Retroviral transduction was used to generate ATC cell lines that overexpress TXNIP, and assays that assess glucose uptake, viable cell proliferation, and invasion were used to characterize the in vitro properties of these cells. An orthotopic thyroid cancer mouse model was used to assess the effect of TXNIP overexpression in ATC cell lines in vivo. Results Using microarray analysis, we show that TXNIP is highly upregulated when PPARγ is depleted from ATC cells. Using Western blot analysis and IHC, we show that DTC and ATC cells exhibit differential TXNIP expression patterns. DTC cell lines and patient tumors have high TXNIP expression in contrast to low or absent expression in ATC cell lines and tumors. Overexpression of TXNIP decreases the growth of HTh74 cells compared to vector controls and inhibits glucose uptake in the ATC cell lines HTh74 and T238. Importantly, TXNIP overexpression in T238 cells results in attenuated tumor growth and decreased metastasis in an orthotopic thyroid cancer mouse model. Conclusions Our findings indicate that TXNIP functions as a tumor suppressor in thyroid cells, and its downregulation is likely important in

  6. DLC-1 operates as a tumor suppressor gene in human non-small cell lung carcinomas.

    PubMed

    Yuan, Bao-Zhu; Jefferson, Amy M; Baldwin, Kimberly T; Thorgeirsson, Snorri S; Popescu, Nicholas C; Reynolds, Steven H

    2004-02-19

    The deleted in liver cancer (DLC-1) gene at chromosome 8p21-22 is altered mainly by genomic deletion or aberrant promoter methylation in a large number of human cancers such as breast, liver, colon and prostate and is known to have an inhibitory effect on breast and liver tumor cell growth. Given the high frequency of deletion involving region 8p21-22 in human non-small cell lung carcinoma (NSCLC), we examined alterations of DLC-1 in a series of primary tumors and tumor cell lines and tested effects of DLC-1 on tumor cell growth. A significant decrease or absence of the DLC-1 mRNA expression was found in 95% of primary NSCLC (20/21) and 58% of NSCLC cell lines (11/19). Transcriptional silencing of DLC-1 was primarily associated with aberrant DNA methylation, rather than genomic deletion as 5-aza-2'-deoxycytidine induced reactivation of DLC-1 expression in 82% (9/11) NSCLC cell lines showing downregulated DLC-1. It was further evidenced by an aberrant DLC-1 promoter methylation pattern, which was detected by Southern blotting in 73% (8/11) of NSCLC cell lines with downregulation of the gene. The transfer of DLC-1 into three DLC-1 negative cell lines caused a significant inhibition in cell proliferation and/or a decrease in colony formation. Furthermore, stable transfer of DLC-1 abolished tumorigenicity in nude mice of two cell lines, suggesting that DLC-1 plays a role in NSCLC by acting as a bona fide new tumor suppressor gene.

  7. Characterization of the novel tumor-suppressor gene CCDC67 in papillary thyroid carcinoma.

    PubMed

    Yin, De Tao; Xu, Jianhui; Lei, Mengyuan; Li, Hongqiang; Wang, Yongfei; Liu, Zhen; Zhou, Yubing; Xing, Mingzhao

    2016-02-02

    Some studies showed an association of coiled-coil domain-containing (CCDC) genes with cancers. Our previous limited data specifically suggested a possible pathogenic role of CCDC67 in papillary thyroid cancer (PTC), but this has not been firmly established. The present study was to further investigate and establish this role of CCDC67 in PTC. The expression of CCDC67, both at mRNA and protein levels, was sharply down-regulated in PTC compared with normal thyroid tissues. Lower CCDC67 expression was significantly associated with aggressive tumor behaviors, such as advanced tumor stages and lymph node metastasis, as well as BRAF mutation. Introduced expression of CCDC67 in TPC-1 cells robustly inhibited cell proliferation, colony formation and migration, induced G1 phase cell cycle arrest, and increased cell apoptosis. Primary PTC tumors and matched normal thyroid tissues were obtained from 200 unselected patients at the initial surgery for detection of CCDC67 mRNA and protein by RT-PCR and Western blotting analyses, respectively. Genomic DNA sequencing was performed to detect BRAF mutation in PTC tumors. Clinicopathological data were retrospectively reviewed for correlation analyses. PTC cell line TPC-1 with stable transfection of CCDC67 was used to investigate the functions of CCDC67. This large study demonstrates down-regulation of CCDC67 in PTC, an inverse relationship between CCDC67 expression and PTC aggressiveness and BRAF mutation, and a robust inhibitory effect of CCDC67 on PTC cellular activities. These results are consistent with CCDC67 being a novel and impaired tumor suppressor gene in PTC, providing important prognostic and therapeutic implications for this cancer.

  8. SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma.

    PubMed

    Merino-Azpitarte, Maite; Lozano, Elisa; Perugorria, María J; Esparza-Baquer, Aitor; Erice, Oihane; Santos-Laso, Álvaro; O'Rourke, Colm J; Andersen, Jesper B; Jiménez-Agüero, Raúl; Lacasta, Adelaida; D'Amato, Mauro; Briz, Óscar; Jalan-Sakrikar, Nidhi; Huebert, Robert C; Thelen, Kristen M; Gradilone, Sergio A; Aransay, Ana M; Lavín, José L; Fernández-Barrena, Maite G; Matheu, Ander; Marzioni, Marco; Gores, Gregory J; Bujanda, Luis; Marin, José J G; Banales, Jesús M

    2017-07-01

    Cholangiocarcinoma (CCA) is a biliary malignancy linked to genetic and epigenetic abnormalities, such as hypermethylation of SOX17 promoter. Here, the role of SOX17 in cholangiocyte differentiation and cholangiocarcinogenesis was studied. SOX17 expression/function was evaluated along the differentiation of human induced pluripotent stem cells (iPSC) into cholangiocytes, in the dedifferentiation process of normal human cholangiocytes (NHC) in culture and in cholangiocarcinogenesis. Lentiviruses for SOX17 overexpression or knockdown were used. Gene expression and DNA methylation profiling were performed. SOX17 expression is induced in the last stage of cholangiocyte differentiation from iPSC and regulates the acquisition of biliary markers. SOX17 becomes downregulated in NHC undergoing dedifferentiation; experimental SOX17 knockdown in differentiated NHC downregulated biliary markers and promoted baseline and Wnt-dependent proliferation. SOX17 expression is lower in human CCA than in healthy tissue, which correlates with worse survival after tumor resection. In CCA cells, SOX17 overexpression decreased their tumorigenic capacity in murine xenograft models, which was related to increased oxidative stress and apoptosis. In contrast, SOX17 overexpression in NHC did not affect their survival but inhibited their baseline proliferation. In CCA cells, SOX17 inhibited migration, anchorage-independent growth and Wnt/β-catenin-dependent proliferation, and restored the expression of biliary markers and primary cilium length. In human CCA, SOX17 promoter was found hypermethylated and its expression inversely correlates with the methylation grade. In NHC, Wnt3a decreased SOX17 expression in a DNMT-dependent manner, whereas in CCA, DNMT1 inhibition or silencing upregulated SOX17. SOX17 regulates the differentiation and maintenance of the biliary phenotype and functions as a tumor suppressor for CCA, being a potential prognostic marker and a promising therapeutic target

  9. The human LIS1 is downregulated in hepatocellular carcinoma and plays a tumor suppressor function

    SciTech Connect

    Xing, Zhen; Tang, Xin; Gao, Yuan; Da, Liang; Song, Hai; Wang, Suiquan; Tiollais, Pierre; Li, Tsaiping; Zhao, Mujun

    2011-06-03

    Highlights: {yields} LIS1 mRNA and protein levels are decreased in 70% HCC tissues. {yields} Downregulation of LIS1 expression induces oncogenic transformation of QSG7701 and NIH3T3 cells in vitro and in vivo. {yields} LIS1 downregulation leads to mitotic errors including spindle and chromosome defects. {yields} Ectopic expression of LIS1 could significantly inhibit HCC cell proliferation and colony formation. {yields} Our results suggest that LIS1 plays a potential tumor suppressor role in the development and progression of HCC. -- Abstract: The human lissencephaly-1 gene (LIS1) is a disease gene responsible for Miller-Dieker lissencephaly syndrome (MDL). LIS1 gene is located in the region of chromosome 17p13.3 that is frequency deleted in MDL patients and in human liver cancer cells. However, the expression and significance of LIS1 in liver cancer remain unknown. Here, we investigated the expression of LIS1 in hepatocellular carcinoma (HCC) tissues by real-time PCR, Western blot, and immunohistochemistry. The results indicated that the mRNA and protein levels of LIS1 were downregulated in about 70% of HCC tissues, and this downregulation was significantly associated with tumor progression. Functional studies showed that the reduction of LIS1 expression in the normal human liver cell line QSG7701 or the mouse fibroblast cell line NIH3T3 by shRNA resulted in colony formation in soft agar and xenograft tumor formation in nude mice, demonstrating that a decrease in the LIS1 level can promote the oncogenic transformation of cells. We also observed that the phenotypes of LIS1-knockdown cells displayed various defective mitotic structures, suggesting that the mechanism by which reduced LIS1 levels results in tumorigenesis is associated with its role in mitosis. Furthermore, we demonstrated that ectopic expression of LIS1 could significantly inhibit HCC cell proliferation and colony formation. Our results suggest that LIS1 plays a potential tumor suppressor role in the

  10. Modification of an apparatus for tumor-suppressor protein crystal growth in the International Space Station

    NASA Astrophysics Data System (ADS)

    de Morais Mendonca Teles, Antonio

    Some human diseases as tumors are being studied continuously for the development of vaccines against them. And a way of doing that is by means of proteins research. There are some kinds of proteins, like the p53 and p73 proteins, which are tumor suppressors. There are other diseases such as A.I.D.S., hansenosis, the Parkinson's and Chagas' diseases which are protein-related. The determination of how proteins geometrically order themselves, during its biological functions is very necessary to understand how a protein's structure affects its function, to design vaccines that intercede in tumor-protein activities and in other proteins related to those other diseases. The protein crystal growth in microgravity environment produces purer crystallization than on the ground, and it is a powerful tool to produce better vaccines. Several data have already been acquired using ground-based research and in spaceflight experiments aboard the Spacelab and Space Shuttle missions, and in the MIR and in the International Space Station (ISS). Here in this paper, I propose to be performed in the ISS Biological Research Facility (which is being developed), multiple crystal growth of proteins related to cancer (as tumors suppressors and oncoproteins), A.I.D.S., hansenosis, the Parkinson's and Chagas' diseases, for the future obtaining of possible vaccines against them. I also propose a simple and practical equipment, a modification of the crystallization plates (which use a vapor diffusion technique) inside each cylinder of the Protein Crystallization Apparatus in Microgravity (PCAM), with multiple chambers with different sizes. Instead of using some chambers with the same size it is better to use several chambers with different sizes. Why is that? The answer is: the energy associated with the surface tension of the liquid in the chamber is directly related to the circle area of it. So, to minimize the total energy of the surface tension of a proteins liquid -making it more stable

  11. Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells enhances tumor-induced immune suppression.

    PubMed

    Ostrand-Rosenberg, Suzanne; Sinha, Pratima; Beury, Daniel W; Clements, Virginia K

    2012-08-01

    The tumor microenvironment is a complex milieu of tumor and host cells. Host cells can include tumor-reactive T cells capable of killing tumor cells. However, more frequently the tumor and host components interact to generate a highly immune suppressive environment that frustrates T cell cytotoxicity and promotes tumor progression through a variety of immune and non-immune mechanisms. Myeloid-derived suppressor cells (MDSC) are a major host component contributing to the immune suppressive environment. In addition to their inherent immune suppressive function, MDSC amplify the immune suppressive activity of macrophages and dendritic cells via cross-talk. This article will review the cell-cell interactions used by MDSC to inhibit anti-tumor immunity and promote progression, and the role of inflammation in promoting cross-talk between MDSC and other cells in the tumor microenvironment.

  12. Unfurling of the band 4.1, ezrin, radixin, moesin (FERM) domain of the merlin tumor suppressor

    SciTech Connect

    Yogesha, S.D.; Sharff, Andrew J.; Giovannini, Marco; Bricogne, Gerard; Izard, Tina

    2014-10-02

    The merlin-1 tumor suppressor is encoded by the Neurofibromatosis-2 (Nf2) gene and loss-of-function Nf2 mutations lead to nervous system tumors in man and to several tumor types in mice. Merlin is an ERM (ezrin, radixin, moesin) family cytoskeletal protein that interacts with other ERM proteins and with components of cell-cell adherens junctions (AJs). Merlin stabilizes the links of AJs to the actin cytoskeleton. Thus, its loss destabilizes AJs, promoting cell migration and invasion, which in Nf2{sup +/-} mice leads to highly metastatic tumors. Paradoxically, the 'closed' conformation of merlin-1, where its N-terminal four-point-one, ezrin, radixin, moesin (FERM) domain binds to its C-terminal tail domain, directs its tumor suppressor functions. Here we report the crystal structure of the human merlin-1 head domain when crystallized in the presence of its tail domain. Remarkably, unlike other ERM head-tail interactions, this structure suggests that binding of the tail provokes dimerization and dynamic movement and unfurling of the F2 motif of the FERM domain. We conclude the 'closed' tumor suppressor conformer of merlin-1 is in fact an 'open' dimer whose functions are disabled by Nf2 mutations that disrupt this architecture.

  13. Modulator of Apoptosis 1 (MOAP-1) Is a Tumor Suppressor Protein Linked to the RASSF1A Protein*

    PubMed Central

    Law, Jennifer; Salla, Mohamed; Zare, Alaa; Wong, Yoke; Luong, Le; Volodko, Natalia; Svystun, Orysya; Flood, Kayla; Lim, Jonathan; Sung, Miranda; Dyck, Jason R. B.; Tan, Chong Teik; Su, Yu-Chin; Yu, Victor C.; Mackey, John; Baksh, Shairaz

    2015-01-01

    Modulator of apoptosis 1 (MOAP-1) is a BH3-like protein that plays key roles in cell death or apoptosis. It is an integral partner to the tumor suppressor protein, Ras association domain family 1A (RASSF1A), and functions to activate the Bcl-2 family pro-apoptotic protein Bax. Although RASSF1A is now considered a bona fide tumor suppressor protein, the role of MOAP-1 as a tumor suppressor protein has yet to be determined. In this study, we present several lines of evidence from cancer databases, immunoblotting of cancer cells, proliferation, and xenograft assays as well as DNA microarray analysis to demonstrate the role of MOAP-1 as a tumor suppressor protein. Frequent loss of MOAP-1 expression, in at least some cancers, appears to be attributed to mRNA down-regulation and the rapid proteasomal degradation of MOAP-1 that could be reversed utilizing the proteasome inhibitor MG132. Overexpression of MOAP-1 in several cancer cell lines resulted in reduced tumorigenesis and up-regulation of genes involved in cancer regulatory pathways that include apoptosis (p53, Fas, and MST1), DNA damage control (poly(ADP)-ribose polymerase and ataxia telangiectasia mutated), those within the cell metabolism (IR-α, IR-β, and AMP-activated protein kinase), and a stabilizing effect on microtubules. The loss of RASSF1A (an upstream regulator of MOAP-1) is one of the earliest detectable epigenetically silenced tumor suppressor proteins in cancer, and we speculate that the additional loss of function of MOAP-1 may be a second hit to functionally compromise the RASSF1A/MOAP-1 death receptor-dependent pathway and drive tumorigenesis. PMID:26269600

  14. Tumor-Derived Tissue Factor Aberrantly Activates Complement and Facilitates Lung Tumor Progression via Recruitment of Myeloid-Derived Suppressor Cells

    PubMed Central

    Han, Xiao; Zha, Haoran; Yang, Fei; Guo, Bo; Zhu, Bo

    2017-01-01

    The initiator of extrinsic coagulation, tissue factor (TF), and its non-coagulant isoform alternatively spliced TF (asTF) are closely associated with tumor development. In the tumor microenvironment, the role of TF-induced coagulation in tumor progression remains to be fully elucidated. Using TF-knockdown lung tumor cells, we showed that TF is the dominant component of procoagulant activity but is dispensable in the cellular biology of tumor cells. In a xenograft model, using immunohistochemical analysis and flow cytometry analysis of the tumor microenvironment, we demonstrated that TF-induced fibrin deposition, which is correlated with complement activation and myeloid-derived suppressor cell (MDSC) recruitment, is positively associated with tumor progression. C5aR antagonism blunted the effect of TF on tumor progression and decreased MDSC recruitment. In conclusion, our data suggested that in tumor microenvironment, TF-induced coagulation activated the complement system and subsequently recruited myeloid-derived suppressor cells to promote tumor growth, which brings new insights into the coagulation-induced complement activation within the tumor microenvironment during tumor progression. PMID:28106852

  15. Tumor-Derived Tissue Factor Aberrantly Activates Complement and Facilitates Lung Tumor Progression via Recruitment of Myeloid-Derived Suppressor Cells.

    PubMed

    Han, Xiao; Zha, Haoran; Yang, Fei; Guo, Bo; Zhu, Bo

    2017-01-19

    The initiator of extrinsic coagulation, tissue factor (TF), and its non-coagulant isoform alternatively spliced TF (asTF) are closely associated with tumor development. In the tumor microenvironment, the role of TF-induced coagulation in tumor progression remains to be fully elucidated. Using TF-knockdown lung tumor cells, we showed that TF is the dominant component of procoagulant activity but is dispensable in the cellular biology of tumor cells. In a xenograft model, using immunohistochemical analysis and flow cytometry analysis of the tumor microenvironment, we demonstrated that TF-induced fibrin deposition, which is correlated with complement activation and myeloid-derived suppressor cell (MDSC) recruitment, is positively associated with tumor progression. C5aR antagonism blunted the effect of TF on tumor progression and decreased MDSC recruitment. In conclusion, our data suggested that in tumor microenvironment, TF-induced coagulation activated the complement system and subsequently recruited myeloid-derived suppressor cells to promote tumor growth, which brings new insights into the coagulation-induced complement activation within the tumor microenvironment during tumor progression.

  16. A Tumorigenic Factor Interactome Connected Through Tumor Suppressor MicroRNA-198 in Human Pancreatic Cancer

    PubMed Central

    Marin-Muller, Christian; Li, Dali; Bharadwaj, Uddalak; Li, Min; Chen, Changyi; Hodges, Sally E.; Fisher, William E.; Mo, Qianxing; Hung, Mien-Chie; Yao, Qizhi

    2013-01-01

    Purpose The majority of pancreatic cancers (PCs) overexpress mesothelin (MSLN), which contributes to enhanced proliferation, invasion and migration. However, the MSLN regulatory network is still unclear. Here, we investigated the regulation of a panel of tumorigenic factors, and explored the potential of MSLN regulated miR-198 treatment in vivo. Experimental Design The expression and functional regulation of the tumorigenic factors MSLN, NF-κB, and the homeobox transcription factors (TFs) POU2F2 (OCT-2), Pre-B-cell leukemia homeobox factor 1 (PBX-1), valosin-containing protein (VCP), and miR-198 were studied in PC cell lines, patient tumor samples and in xenograft PC mouse models. Results We found that miR-198 is downregulated in PC and is involved in an intricate reciprocal regulatory loop with MSLN, which represses miR-198 through NF-κB-mediated OCT-2 induction. Furthermore, miR-198 repression leads to overexpression of PBX-1 and VCP. The dysregulated PBX-1/VCP axis leads to increased tumorigenicity. Reconstitution of miR-198 in PC cells results in reduced tumor growth, metastasis, and increased survival through direct targeting MSLN, PBX-1, and VCP. Most interestingly, reduced levels of miR-198 in human tissue samples are associated with upregulation of these tumorigenic factors (MSLN, OCT-2, PBX-1, VCP) and predict poor survival. Reduced miR-198 expression links this tumor network signature and prognosticates poor patient outcome. High miR-198 disrupts the network and predicts better prognosis and increased survival. Conclusions MiR-198 acts as a central tumor suppressor and modulates the molecular makeup of a critical interactome in PC, indicating a potential prognostic marker signature and the therapeutic potential of attacking this tumorigenic network through a central vantage point. PMID:23989979

  17. Regulator of G protein signaling 6 is a novel suppressor of breast tumor initiation and progression.

    PubMed

    Maity, Biswanath; Stewart, Adele; O'Malley, Yunxia; Askeland, Ryan W; Sugg, Sonia L; Fisher, Rory A

    2013-08-01

    Breast cancer is a large global health burden and the most frequently diagnosed malignancy in women worldwide. Here, we utilize RGS6(-/-) mice to interrogate the role of regulator of G protein signaling 6 (RGS6), localized to the ductal epithelium in mouse and human breast, as a novel tumor suppressor in vivo. RGS6(-/-) mice exhibit accelerated 7,12-dimethylbenza[α]anthracene (DMBA)-induced tumor initiation and progression, as well as decreased overall survival. Analysis of carcinogenic aberrations in the mammary glands of DMBA-treated mice revealed a failure of the DNA damage response concurrent with augmented oncogenesis in RGS6(-/-) animals. Furthermore, RGS6 suppressed cell growth induced by either human epidermal growth factor receptor 2 or estrogen receptor activation in both MCF-7 breast cancer cells and mammary epithelial cells (MECs). MECs isolated from RGS6(-/-) mice also showed a deficit in DMBA-induced ATM/p53 activation, reactive oxygen species generation and apoptosis confirming that RGS6 is required for effective activation of the DNA damage response in these cells, a critical countermeasure against carcinogen-mediated genotoxic stress. The ability of RGS6 to simultaneously enhance DNA-damage-induced apoptotic signaling and suppress oncogenic cell growth likely underlie the accelerated tumorigenesis and cellular transformation observed in DMBA-treated RGS6(-/-) mice and isolated MECs, respectively. Unsurprisingly, spontaneous tumor formation was also seen in old female RGS6(-/-) but not in wild-type mice. Our finding that RGS6 is downregulated in all human breast cancer subtypes independent of their molecular classification indicates that obtaining a means to restore the growth suppressive and pro-apoptotic actions of RGS6 in breast might be a viable means to treat a large spectrum of breast tumors.

  18. The Drosophila Netrin receptor frazzled/DCC functions as an invasive tumor suppressor

    PubMed Central

    2011-01-01

    Background Loss of heterozygosity at 18q, which includes the Deleted in Colorectal Cancer (DCC) gene, has been linked to many human cancers. However, it is unclear if loss of DCC is the specific underlying cause of these cancers. The Drosophila imaginal discs are excellent systems in which to study DCC function, as it is possible to model human tumors through the generation of somatic clones of cells bearing multiple genetic lesions. Here, these attributes of the fly system were utilized to investigate the potential tumor suppressing functions of the Drosophila DCC homologue frazzled (fra) during eye-antennal disc development. Results Most fra loss of function clones are eliminated during development. However, when mutant clone cells generated in the developing eye were rescued from death, partially differentiated eye cells were found outside of the normal eye field, and in extreme cases distant sites of the body. Characterization of these cells during development indicates that fra mutant cells display characteristics of invasive tumor cells, including increased levels of phospho-ERK, phospho-JNK, and Mmp-1, changes in cadherin expression, remodeling of the actin cytoskeleton, and loss of polarity. Mutation of fra promotes basement membrane degradation and invasion which are repressed by inhibition of Rho1 signaling. Although inhibition of JNK signaling blocks invasive phenotypes in some metastatic cancer models in flies, blocking JNK signaling inhibits fra mutant cell death, thereby enhancing the fra mutant phenotype. Conclusions The results of this investigation provide the first direct link between point mutations in fra/DCC and metastatic phenotypes in an animal model and suggest that Fra functions as an invasive tumor suppressor during Drosophila development. PMID:21672235

  19. A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas.

    PubMed

    Agnihotri, Sameer; Wolf, Amparo; Munoz, Diana M; Smith, Christopher J; Gajadhar, Aaron; Restrepo, Andres; Clarke, Ian D; Fuller, Gregory N; Kesari, Santosh; Dirks, Peter B; McGlade, C Jane; Stanford, William L; Aldape, Kenneth; Mischel, Paul S; Hawkins, Cynthia; Guha, Abhijit

    2011-04-11

    Glioblastoma Multiforme (GBM), the most common and lethal primary human brain tumor, exhibits multiple molecular aberrations. We report that loss of the transcription factor GATA4, a negative regulator of normal astrocyte proliferation, is a driver in glioma formation and fulfills the hallmarks of a tumor suppressor gene (TSG). Although GATA4 was expressed in normal brain, loss of GATA4 was observed in 94/163 GBM operative samples and was a negative survival prognostic marker. GATA4 loss occurred through promoter hypermethylation or novel somatic mutations. Loss of GATA4 in normal human astrocytes promoted high-grade astrocytoma formation, in cooperation with other relevant genetic alterations such as activated Ras or loss of TP53. Loss of GATA4 with activated Ras in normal astrocytes promoted a progenitor-like phenotype, formation of neurospheres, and the ability to differentiate into astrocytes, neurons, and oligodendrocytes. Re-expression of GATA4 in human GBM cell lines, primary cultures, and brain tumor-initiating cells suppressed tumor growth in vitro and in vivo through direct activation of the cell cycle inhibitor P21(CIP1), independent of TP53. Re-expression of GATA4 also conferred sensitivity of GBM cells to temozolomide, a DNA alkylating agent currently used in GBM therapy. This sensitivity was independent of MGMT (O-6-methylguanine-DNA-methyltransferase), the DNA repair enzyme which is often implicated in temozolomide resistance. Instead, GATA4 reduced expression of APNG (alkylpurine-DNA-N-glycosylase), a DNA repair enzyme which is poorly characterized in GBM-mediated temozolomide resistance. Identification and validation of GATA4 as a TSG and its downstream targets in GBM may yield promising novel therapeutic strategies.

  20. Regulator of G protein signaling 6 is a novel suppressor of breast tumor initiation and progression

    PubMed Central

    Fisher, Rory A.

    2013-01-01

    Breast cancer is a large global health burden and the most frequently diagnosed malignancy in women worldwide. Here, we utilize RGS6− /− mice to interrogate the role of regulator of G protein signaling 6 (RGS6), localized to the ductal epithelium in mouse and human breast, as a novel tumor suppressor in vivo. RGS6− /− mice exhibit accelerated 7,12-dimethylbenza[α]anthracene (DMBA)-induced tumor initiation and progression, as well as decreased overall survival. Analysis of carcinogenic aberrations in the mammary glands of DMBA-treated mice revealed a failure of the DNA damage response concurrent with augmented oncogenesis in RGS6−/− animals. Furthermore, RGS6 suppressed cell growth induced by either human epidermal growth factor receptor 2 or estrogen receptor activation in both MCF-7 breast cancer cells and mammary epithelial cells (MECs). MECs isolated from RGS6−/− mice also showed a deficit in DMBA-induced ATM/p53 activation, reactive oxygen species generation and apoptosis confirming that RGS6 is required for effective activation of the DNA damage response in these cells, a critical countermeasure against carcinogen-mediated genotoxic stress. The ability of RGS6 to simultaneously enhance DNA-damage-induced apoptotic signaling and suppress oncogenic cell growth likely underlie the accelerated tumorigenesis and cellular transformation observed in DMBA-treated RGS6−/− mice and isolated MECs, respectively. Unsurprisingly, spontaneous tumor formation was also seen in old female RGS6−/− but not in wild-type mice. Our finding that RGS6 is downregulated in all human breast cancer subtypes independent of their molecular classification indicates that obtaining a means to restore the growth suppressive and pro-apoptotic actions of RGS6 in breast might be a viable means to treat a large spectrum of breast tumors. PMID:23598467

  1. Detection of Tumor Suppressor Genes in Cancer Development by a Novel shRNA-Based Method.

    PubMed

    von Burstin, Johannes; Diersch, Sandra; Schneider, Günter; Reichert, Maximilian; Rustgi, Anil K; Schmid, Roland M

    2015-05-01

    Pancreatic cancer is one of the deadliest cancers with poor survival rates and limited therapeutic options. To improve the understanding of this disease's biology, a prerequisite for the generation of novel therapeutics, new platforms for rapid and efficient genetic and therapeutic screening are needed. Therefore, a combined in vitro/in vivo hybrid shRNA assay was developed using isolated murine primary pancreatic ductal cells (PDCs), in which oncogenic Kras(G12D) could be activated in vitro by genomic recombination through 4OH-tamoxifen-induced nuclear translocation of Cre-ERT2 expressed under control of the ROSA26 promoter. Further genetic manipulation was achieved through selective and stable RNAi against the tumor suppressors p16(Ink4a) (CDKN2A) or Trp53 (TP53) using lentiviral gene delivery. Treatment of PDCs with 4OH-tamoxifen increased phosphorylation of ERK downstream of KRAS, and subsequent lentiviral transduction resulted in sustained target gene repression. Double-mutant PDCs were then reintroduced into the pancreata of NOD-SCID-gamma (NSG) mice and monitored for tumor growth. Orthotopic implantation of PDCs carrying the activated Kras(G12D)-allele and shRNA against p16(Ink4a) or Trp53 resulted in tumor growth, metastasis, and reduced survival of NSG mice. In contrast, Kras(G12D) alone was not sufficient to induce tumor growth. The combinatory in vitro/in vivo approach described in this study allows for rapid and efficient identification of genes involved in carcinogenesis and opens new avenues for the development of therapeutic strategies to improve cancer treatment. ©2015 American Association for Cancer Research.

  2. Genistein Up-Regulates Tumor Suppressor MicroRNA-574-3p in Prostate Cancer

    PubMed Central

    Chiyomaru, Takeshi; Yamamura, Soichiro; Fukuhara, Shinichiro; Hidaka, Hideo; Majid, Shahana; Saini, Sharanjot; Arora, Sumit; Deng, Guoren; Shahryari, Varahram; Chang, Inik; Tanaka, Yuichiro; Tabatabai, Z. Laura; Enokida, Hideki; Seki, Naohiko; Nakagawa, Masayuki; Dahiya, Rajvir

    2013-01-01

    Genistein has been shown to inhibit cancers both in vitro and in vivo, by altering the expression of several microRNAs (miRNAs). In this study, we focused on tumor suppressor miRNAs regulated by genistein and investigated their function in prostate cancer (PCa) and target pathways. Using miRNA microarray analysis and real-time RT-PCR we observed that miR-574-3p was significantly up-regulated in PCa cells treated with genistein compared with vehicle control. The expression of miR-574-3p was significantly lower in PCa cell lines and clinical PCa tissues compared with normal prostate cells (RWPE-1) and adjacent normal tissues. Low expression level of miR-574-3p was correlated with advanced tumor stage and higher Gleason score in PCa specimens. Re-expression of miR-574-3p in PCa cells significantly inhibited cell proliferation, migration and invasion in vitro and in vivo. miR-574-3p restoration induced apoptosis through reducing Bcl-xL and activating caspase-9 and caspase-3. Using GeneCodis software analysis, several pathways affected by miR-574-3p were identified, such as ‘Pathways in cancer’, ‘Jak-STAT signaling pathway’, and ‘Wnt signaling pathway’. Luciferase reporter assays demonstrated that miR-574-3p directly binds to the 3′ UTR of several target genes (such as RAC1, EGFR and EP300) that are components of ‘Pathways in cancer’. Quantitative real-time PCR and Western analysis showed that the mRNA and protein expression levels of the three target genes in PCa cells were markedly down-regulated with miR-574-3p. Loss-of-function studies demonstrated that the three target genes significantly affect cell proliferation, migration and invasion in PCa cell lines. Our results show that genistein up-regulates tumor suppressor miR-574-3p expression targeting several cell signaling pathways. These findings enhance understanding of how genistein regulates with miRNA in PCa. PMID:23554959

  3. Quantitative analysis of the tumor suppressor dendrogenin A using liquid chromatography tandem mass spectrometry.

    PubMed

    Noguer, Emmanuel; Soules, Régis; Netter, Claude; Nagarathinam, Citra; Leignadier, Julie; Huc-Claustre, Emilie; Serhan, Nizar; Rives, Arnaud; de Medina, Philippe; Silvente-Poirot, Sandrine; Poirot, Marc

    2017-07-03

    Dendrogenin A (DDA) was recently identified as a mammalian cholesterol metabolite that displays tumor suppressor and neurostimulating properties at low doses. In breast tumors, DDA levels were found to be decreased compared to normal tissues, evidencing a metabolic deregulation of DDA production in cancers. DDA is an amino-oxysterol that contains three protonatable nitrogen atoms. This makes it physico-chemically different from other oxysterols and it therefore requires specific analytical methods We have previously used a two-step method for the quantification of DDA in biological samples: 1) DDA purification from a Bligh and Dyer extract by RP-HPLC using a 250×4.6mm column, followed by 2) nano-electrospray ionization mass spectrometry (MS) fragmentation to analyze the HPLC fraction of interest. We report here the development a liquid chromatography tandem mass spectrometry method for the analysis of DDA and its analogues. This new method is fast (10min), resolving (peak width <4s) and has a weak carryover (<0.01%). We show that this technique efficiently separates DDA from its C17 isomer and other steroidal alkaloids from the same family establishing a proof of concept for the analysis of this family of amino-oxysterols. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

    PubMed

    Zhang, Min; Biswas, Sangita; Qin, Xin; Gong, Wenrong; Deng, Wenbing; Yu, Hongjun

    2016-08-01

    The role of Notch pathway in tumorigenesis is highly variable. It can be tumor suppressive or pro-oncogenic, typically depending on the cellular context. Squamous cell carcinoma (SCC) is a cancer of the squamous cell, which can occur in diverse human tissues. SCCs are one of the most frequent human malignancies for which the pathologic mechanisms remain elusive. Recent genomic analysis of diverse SCCs identified marked levels of mutations in NOTCH1, implicating Notch signaling pathways in the pathogenesis of SCCs. In this review, evidences highlighting NOTCH's role in different types of SCCs are summarized. Moreover, based on accumulating structural information of the NOTCH receptor, the functional consequences of NOTCH1 gene mutations identified from diverse SCCs are analyzed, emphasizing loss of function of Notch in these cancers. Finally, we discuss the convergent view on an intriguing possibility that Notch may function as tumor suppressor in SCCs across different tissues. These mechanistic insights into Notch signaling pathways will help to guide the research of SCCs and development of therapeutic strategies for these cancers.

  5. Cluster Analysis of Tumor Suppressor Genes in Canine Leukocytes Identifies Activation State

    PubMed Central

    Daly, Julie-Anne; Mortlock, Sally-Anne; Taylor, Rosanne M.; Williamson, Peter

    2015-01-01

    Cells of the immune system undergo activation and subsequent proliferation in the normal course of an immune response. Infrequently, the molecular and cellular events that underlie the mechanisms of proliferation are dysregulated and may lead to oncogenesis, leading to tumor formation. The most common forms of immunological cancers are lymphomas, which in dogs account for 8%–20% of all cancers, affecting up to 1.2% of the dog population. Key genes involved in negatively regulating proliferation of lymphocytes include a group classified as tumor suppressor genes (TSGs). These genes are also known to be associated with progression of lymphoma in humans, mice, and dogs and are potential candidates for pathological grading and diagnosis. The aim of the present study was to analyze TSG profiles in stimulated leukocytes from dogs to identify genes that discriminate an activated phenotype. A total of 554 TSGs and three gene set collections were analyzed from microarray data. Cluster analysis of three subsets of genes discriminated between stimulated and unstimulated cells. These included 20 most upregulated and downregulated TSGs, TSG in hallmark gene sets significantly enriched in active cells, and a selection of candidate TSGs, p15 (CDKN2B), p18 (CDKN2C), p19 (CDKN1A), p21 (CDKN2A), p27 (CDKN1B), and p53 (TP53) in the third set. Analysis of two subsets suggested that these genes or a subset of these genes may be used as a specialized PCR set for additional analysis. PMID:27478369

  6. E3 ubiquitin ligase TRIM32 negatively regulates tumor suppressor p53 to promote tumorigenesis.

    PubMed

    Liu, Ju; Zhang, C; Wang, X L; Ly, P; Belyi, V; Xu-Monette, Z Y; Young, K H; Hu, W; Feng, Z

    2014-11-01

    Tumor suppressor p53 has a key role in maintaining genomic stability and preventing tumorigenesis through its regulation of cellular stress responses, including apoptosis, cell cycle arrest and senescence. To ensure its proper levels and functions in cells, p53 is tightly regulated mainly through post-translational modifications, such as ubiquitination. Here, we identified E3 ubiquitin ligase TRIM32 as a novel p53 target gene and negative regulator to regulate p53-mediated stress responses. In response to stress, such as DNA damage, p53 binds to the p53 responsive element in the promoter of the TRIM32 gene and transcriptionally induces the expression of TRIM32 in cells. In turn, TRIM32 interacts with p53 and promotes p53 degradation through ubiquitination. Thus, TRIM32 negatively regulates p53-mediated apoptosis, cell cycle arrest and senescence in response to stress. TRIM32 is frequently overexpressed in different types of human tumors. TRIM32 overexpression promotes cell oncogenic transformation and tumorigenesis in mice in a largely p53-dependent manner. Taken together, our results demonstrated that as a novel p53 target and a novel negative regulator for p53, TRIM32 has an important role in regulation of p53 and p53-mediated cellular stress responses. Furthermore, our results also revealed that impairing p53 function is a novel mechanism for TRIM32 in tumorigenesis.

  7. Identifying the ubiquitin ligase complex that regulates the NF1 tumor suppressor and Ras

    PubMed Central

    Hollstein, Pablo E.; Cichowski, Karen

    2013-01-01

    The NF1 tumor suppressor protein, neurofibromin, is a negative regulator of Ras. Neurofibromin is dynamically regulated by the proteasome and its degradation and re-expression are essential for maintaining appropriate levels of Ras-GTP. Like p53, NF1/neurofibromin can be inactivated in cancer by both mutations and excessive proteasomal destruction; however, little is known about the mechanisms that underlie this latter process. Here we show that a Cullin 3 (Cul3)/KBTBD7 complex controls both the regulated proteasomal degradation of neurofibromin and the pathogenic destabilization of neurofibromin in glioblastomas. Importantly RNAi-mediated Cul3 ablation and a dominant-negative Cul3 directly stabilize neurofibromin, suppress Ras and ERK, and inhibit proliferation in an NF1-dependent manner. Moreover, in glioblastomas where neurofibromin is chronically destabilized, Cul3 inhibition re-stabilizes the protein and suppresses tumor development. Collectively these studies demonstrate a previously unrecognized role for Cul3 in regulating Ras and provide a molecular framework that can be exploited to develop potential cancer therapies. PMID:23661552

  8. The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1.

    PubMed

    Zhou, Mina I; Wang, Hongmei; Ross, Jonathan J; Kuzmin, Igor; Xu, Chengen; Cohen, Herbert T

    2002-10-18

    The von Hippel-Lindau disease gene (VHL) is the causative gene for most adult renal cancers. However, the mechanism by which VHL protein functions as a renal tumor suppressor remains largely unknown. To identify low occupancy VHL protein partners with potential relevance to renal cancer, we screened a human kidney library against human VHL p30 using a yeast two-hybrid approach. Jade-1 (gene for Apoptosis and Differentiation in Epithelia) encodes a previously uncharacterized 64-kDa protein that interacts strongly with VHL protein and is most highly expressed in kidney. Jade-1 protein is short-lived and contains a candidate destabilizing (PEST) motif and plant homeodomains that are not required for the VHL interaction. Jade-1 is abundant in proximal tubule cells, which are clear-cell renal cancer precursors, and expression increases with differentiation. Jade-1 is expressed in cytoplasm and the nucleus diffusely and in speckles, where it partly colocalizes with VHL. VHL reintroduction into renal cancer cells increases endogenous Jade-1 protein abundance up to 10-fold. Furthermore, VHL increases Jade-1 protein half-life up to 3-fold. Thus, direct protein stabilization is identified as a new VHL function. Moreover, Jade-1 protein represents a novel candidate regulatory factor in VHL-mediated renal tumor suppression.

  9. Susceptibility for N-ras-mediated transformation requires loss of tumor suppressor activity.

    PubMed

    Krizman, D B; Giovanella, B C; Tainsky, M A

    1990-01-01

    We have been using PA-1 human teratocarcinoma cells to study mechanisms by which oncogenes induce transformation. Tumorigenic PA-1 cells at passages greater than 100 (greater than P100) contain a spontaneously activated N-ras oncogene, while earlier-passage preneoplastic cells contain only the germ-line protooncogene and are nontumorigenic. One preneoplastic cell clone of PA-1 cells can be transformed by introduction of the cloned PA-1 N-ras in gene-transfer experiments, while another earlier-passage clonal cell line cannot be transformed. The goal of this investigation was to determine how human cells progress from resistance to susceptibility to ras oncogene-induced transformation. Somatic cell hybridization experiments described in this report indicate that the resistance of the low-passage cells to transformation is a dominant trait suppressing transformation. Loss of chromosomes from hybrid segregants suggested that tumor suppressors exist on chromosomes 1, 4, and 11. Extended in vitro passaging of somatic cell hybrids also resulted in the loss of chromosomes. Chromosome 1 was lost in these populations of cells, implying that reduction of this chromosome may promote proliferation and not specifically affect tumor formation.

  10. The tumor suppressor protein menin inhibits AKT activation by regulating its cellular localization

    PubMed Central

    Wang, Yan; Ozawa, Atsushi; Zaman, Shadia; Prasad, Nijaguna B.; Chandrasekharappa, Settara C.; Agarwal, Sunita K.; Marx, Stephen J.

    2010-01-01

    Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder associated mainly with tumors of multiple endocrine organs. Mutations in the MEN1 gene that encodes for the menin protein are the predominant cause for hereditary MEN1 syndrome. Though menin is a tumor suppressor, its molecular mechanism of action has not been defined. Here we report that menin interacts with AKT1 in vitro and in vivo. Menin downregulates the level of active AKT and its kinase activity. Through interaction with AKT1, menin suppresses both AKT1 induced proliferation and anti-apoptosis in non-endocrine and endocrine cells. Confocal microscopy analysis revealed that menin regulates AKT1 in part by reducing the translocation of AKT1 from the cytoplasm to the plasma membrane during growth factor stimulation. Our findings may be generalizable to other cancers, insofar as we found that loss of menin expression was also associated with AKT activation in a mouse model of pancreatic islet adenoma. Together, our results suggest menin as an important novel negative regulator of AKT kinase activity. PMID:21127195

  11. Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions.

    PubMed

    Urman, Nicole M; Mirza, Amar; Atwood, Scott X; Whitson, Ramon J; Sarin, Kavita Y; Tang, Jean Y; Oro, Anthony E

    2016-01-01

    The Hedgehog pathway is a potent regulator of cellular growth and plays a central role in the development of many cancers including basal cell carcinoma (BCC). The majority of BCCs arise from mutations in the Patched receptor resulting in constitutive activation of the Hedgehog pathway. Secondary driver mutations promote BCC oncogenesis and occur frequently due to the high mutational burden resulting from sun exposure of the skin. Here, we uncover novel secondary mutations in Suppressor of Fused (SUFU), the major negative regulator of the Hedgehog pathway. SUFU normally binds to a Hedgehog transcriptional activator, GLI1, in order to prevent it from initiating transcription of Hedgehog target genes. We sequenced tumor-normal pairs from patients with early sporadic BCCs. This resulted in the discovery of nine mutations in SUFU, which were functionally investigated to determine whether they help drive BCC formation. Our results show that four of the SUFU mutations inappropriately activate the Hedgehog pathway, suggesting they may act as driver mutations for BCC development. Indeed, all four of the loss of function SUFU variants were found to disrupt its binding to GLI, leading to constitutive pathway activation. Our results from functional characterization of these mutations shed light on SUFU's role in Hedgehog signaling, tumor progression, and highlight a way in which BCCs can arise.

  12. Expression of the tumor suppressor gene hypermethylated in cancer 1 in laryngeal carcinoma.

    PubMed

    Markowski, Jarosław; Sieroń, Aleksander L; Kasperczyk, Katarzyna; Ciupińska-Kajor, Monika; Auguściak-Duma, Aleksandra; Likus, Wirginia

    2015-05-01

    Hypermethylated in cancer 1 (HIC1) is a putative suppressor gene, cooperating with TP53 in the regulation of apoptosis. The promoter site of this gene contains CpG islands susceptible to methylation. Altered methylation leads to the silencing of HIC1. Persistent loss of HIC1 function reflects the attenuation of proapoptotic characteristics of TP53 and may constitute the background for carcinogenesis. Altered methylation profiles along with diminished expression of HIC1 were documented in a number of solid neoplasms. The aim of this study was to evaluate the expression of the HIC1 gene in laryngeal carcinoma. RNA was extracted from samples of laryngeal cancer and corresponding healthy tissues of 21 patients with advanced laryngeal cancer (T3-T4). The amount of RNA (cDNA) was evaluated using reverse transcription-quantitative polymerase chain reaction with GADPH as the reference gene. Data demonstrated that HIC1 expression was significantly reduced in laryngeal cancer tissues. The relative expression of HIC1 was found to be ~40% lower in tumor samples compared to that in healthy controls. The median tumor/normal tissue ratio for HIC1 was 0.615. These results suggest that low HIC1 expression may be associated with neoplastic transformation in the larynx.

  13. Expression of the tumor suppressor gene hypermethylated in cancer 1 in laryngeal carcinoma

    PubMed Central

    MARKOWSKI, JAROSŁAW; SIEROŃ, ALEKSANDER L.; KASPERCZYK, KATARZYNA; CIUPIŃSKA-KAJOR, MONIKA; AUGUŚCIAK-DUMA, ALEKSANDRA; LIKUS, WIRGINIA

    2015-01-01

    Hypermethylated in cancer 1 (HIC1) is a putative suppressor gene, cooperating with TP53 in the regulation of apoptosis. The promoter site of this gene contains CpG islands susceptible to methylation. Altered methylation leads to the silencing of HIC1. Persistent loss of HIC1 function reflects the attenuation of proapoptotic characteristics of TP53 and may constitute the background for carcinogenesis. Altered methylation profiles along with diminished expression of HIC1 were documented in a number of solid neoplasms. The aim of this study was to evaluate the expression of the HIC1 gene in laryngeal carcinoma. RNA was extracted from samples of laryngeal cancer and corresponding healthy tissues of 21 patients with advanced laryngeal cancer (T3-T4). The amount of RNA (cDNA) was evaluated using reverse transcription-quantitative polymerase chain reaction with GADPH as the reference gene. Data demonstrated that HIC1 expression was significantly reduced in laryngeal cancer tissues. The relative expression of HIC1 was found to be ~40% lower in tumor samples compared to that in healthy controls. The median tumor/normal tissue ratio for HIC1 was 0.615. These results suggest that low HIC1 expression may be associated with neoplastic transformation in the larynx. PMID:26137060

  14. Molecular pathology of pancreatic cancer: in quest of tumor suppressor genes.

    PubMed

    Furukawa, Toru; Horii, Akira

    2004-04-01

    To find molecular clues useful for early detection and effective therapy for pancreatic cancer, we first carried out genomic analysis by means of comparative genomic hybridization and micro-satellite analysis. We found very complicated molecular alterations in multiple chromosomal regions, including 1p, 6q, 9p, 12q, 17p, 18q, and 21q for losses and 8q and 20q for gains. These diverse changes are very characteristic of pancreatic cancer, and from this information, we developed a method for detecting the aberrant copy numbers of specific chromosomal regions by fluorescence in situ hybridization in cells collected from pancreatic juice for early diagnosis of pancreatic neoplasms. The regions of losses suggest the existence of tumor suppressor genes (TSGs). We identified DUSP6/MKP-3 at 12q21-q22 as a strong candidate TSG; it showed epigenetic inactivation in some fractions of invasive pancreatic cancer and growth suppression and apoptosis by overexpression in vitro. To determine the pathologic roles of 18q, we introduced a normal copy of chromosome 18 into cultured pancreatic cancer cells. The introduction induced marked suppressions of tumor formation and metastasis formation in vivo. We continue work to more completely understand the complex molecular mechanisms of pancreatic carcinogenesis and to apply the information gained to the clinical treatment of pancreatic cancer.

  15. miR-203, a Tumor Suppressor Frequently Down-regulated by Promoter Hypermethylation in Rhabdomyosarcoma*

    PubMed Central

    Diao, Yarui; Guo, Xing; Jiang, Lei; Wang, Gang; Zhang, Chao; Wan, Jun; Jin, Yan; Wu, Zhenguo

    2014-01-01

    Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma found in children and young adults. It is characterized by the expression of a number of skeletal muscle-specific proteins, including MyoD and muscle α-actin. However, unlike normal myoblasts, RMS cells differentiate poorly both in vivo and in culture. As microRNAs are known to regulate tumorigenesis, intensive efforts have been made to identify microRNAs that are involved in RMS development. In this work, we found that miR-203 was frequently down-regulated by promoter hypermethylation in both RMS cell lines and RMS biopsies and could be reactivated by DNA-demethylating agents. Re-expression of miR-203 in RMS cells inhibited their migration and proliferation and promoted terminal myogenic differentiation. Mechanistically, miR-203 exerts its tumor-suppressive effect by directly targeting p63 and leukemia inhibitory factor receptor in RMS cells, which promotes myogenic differentiation by inhibiting the Notch and the JAK1/STAT1/STAT3 pathways, respectively. Our work reveals that miR-203 functions as a tumor suppressor in RMS development. PMID:24247238

  16. DNA recognition by splicing variants of the Wilms' tumor suppressor, WT1.

    PubMed Central

    Drummond, I A; Rupprecht, H D; Rohwer-Nutter, P; Lopez-Guisa, J M; Madden, S L; Rauscher, F J; Sukhatme, V P

    1994-01-01

    The Wilms' tumor suppressor, WT1, is a zinc finger transcriptional regulator which exists as multiple forms owing to alternative mRNA splicing. The most abundant splicing variants contain a nine-nucleotide insertion encoding lysine, threonine, and serine (KTS) in the H-C link region between the third and fourth WT1 zinc fingers which disrupts binding to a previously defined WT1-EGR1 binding site. We have identified WT1[+KTS] binding sites in the insulin-like growth factor II gene and show that WT1[+KTS] represses transcription from the insulin-like growth factor II P3 promoter. The highest affinity WT1[+KTS] DNA binding sites included nucleotide contacts involving all four WT1 zinc fingers. We also found that different subsets of three WT1 zinc fingers could bind to distinct DNA recognition elements. A tumor-associated, WT1 finger 3 deletion mutant was shown to bind to juxtaposed nucleotide triplets for the remaining zinc fingers 1, 2, and 4. The characterization of novel WT1 DNA recognition elements adds a new level of complexity to the potential gene regulatory activity of WT1. The results also present the possibility that altered DNA recognition by the dominant WT1 zinc finger 3 deletion mutant may contribute to tumorigenesis. Images PMID:8196623

  17. TCP10L acts as a tumor suppressor by inhibiting cell proliferation in hepatocellular carcinoma

    SciTech Connect

    Zuo, Jie; Cai, Hao; Wu, Yanhua; Ma, Haijie; Jiang, Wei; Liu, Chao; Han, Dingding; Ji, Guoqing; Yu, Long

    2014-03-28

    Highlights: • TCP10L was down-regulated in clinical hepatocellular carcinoma (HCC). • Expression of TCP10L correlated significantly with tumor size and Milan criteria. • Overexpression of TCP10L attenuated growth of HCC cells both in vitro and in vivo. • Knocking down TCP10L promoted cell proliferation and tumorigenesis of HCC cells. - Abstract: TCP10L (T-complex 10 (mouse)-like) has been identified as a liver and testis-specific gene. Although a potential transcriptional suppression function of TCP10L has been reported previously, biological function of this gene still remains largely elusive. In this study, we reported for the first time that TCP10L was significantly down-regulated in clinical hepatocellular carcinoma (HCC) samples when compared to the corresponding non-tumorous liver tissues. Furthermore, TCP10L expression was highly correlated with advanced cases exceeding the Milan criteria. Overexpression of TCP10L in HCC cells suppressed colony formation, inhibited cell cycle progression through G0/G1 phase, and attenuated cell growth in vivo. Consistently, silencing of TCP10L promoted cell cycle progression and cell growth. Therefore, our study has revealed a novel suppressor role of TCP10L in HCC, by inhibiting proliferation of HCC cells, which may facilitate the diagnosis and molecular therapy in HCC.

  18. Tumor suppressor Lzap regulates cell cycle progression, doming and zebrafish epiboly

    PubMed Central

    Liu, Dan; Wang, Wen-Der; Melville, David B.; Cha, Yong I.; Yin, Zhirong; Issaeva, Natalia; Knapik, Ela W.; Yarbrough, Wendell G.

    2012-01-01

    Initial stages of embryonic development rely on rapid, synchronized cell divisions of the fertilized egg followed by a set of morphogenetic movements collectively called epiboly and gastrulation. Lzap is a putative tumor suppressor whose expression is lost in 30% of head and neck squamous cell carcinomas. Lzap activities include regulation of cell cycle progression and response to therapeutic agents. Here we explore developmental roles of the lzap gene during zebrafish morphogenesis. Lzap is highly conserved among vertebrates and is maternally deposited. Expression is initially ubiquitous during gastrulation, and later becomes more prominent in the pharyngeal arches, digestive tract and brain. Antisense morpholino-mediated depletion of Lzap resulted in delayed cell divisions and apoptosis during blastomere formation, resulting in fewer, larger cells. Cell cycle analysis suggested that Lzap loss in early embryonic cells resulted in a G2/M arrest. Furthermore, the Lzap-deficient embryos failed to initiate epiboly – the earliest morphogenetic movement in animal development – which has been shown to be dependent on cell adhesion and migration of epithelial sheets. Our results strongly implicate Lzap in regulation of cell cycle progression, adhesion and migratory activity of epithelial cell sheets during early development. These functions provide further insight into Lzap activity that may contribute not only to development, but also to tumor formation. PMID:21523853

  19. Inactivating ARID1A Tumor Suppressor Enhances TERT Transcription and Maintains Telomere Length in Cancer Cells*

    PubMed Central

    Rahmanto, Yohan Suryo; Jung, Jin-Gyoung; Wu, Ren-Chin; Kobayashi, Yusuke; Heaphy, Christopher M.; Meeker, Alan K.; Wang, Tian-Li; Shih, Ie-Ming

    2016-01-01

    ARID1A is a tumor suppressor gene that belongs to the switch/sucrose non-fermentable chromatin remodeling gene family. It is mutated in many types of human cancer with the highest frequency in endometrium-related ovarian and uterine neoplasms including ovarian clear cell, ovarian endometrioid, and uterine endometrioid carcinomas. We have previously reported that mutations in the promoter of human telomerase reverse transcriptase (TERT) rarely co-occur with the loss of ARID1A protein expression, suggesting a potential role of ARID1A in telomere biology. In this study, we demonstrate that ARID1A negatively regulates TERT transcriptional regulation and activity via binding to the regulatory element of TERT and promotes a repressive histone mode. Induction of ARID1A expression was associated with increased occupancy of SIN3A and H3K9me3, known transcription repressor and histone repressor marks, respectively. Thus, loss of ARID1A protein expression caused by inactivating mutations reactivates TERT transcriptional activity and confers a survival advantage of tumor cells by maintaining their telomeres. PMID:26953344

  20. Comparative oncogenomics identifies tyrosine kinase FES as a tumor suppressor in melanoma

    PubMed Central

    Olvedy, Michael; Tisserand, Julie C.; Luciani, Flavie; Boeckx, Bram; Lopez, Sophie; Rambow, Florian; Aibar, Sara; Barra, Jasmine; Köhler, Corinna; Radaelli, Enrico; Aerts, Stein; Dubreuil, Patrice; van den Oord, Joost J.; Lambrechts, Diether; Marine, Jean-Christophe

    2017-01-01

    Identification and functional validation of oncogenic drivers are essential steps toward advancing cancer precision medicine. Here, we have presented a comprehensive analysis of the somatic genomic landscape of the widely used BRAFV600E- and NRASQ61K-driven mouse models of melanoma. By integrating the data with publically available genomic, epigenomic, and transcriptomic information from human clinical samples, we confirmed the importance of several genes and pathways previously implicated in human melanoma, including the tumor-suppressor genes phosphatase and tensin homolog (PTEN), cyclin dependent kinase inhibitor 2A (CDKN2A), LKB1, and others. Importantly, this approach also identified additional putative melanoma drivers with prognostic and therapeutic relevance. Surprisingly, one of these genes encodes the tyrosine kinase FES. Whereas FES is highly expressed in normal human melanocytes, FES expression is strongly decreased in over 30% of human melanomas. This downregulation correlates with poor overall survival. Correspondingly, engineered deletion of Fes accelerated tumor progression in a BRAFV600E-driven mouse model of melanoma. Together, these data implicate FES as a driver of melanoma progression and demonstrate the potential of cross-species oncogenomic approaches combined with mouse modeling to uncover impactful mutations and oncogenic driver alleles with clinical importance in the treatment of human cancer. PMID:28463229

  1. Comparative oncogenomics identifies tyrosine kinase FES as a tumor suppressor in melanoma.

    PubMed

    Olvedy, Michael; Tisserand, Julie C; Luciani, Flavie; Boeckx, Bram; Wouters, Jasper; Lopez, Sophie; Rambow, Florian; Aibar, Sara; Thienpont, Bernard; Barra, Jasmine; Köhler, Corinna; Radaelli, Enrico; Tartare-Deckert, Sophie; Aerts, Stein; Dubreuil, Patrice; van den Oord, Joost J; Lambrechts, Diether; De Sepulveda, Paulo; Marine, Jean-Christophe

    2017-06-01

    Identification and functional validation of oncogenic drivers are essential steps toward advancing cancer precision medicine. Here, we have presented a comprehensive analysis of the somatic genomic landscape of the widely used BRAFV600E- and NRASQ61K-driven mouse models of melanoma. By integrating the data with publically available genomic, epigenomic, and transcriptomic information from human clinical samples, we confirmed the importance of several genes and pathways previously implicated in human melanoma, including the tumor-suppressor genes phosphatase and tensin homolog (PTEN), cyclin dependent kinase inhibitor 2A (CDKN2A), LKB1, and others. Importantly, this approach also identified additional putative melanoma drivers with prognostic and therapeutic relevance. Surprisingly, one of these genes encodes the tyrosine kinase FES. Whereas FES is highly expressed in normal human melanocytes, FES expression is strongly decreased in over 30% of human melanomas. This downregulation correlates with poor overall survival. Correspondingly, engineered deletion of Fes accelerated tumor progression in a BRAFV600E-driven mouse model of melanoma. Together, these data implicate FES as a driver of melanoma progression and demonstrate the potential of cross-species oncogenomic approaches combined with mouse modeling to uncover impactful mutations and oncogenic driver alleles with clinical importance in the treatment of human cancer.

  2. Inactivating ARID1A Tumor Suppressor Enhances TERT Transcription and Maintains Telomere Length in Cancer Cells.

    PubMed

    Suryo Rahmanto, Yohan; Jung, Jin-Gyoung; Wu, Ren-Chin; Kobayashi, Yusuke; Heaphy, Christopher M; Meeker, Alan K; Wang, Tian-Li; Shih, Ie-Ming

    2016-04-29

    ARID1A is a tumor suppressor gene that belongs to the switch/sucrose non-fermentable chromatin remodeling gene family. It is mutated in many types of human cancer with the highest frequency in endometrium-related ovarian and uterine neoplasms including ovarian clear cell, ovarian endometrioid, and uterine endometrioid carcinomas. We have previously reported that mutations in the promoter of human telomerase reverse transcriptase (TERT) rarely co-occur with the loss of ARID1A protein expression, suggesting a potential role of ARID1A in telomere biology. In this study, we demonstrate that ARID1A negatively regulates TERT transcriptional regulation and activity via binding to the regulatory element of TERT and promotes a repressive histone mode. Induction of ARID1A expression was associated with increased occupancy of SIN3A and H3K9me3, known transcription repressor and histone repressor marks, respectively. Thus, loss of ARID1A protein expression caused by inactivating mutations reactivates TERT transcriptional activity and confers a survival advantage of tumor cells by maintaining their telomeres. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Identification and characterization of a retinoid-induced class II tumor suppressor/growth regulatory gene.

    PubMed

    DiSepio, D; Ghosn, C; Eckert, R L; Deucher, A; Robinson, N; Duvic, M; Chandraratna, R A; Nagpal, S

    1998-12-08

    Retinoids, synthetic and natural analogs of retinoic acid, exhibit potent growth inhibitory and cell differentiation activities that account for their beneficial effects in treating hyperproliferative diseases such as psoriasis, actinic keratosis, and certain neoplasias. Tazarotene is a synthetic retinoid that is used in the clinic for the treatment of psoriasis. To better understand the mechanism of retinoid action in the treatment of hyperproliferative diseases, we used a long-range differential display-PCR to isolate retinoid-responsive genes from primary human keratinocytes. We have identified a cDNA, tazarotene-induced gene 3 (TIG3; Retinoic Acid Receptor Responder 3) showing significant homology to the class II tumor suppressor gene, H-rev 107. Tazarotene treatment increases TIG3 expression in primary human keratinocytes and in vivo in psoriatic lesions. Increased TIG3 expression is correlated with decreased proliferation. TIG3 is expressed in a number of tissues, and expression is reduced in cancer cell lines and some primary tumors. In breast cancer cell lines, retinoid-dependent TIG3 induction is observed in lines that are growth suppressed by retinoids but not in nonresponsive lines. Transient over-expression of TIG3 in T47D or Chinese hamster ovary cells inhibits colony expansion. Finally, studies in 293 cells expressing TIG3 linked to an inducible promoter demonstrated decreased proliferation with increased TIG3 levels. These studies suggest that TIG3 may be a growth regulator that mediates some of the growth suppressive effects of retinoids.

  4. Hepatocellular carcinoma mouse models: Hepatitis B virus-associated hepatocarcinogenesis and haploinsufficient tumor suppressor genes

    PubMed Central

    Teng, Yuan-Chi; Shen, Zhao-Qing; Kao, Cheng-Heng; Tsai, Ting-Fen

    2016-01-01

    The multifactorial and multistage pathogenesis of hepatocellular carcinoma (HCC) has fascinated a wide spectrum of scientists for decades. While a number of major risk factors have been identified, their mechanistic roles in hepatocarcinogenesis still need to be elucidated. Many tumor suppressor genes (TSGs) have been identified as being involved in HCC. These TSGs can be classified into two groups depending on the situation with respect to allelic mutation/loss in the tumors: the recessive TSGs with two required mutated alleles and the haploinsufficient TSGs with one required mutated allele. Hepatitis B virus (HBV) is one of the most important risk factors associated with HCC. Although mice cannot be infected with HBV due to the narrow host range of HBV and the lack of a proper receptor, one advantage of mouse models for HBV/HCC research is the numerous and powerful genetic tools that help investigate the phenotypic effects of viral proteins and allow the dissection of the dose-dependent action of TSGs. Here, we mainly focus on the application of mouse models in relation to HBV-associated HCC and on TSGs that act either in a recessive or in a haploinsufficient manner. Discoveries obtained using mouse models will have a great impact on HCC translational medicine. PMID:26755878

  5. The tumor suppressor, parafibromin, mediates histone H3 K9 methylation for cyclin D1 repression.

    PubMed

    Yang, Yong-Jin; Han, Jeung-Whan; Youn, Hong-Duk; Cho, Eun-Jung

    2010-01-01

    Parafibromin, a component of the RNA polymerase II-associated PAF1 complex, is a tumor suppressor linked to hyperparathyroidism-jaw tumor syndrome and sporadic parathyroid carcinoma. Parafibromin induces cell cycle arrest by repressing cyclin D1 via an unknown mechanism. Here, we show that parafibromin interacts with the histone methyltransferase, SUV39H1, and functions as a transcriptional repressor. The central region (128-227 amino acids) of parafibromin is important for both the interaction with SUV39H1 and transcriptional repression. Parafibromin associated with the promoter and coding regions of cyclin D1 and was required for the recruitment of SUV39H1 and the induction of H3 K9 methylation but not H3 K4 methylation. RNA interference analysis showed that SUV39H1 was critical for cyclin D1 repression. These data suggest that parafibromin plays an unexpected role as a repressor in addition to its widely known activity associated with transcriptional activation. Parafibromin as a part of the PAF1 complex might downregulate cyclin D1 expression by integrating repressive H3 K9 methylation during transcription.

  6. Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions

    PubMed Central

    Urman, Nicole M.; Mirza, Amar; Atwood, Scott X.; Whitson, Ramon J.; Sarin, Kavita Y.; Tang, Jean Y.; Oro, Anthony E.

    2016-01-01

    The Hedgehog pathway is a potent regulator of cellular growth and plays a central role in the development of many cancers including basal cell carcinoma (BCC). The majority of BCCs arise from mutations in the Patched receptor resulting in constitutive activation of the Hedgehog pathway. Secondary driver mutations promote BCC oncogenesis and occur frequently due to the high mutational burden resulting from sun exposure of the skin. Here, we uncover novel secondary mutations in Suppressor of Fused (SUFU), the major negative regulator of the Hedgehog pathway. SUFU normally binds to a Hedgehog transcriptional activator, GLI1, in order to prevent it from initiating transcription of Hedgehog target genes. We sequenced tumor-normal pairs from patients with early sporadic BCCs. This resulted in the discovery of nine mutations in SUFU, which were functionally investigated to determine whether they help drive BCC formation. Our results show that four of the SUFU mutations inappropriately activate the Hedgehog pathway, suggesting they may act as driver mutations for BCC development. Indeed, all four of the loss of function SUFU variants were found to disrupt its binding to GLI, leading to constitutive pathway activation. Our results from functional characterization of these mutations shed light on SUFU’s role in Hedgehog signaling, tumor progression, and highlight a way in which BCCs can arise. PMID:28030567

  7. Absence of p16INK4a and truncation of ARF tumor suppressors in chickens

    PubMed Central

    Kim, Soo-Hyun; Mitchell, Michael; Fujii, Hideta; Llanos, Susana; Peters, Gordon

    2003-01-01

    The INK4b-ARF-INK4a locus on human chromosome 9p21 (Human Genome Organization designation CDKN2B-CDKN2A), and the corresponding locus on mouse chromosome 4, encodes three distinct products: two members of the INK4 cyclin-dependent kinase inhibitor family and a completely unrelated protein, ARF, whose carboxyl-terminal half is specified by the second exon of INK4a but in an alternative reading frame. As INK4 proteins block the phosphorylation of the retinoblastoma gene product and ARF protects p53 from degradation, the locus plays a key role in tumor suppression and the control of cell proliferation. To gain further insights into the relative importance of INK4a and ARF in different settings, we have isolated and characterized the equivalent locus in chickens. Surprisingly, although we identified orthologues of INK4b and ARF, chickens do not encode an equivalent of INK4a. Moreover, the reading frame for chicken ARF does not extend into exon 2, because splicing occurs in a different register to that used in mammals. The resultant 60-aa product nevertheless shares functional attributes with its mammalian counterparts. As well as indicating that the locus has been subject to dynamic evolutionary pressures, these unexpected findings suggest that in chickens, the tumor-suppressor functions of INK4a have been compensated for by other genes. PMID:12506196

  8. HOXB1 Is a Tumor Suppressor Gene Regulated by miR-3175 in Glioma

    PubMed Central

    Han, Liang; Liu, Dehua; Li, Zhaohui; Tian, Nan; Han, Ziwu; Wang, Guang; Fu, Yao; Guo, Zhigang; Zhu, Zifeng

    2015-01-01

    The HOXB1 gene plays a critical role as an oncogene in diverse tumors. However, the functional role of HOXB1 and the mechanism regulating HOXB1 expression in glioma are not fully understood. A preliminary bioinformatics analysis showed that HOXB1 is ectopically expressed in glioma, and that HOXB1 is a possible target of miR-3175. In this study, we investigated the function of HOXB1 and the relationship between HOXB1 and miR-3175 in glioma. We show that HOXB1 expression is significantly downregulated in glioma tissues and cell lines, and that its expression may be closely associated with the degree of malignancy. Reduced HOXB1 expression promoted the proliferation and invasion of glioma cells, and inhibited their apoptosis in vitro, and the downregulation of HOXB1 was also associated with worse survival in glioma patients. More importantly, HOXB1 was shown experimentally to be a direct target of miR-3175 in this study. The downregulated expression of miR-3175 inhibited cell proliferation and invasion, and promoted apoptosis in glioma. The oncogenicity induced by low HOXB1 expression was prevented by an miR-3175 inhibitor in glioma cells. Our results suggest that HOXB1 functions as a tumor suppressor, regulated by miR-3175 in glioma. These results clarify the pathogenesis of glioma and offer a potential target for its treatment. PMID:26565624

  9. The ubiquitin E3 ligase ITCH enhances breast tumor progression by inhibiting the Hippo tumor suppressor pathway.

    PubMed

    Salah, Zaidoun; Itzhaki, Ella; Aqeilan, Rami I

    2014-11-15

    The Hippo kinase pathway is emerging as a conserved signaling pathway that is essential for organ growth and tumorigenesis. Recently, we reported that the ubiquitin E3 ligase ITCH negatively regulates LATS1, thereby increasing YAP activity, which leads to increased cell proliferation and decreased apoptosis. Here, we investigated the role of ITCH in breast tumorigenesis. In particular, we show that ITCH enhances epithelial-to-mesenchymal transition (EMT) through boosting YAP oncogenic function. By contrast, a point mutation in the catalytic domain or WW1 domain of ITCH abolished its EMT-mediated effects. Furthermore, while overexpression of ITCH expression in breast cells is associated with increased incidence of mammary tumor formation and progression, its knockdown inhibited breast cancer cell tumorigenicity and metastasis. Importantly, YAP knockdown was able to attenuate ITCH pro-tumorigenic functions. Lastly, we found that ITCH expression is significantly upregulated in invasive and metastatic breast cancer cases and is associated with worse survival. Together, our results reveal that ITCH pro-tumorigenic functions in breast cancer are mediated, at least in part, through inactivation of the Hippo tumor suppressor pathway.

  10. The ubiquitin E3 ligase ITCH enhances breast tumor progression by inhibiting the Hippo tumor suppressor pathway

    PubMed Central

    Salah, Zaidoun; Itzhaki, Ella; Aqeilan, Rami I

    2014-01-01

    The Hippo kinase pathway is emerging as a conserved signaling pathway that is essential for organ growth and tumorigenesis. Recently, we reported that the ubiquitin E3 ligase ITCH negatively regulates LATS1, thereby increasing YAP activity, which leads to increased cell proliferation and decreased apoptosis. Here, we investigated the role of ITCH in breast tumorigenesis. In particular, we show that ITCH enhances epithelial-to-mesenchymal transition (EMT) through boosting YAP oncogenic function. By contrast, a point mutation in the catalytic domain or WW1 domain of ITCH abolished its EMT-mediated effects. Furthermore, while overexpression of ITCH expression in breast cells is associated with increased incidence of mammary tumor formation and progression, its knockdown inhibited breast cancer cell tumorigenicity and metastasis. Importantly, YAP knockdown was able to attenuate ITCH pro-tumorigenic functions. Lastly, we found that ITCH expression is significantly upregulated in invasive and metastatic breast cancer cases and is associated with worse survival. Together, our results reveal that ITCH pro-tumorigenic functions in breast cancer are mediated, at least in part, through inactivation of the Hippo tumor suppressor pathway. PMID:25350971

  11. Refined deletion mapping of the chromosome 19q glioma tumor suppressor gene to the D19S412-STD interval.

    PubMed

    Rosenberg, J E; Lisle, D K; Burwick, J A; Ueki, K; von Deimling, A; Mohrenweiser, H W; Louis, D N

    1996-12-05

    Allelic loss of chromsome 19q occurs frequently in malignant gliomas, suggesting the presence of a chromosome 19q glioma tumor suppressor gene. Deletion mapping studies have delineated a 3.5 Mb candidate region between D19S219 and HRC. Cloned sequences from the proximal 425 kb of this interval, however, have not shown tumor-specific alterations. To refine the location of the tumor suppressor gene further, we conducted loss of heterozygosity studies on 191 malignant gliomas using nine PCR-based polymorphisms. These included the previously identified and physically mapped markers D19S219, DM, D19S112, HRC and the recently physically mapped polymorphisms at D19S412, STD, D19S596 and GYS. In addition, we isolated a novel microsatellite polymorphism that maps 400 kb telomeric to D19S112. Oligodendroglial tumors showed frequent loss of heterozygosity in all grades, and typically displayed allelic loss at all studied markers. Astrocytomas, however, showed frequent loss primarily in anaplastic astrocytomas and displayed deletion breakpoints within the candidate region. Deletion mapping revealed a minimal region of overlap between D19S412 and STD, a distance of 900 kb. These data suggest that the D19S412-STD interval represents the most likely location for a chromsome 19q glioma tumor suppressor gene involved in astrocytoma, and perhaps oligodendroglioma, tumorigenesis.

  12. Targeting A Tumor Suppressor To Suppress Tumor Growth: News and Views on Protein Phosphatase 2A (PP2A) as a Target for Anti-cancer Therapy

    PubMed Central

    Perrotti, Danilo; Neviani, Paolo

    2013-01-01

    Protein phosphatase 2A (PP2A), one of the major serine-threonine phosphatases in mammalian cells, maintains cell homeostasis by counteracting most of the kinase-driven intracellular signaling pathways. Unrestrained activation of oncogenic kinases together with inhibition of tumor suppressors is frequently required for the development of cancer. Because it has been found genetically altered or functionally inactivated in many solid cancers and leukemias, PP2A is indeed a bona fide tumor suppressor. For example, the phosphatase activity of PP2A is suppressed in chronic myelogenous leukemia and other malignancies characterized by the aberrant activity of oncogenic kinases. Notably, preclinical studies indicate that pharmacologic restoration of PP2A tumor suppressor activity by PP2A activating drugs (PADs, e.g. FTY720) effectively antagonizes cancer development and progression. Herein, we systematically discuss the importance of PP2A as a druggable tumor suppressor in light of the possible introduction of PADs into anti-cancer therapeutic protocols. PMID:23639323

  13. Identification of Two Candidate Tumor Suppressor Genes on Chromosome l7p13.3: Assessment of their Roles in Breast and Ovarian Carcinogenesis

    DTIC Science & Technology

    2000-07-01

    also been reported in primitive neuroectodermal tumors , carcinoma of the cervix uteri, medulloblastoma, osteosarcoma, astrocytoma (22), and acute...AD______ GRANT NUMBER: DAMD17-96-1-6088 TITLE: Identification of Two Candidate Tumor Suppressor Genes on Chromosome 17p13.3: Assessment of their...Identification of Two Candidate Tumor Suppressor Genes on Chromosome 17 p13 .3 : Assessment of their Roles in Breast... DAMD17-96-1-6088 6. AUTHOR(S

  14. Epigenetic identification of ZNF545 as a functional tumor suppressor in multiple myeloma via activation of p53 signaling pathway

    SciTech Connect

    Fan, Yu; Zhan, Qian; Xu, Hongying; Li, Lili; Li, Chen; Xiao, Qian; Xiang, Shili; Hui, Tianli; Xiang, Tingxiu; Ren, Guosheng

    2016-06-10

    The KRAB–zinc-finger protein ZNF545 was recently identified as a potential suppressor gene in several tumors. However, the regulatory mechanisms of ZNF545 in tumorigenesis remain unclear. In this study, we investigated the expression and roles of ZNF545 in multiple myeloma (MM). ZNF545 was frequently downregulated in MM tissues compared with non-tumor bone marrow tissues. ZNF545 expression was silenced by promoter methylation in MM cell lines, and could be restored by demethylation treatment. ZNF545 methylation was detected in 28.3% of MM tissues, compared with 4.3% of normal bone marrow tissues. ZNF545 transcriptionally activated the p53 signaling pathway but had no effect on Akt in MM, whereas ectopic expression of ZNF545 in silenced cells suppressed their proliferation and induced apoptosis. We therefore identified ZNF545 as a novel tumor suppressor inhibiting tumor growth through activation of the p53 pathway in MM. Moreover, tumor-specific methylation of ZNF545 may represent an epigenetic biomarker for MM diagnosis, and a potential target for specific therapy. -- Highlights: •Downregulated ZNF545 in MM tissues and cell lines and ectopic expression of ZNF545 suppresses tumor growth. •Tumor-specific methylation of ZNF545 represents an epigenetic biomarker for MM diagnosis, and a potential target for specific therapy. •ZNF545 exerts its tumor suppressive effects via transcriptional activating p53 pathway.

  15. Patterns of somatic uniparental disomy identify novel tumor suppressor genes in colorectal cancer.

    PubMed

    Torabi, Keyvan; Miró, Rosa; Fernández-Jiménez, Nora; Quintanilla, Isabel; Ramos, Laia; Prat, Esther; del Rey, Javier; Pujol, Núria; Killian, J Keith; Meltzer, Paul S; Fernández, Pedro Luis; Ried, Thomas; Lozano, Juan José; Camps, Jordi; Ponsa, Immaculada

    2015-10-01

    Colorectal cancer (CRC) is characterized by specific patterns of copy number alterations (CNAs), which helped with the identification of driver oncogenes and tumor suppressor genes (TSGs). More recently, the usage of single nucleotide polymorphism arrays provided information of copy number neutral loss of heterozygosity, thus suggesting the occurrence of somatic uniparental disomy (UPD) and uniparental polysomy (UPP) events. The aim of this study is to establish an integrative profiling of recurrent UPDs/UPPs and CNAs in sporadic CRC. Our results indicate that regions showing high frequencies of UPD/UPP mostly coincide with regions typically involved in genomic losses. Among them, chromosome arms 3p, 5q, 9q, 10q, 14q, 17p, 17q, 20p, 21q and 22q preferentially showed UPDs/UPPs over genomic losses suggesting that tumor cells must maintain the disomic state of certain genes to favor cellular fitness. A meta-analysis using over 300 samples from The Cancer Genome Atlas confirmed our findings. Several regions affected by recurrent UPDs/UPPs contain well-known TSGs, as well as novel candidates such as ARID1A, DLC1, TCF7L2 and DMBT1. In addition, VCAN, FLT4, SFRP1 and GAS7 were also frequently involved in regions of UPD/UPP and displayed high levels of methylation. Finally, sequencing and fluorescence in situ hybridization analysis of the gene APC underlined that a somatic UPD event might represent the second hit to achieve biallelic inactivation of this TSG in colorectal tumors. In summary, our data define a profile of somatic UPDs/UPPs in sporadic CRC and highlights the importance of these events as a mechanism to achieve the inactivation of TSGs.

  16. The Opportunity of Precision Medicine for Breast Cancer with Context-Sensitive Tumor Suppressor Maspin.

    PubMed

    Bernardo, Margarida M; Dzinic, Sijana H; Matta, Maria J; Dean, Ivory; Saker, Lina; Sheng, Shijie

    2017-03-06

    To improve the precision of molecular diagnosis and to develop and guide targeted therapies of breast cancer, it is essential to determine mechanisms that underlie the specific tumor phenotypes. To this end, the application of a snapshot of gene expression profile for breast cancer diagnosis and prognosis is fundamentally challenged since the tissue-based data are derived from heterogonous cell types and are not likely to reflect the dynamics of context-dependent tumor progression and drug sensitivity. The intricate network of epithelial differentiation program can be concertedly controlled by tumor suppressor maspin, a homologue of clade B serine protease inhibitors (serpin), through its multifaceted molecular interactions in multiple subcellular localizations. Unlike most other serpins that are expressed in multiple and cell types, maspin is epithelial specific and has distinct roles in luminal and myoepithelial cells. Endogenously expressed maspin has been found in the nucleus and cytoplasm, and detected on the surface of cell membrane. It is also secreted free and as an exosomal cargo protein. Research in the field has led to the identification of the maspin targets and maspin-associated molecules, as well as the structural determinants of its suppressive functions. The current review discusses the possibility for maspin to serve as a cell type-specific and context-sensitive marker to improve the precision of breast cancer diagnosis and prognosis. These advancements further suggest a new window of opportunity for designing novel maspin-based chemotherapeutic agents with improved anti-cancer potency. This article is protected by copyright. All rights reserved.

  17. MicroRNA-23b* targets proline oxidase, a mitochondrial tumor suppressor protein in renal cancer

    PubMed Central

    Liu, W; Zabirnyk, O; Wang, H; Shiao, Y-H; Nickerson, M L; Khalil, S; Anderson, L M; Perantoni, A O; Phang, J M

    2010-01-01

    Proline oxidase (POX) is a novel mitochondrial tumor suppressor, which can suppress proliferation and induce apoptosis through the generation of reactive oxygen species (ROS) and decreasing hypoxia inducible factor (HIF) signaling. Recent studies have demonstrated the absent expression of POX in human cancer tissues, including renal cancer. However, the mechanism for the loss of POX remains obscure. No genetic or epigenetic variation of POX gene was found. Here, we identified the up-regulated miR-23b* in renal cancer as an important regulator of POX. Ectopic overexpression of miR-23b* in normal renal cells resulted in striking down-regulation of POX, while POX expression increased markedly when endogenous miR-23b* was knocked down by its antagomirs in renal cancer cells. Consistent with POX-mediated tumor suppression pathway, these antagomirs induced ROS, inhibited HIF signaling and increased apoptosis. Furthermore, we confirmed the regulation of miR-23b* on POX and its function in the DLD1 Tet-off POX cell system. Using a luciferase reporter system, we verified the direct binding of miR-23b* to POX mRNA 3′UTR. In addition, pairs of human renal carcinoma and normal tissues showed the negative correlation between miR-23b* and POX protein expression, providing its clinical corroboration. Taken together, our results suggested miR-23b*, by targeting POX, could function as an oncogene; decreasing miR-23b* expression may prove to be an effective way of inhibiting kidney tumor growth. PMID:20562915

  18. A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas

    PubMed Central

    Agnihotri, Sameer; Wolf, Amparo; Munoz, Diana M.; Smith, Christopher J.; Gajadhar, Aaron; Restrepo, Andres; Clarke, Ian D.; Fuller, Gregory N.; Kesari, Santosh; Dirks, Peter B.; McGlade, C. Jane; Stanford, William L.; Aldape, Kenneth; Mischel, Paul S.; Hawkins, Cynthia

    2011-01-01

    Glioblastoma Multiforme (GBM), the most common and lethal primary human brain tumor, exhibits multiple molecular aberrations. We report that loss of the transcription factor GATA4, a negative regulator of normal astrocyte proliferation, is a driver in glioma formation and fulfills the hallmarks of a tumor suppressor gene (TSG). Although GATA4 was expressed in normal brain, loss of GATA4 was observed in 94/163 GBM operative samples and was a negative survival prognostic marker. GATA4 loss occurred through promoter hypermethylation or novel somatic mutations. Loss of GATA4 in normal human astrocytes promoted high-grade astrocytoma formation, in cooperation with other relevant genetic alterations such as activated Ras or loss of TP53. Loss of GATA4 with activated Ras in normal astrocytes promoted a progenitor-like phenotype, formation of neurospheres, and the ability to differentiate into astrocytes, neurons, and oligodendrocytes. Re-expression of GATA4 in human GBM cell lines, primary cultures, and brain tumor–initiating cells suppressed tumor growth in vitro and in vivo through direct activation of the cell cycle inhibitor P21CIP1, independent of TP53. Re-expression of GATA4 also conferred sensitivity of GBM cells to temozolomide, a DNA alkylating agent currently used in GBM therapy. This sensitivity was independent of MGMT (O-6-methylguanine-DNA-methyltransferase), the DNA repair enzyme which is often implicated in temozolomide resistance. Instead, GATA4 reduced expression of APNG (alkylpurine-DNA-N-glycosylase), a DNA repair enzyme which is poorly characterized in GBM-mediated temozolomide resistance. Identification and validation of GATA4 as a TSG and its downstream targets in GBM may yield promising novel therapeutic strategies. PMID:21464220

  19. A phase I study of hydralazine to demethylate and reactivate the expression of tumor suppressor genes

    PubMed Central

    Zambrano, Pilar; Segura-Pacheco, Blanca; Perez-Cardenas, Enrique; Cetina, Lucely; Revilla-Vazquez, Alma; Taja-Chayeb, Lucía; Chavez-Blanco, Alma; Angeles, Enrique; Cabrera, Gustavo; Sandoval, Karina; Trejo-Becerril, Catalina; Chanona-Vilchis, Jose; Duenas-González, Alfonso

    2005-01-01

    Background The antihypertensive compound hydralazine is a known demethylating agent. This phase I study evaluated the tolerability and its effects upon DNA methylation and gene reactivation in patients with untreated cervical cancer. Methods Hydralazine was administered to cohorts of 4 patients at the following dose levels: I) 50 mg/day, II) 75 mg/day, III) 100 mg/day and IV) 150 mg/day. Tumor biopsies and peripheral blood samples were taken the day before and after treatment. The genes APC, MGMT; ER, GSTP1, DAPK, RARβ, FHIT and p16 were evaluated pre and post-treatment for DNA promoter methylation and gene expression by MSP (Methylation-Specific PCR) and RT-PCR respectively in each of the tumor samples. Methylation of the imprinted H19 gene and the "normally methylated" sequence clone 1.2 was also analyzed. Global DNA methylation was analyzed by capillary electrophoresis and cytosine extension assay. Toxicity was evaluated using the NCI Common Toxicity Criteria. Results Hydralazine was well tolerated. Toxicities were mild being the most common nausea, dizziness, fatigue, headache and palpitations. Overall, 70% of the pretreatment samples and all the patients had at least one methylated gene. Rates of demethylation at the different dose levels were as follows: 50 mg/day, 40%; 75 mg/day, 52%, 100 mg/day, 43%, and 150 mg/day, 32%. Gene expression analysis showed only 12 informative cases, of these 9 (75%) re-expressed the gene. There was neither change in the methylation status of H19 and clone 1.2 nor changes in global DNA methylation. Conclusion Hydralazine at doses between 50 and 150 mg/day is well tolerated and effective to demethylate and reactivate the expression of tumor suppressor genes without affecting global DNA methylation PMID:15862127

  20. Tumor suppressor roles of CENP-E and Nsl1 in Drosophila epithelial tissues.

    PubMed

    Clemente-Ruiz, Marta; Muzzopappa, Mariana; Milán, Marco

    2014-01-01

    Depletion of spindle assembly checkpoint (SAC) genes in Drosophila epithelial tissues leads to JNK-dependent programmed cell death and additional blockade of the apoptotic program drives tumorigenesis. A recent report proposes that chromosomal instability (CIN) is not the driving force in the tumorigenic response of the SAC-deficient tissue, and that checkpoint proteins exert a SAC-independent tumor suppressor role. This notion is based on observations that the depletion of CENP-E levels or prevention of Bub3 from binding to the kinetochore in Drosophila tissues unable to activate the apoptotic program induces CIN but does not cause hyperproliferation. Here we re-examined this proposal. In contrast to the previous report, we observed that depletion of CENP-E or Nsl1-the latter mediating kinetochore targeting of Bub3-in epithelial tissues unable to activate the apoptotic program induces significant levels of aneuploidy and drives tumor-like growth. The induction of the JNK transcriptional targets Wingless, a mitogenic molecule, and MMP1, a matrix metaloproteinase 1 involved in basement membrane degradation was also observed in these tumors. An identical response of the tissue was previously detected upon depletion of several SAC genes or genes involved in spindle assembly, chromatin condensation, and cytokinesis, all of which have been described to cause CIN. All together, these results reinforce the role of CIN in driving tumorigenesis in Drosophila epithelial tissues and question the proposed SAC-independent roles of checkpoint proteins in suppressing tumorigenesis. Differences in aneuploidy rates might explain the discrepancy between the previous report and our results.

  1. The von Hippel-Lindau tumor suppressor gene expression level has prognostic value in neuroblastoma.

    PubMed

    Hoebeeck, Jasmien; Vandesompele, Jo; Nilsson, Helén; De Preter, Katleen; Van Roy, Nadine; De Smet, Els; Yigit, Nurten; De Paepe, Anne; Laureys, Geneviève; Påhlman, Sven; Speleman, Frank

    2006-08-01

    Deletions of the short arm of chromosome 3 are often observed in a specific subset of aggressive neuroblastomas (NBs) with loss of distal 11q and without MYCN amplification. The critical deleted region encompasses the locus of the von Hippel-Lindau gene (VHL, 3p25). Constitutional loss of function mutations in the VHL gene are responsible for the VHL syndrome, a dominantly inherited familial cancer syndrome predisposing to a variety of neoplasms, including pheochromocytoma. Pheochromocytomas are, like NB, derived from neural crest cells, but, unlike NB, consist of more mature chromaffin cells instead of immature neuroblasts. Further arguments for a putative role of VHL in NB are its function as oxygen sensitizer and the reported relation between hypoxia and dedifferentiation of NB cells, leading to a more aggressive phenotype. To test the possible involvement of VHL in NB, we did mRNA expression analysis and sought evidence for VHL gene inactivation. Although no evidence for a classic tumor suppressor role for VHL in NB could be obtained, a strong correlation was observed between reduced levels of VHL mRNA and low patient survival probability (p=0.013). Furthermore, VHL appears to have predictive power in NTRK1 (TRKA) positive tumor samples with presumed favorable prognosis, which makes it a potentially valuable marker for more accurate risk assessment in this subgroup of patients. The significance of the reduced VHL expression levels in relation to NB tumor biology remains unexplained, as functional analysis demonstrated no clear effect of the reduction in VHL mRNA expression on protein stability of its downstream target hypoxia-inducible factor alpha.

  2. Identification of LZAP as a New Candidate Tumor Suppressor in Hepatocellular Carcinoma

    PubMed Central

    Zhao, Jing-jing; Pan, Ke; Li, Jian-jun; Chen, Yi-bing; Chen, Ju-gao; Lv, Lin; Wang, Dan-dan; Pan, Qiu-zhong; Chen, Min-shan; Xia, Jian-chuan

    2011-01-01

    Background LZAP was isolated as a binding protein of the Cdk5 activator p35. LZAP has been highly conserved during evolution and has been shown to function as a tumor suppressor in various cancers. This study aimed to investigate LZAP expression and its prognostic value in hepatocellular carcinoma (HCC). Meanwhile, the function of LZAP in hepatocarcinogenesis was further investigated in cell culture models and mouse models. Methods Real-time quantitative PCR, western blot and immunohistochemistry were used to explore LZAP expression in HCC cell lines and primary HCC clinical specimens. The functions of LZAP in the proliferation, colony formation, cell cycle, migration, invasion and apoptosis of HCC cell lines were also analyzed by infecting cells with an adenovirus containing full-length LZAP. The effect of LZAP on tumorigenicity in nude mice was also investigated. Results LZAP expression was significantly decreased in the tumor tissues and HCC cell lines. Clinicopathological analysis showed that LZAP expression was significantly correlated with tumor size, histopathological classification and serum α-fetoprotein (AFP). The Kaplan–Meier survival curves revealed that decreasing LZAP expression was associated with poor prognosis in HCC patients. LZAP expression was an independent prognostic marker of overall HCC patient survival in a multivariate analysis. The re-introduction of LZAP expression in the HepG2 and sk-Hep1 HCC cell lines significantly inhibited proliferation and colony formation in the HCC cells and induced G1 phase arrest and apoptosis of the HCC cells in vitro. Restoring LZAP expression in the HCC cell lines also inhibited migration and invasion. In addition, experiments with a mouse model revealed that LZAP overexpression could suppress HCC tumorigenicity in vivo. Conclusions Our data suggest that LZAP may play an important role in HCC progression and could be a potential molecular therapy target for HCC. PMID:22028922

  3. Identification of new mutations in the NF2 tumor suppressor gene in schwannomas

    SciTech Connect

    Guida, M.; Welling, B.; Prior, T.W.

    1994-09-01

    Neurofibromatosis type 2 (NF2) is a severe genetic disorder with an incidence of approximately 1 in 40,000 individuals and is characterized by the formation of multiple benign nervous system tumors. The clinical hallmark of NF2 is the bilateral occurrence of schwannomas on the eighth cranial nerve (vestibular schwannomas). Recently, it has been shown that loss or inactivation of a tumor suppressor gene located in chromosome band 22q12 is the molecular cause of NF2 tumorigenesis. Also, mutations in the NF2 gene have now been identified in patients with sporadic vestibular schwannomas (unilateral schwannomas). We have completed the screening of 80% of the NF2 coding sequence of DNA from 13 sporadic schwannomas and 2 schwannomas from NF2 patients. Using heteroduplex analysis and direct sequencing, we found 13 novel mutations located in 7 different exons with a small cluster (46% of the mutations) located in the central portion of the gene. All of the mutations were unique to single patients. In three tumors, both NF2 alleles were mutated. The types of mutations found include: small deletions ranging from 1 to 30 base pairs, nonsense mutations, a single missense mutation and a splice donor site alteration. It appears that small deletions are the most common type of NF2 gene mutation. We also have developed a dosage test based on quantitative PCR and hybridization with specific probes to detect the loss of heterozygosity. We found that 7 out of 15 schwannomas (47%) show loss of heterozygosity. We are currently extending the analysis to all of the NF2 exons and DNA from 60 additional schwannomas.

  4. Patterns of somatic uniparental disomy identify novel tumor suppressor genes in colorectal cancer

    PubMed Central

    Torabi, Keyvan; Miró, Rosa; Fernández-Jiménez, Nora; Quintanilla, Isabel; Ramos, Laia; Prat, Esther; del Rey, Javier; Pujol, Núria; Killian, J. Keith; Meltzer, Paul S.; Fernández, Pedro Luis; Ried, Thomas; Lozano, Juan José; Camps, Jordi; Ponsa, Immaculada

    2015-01-01

    Colorectal cancer (CRC) is characterized by specific patterns of copy number alterations (CNAs), which helped with the identification of driver oncogenes and tumor suppressor genes (TSGs). More recently, the usage of single nucleotide polymorphism arrays provided information of copy number neutral loss of heterozygosity, thus suggesting the occurrence of somatic uniparental disomy (UPD) and uniparental polysomy (UPP) events. The aim of this study is to establish an integrative profiling of recurrent UPDs/UPPs and CNAs in sporadic CRC. Our results indicate that regions showing high frequencies of UPD/UPP mostly coincide with regions typically involved in genomic losses. Among them, chromosome arms 3p, 5q, 9q, 10q, 14q, 17p, 17q, 20p, 21q and 22q preferentially showed UPDs/UPPs over genomic losses suggesting that tumor cells must maintain the disomic state of certain genes to favor cellular fitness. A meta-analysis using over 300 samples from The Cancer Genome Atlas confirmed our findings. Several regions affected by recurrent UPDs/UPPs contain well-known TSGs, as well as novel candidates such as ARID1A, DLC1, TCF7L2 and DMBT1. In addition, VCAN, FLT4, SFRP1 and GAS7 were also frequently involved in regions of UPD/UPP and displayed high levels of methylation. Finally, sequencing and fluorescence in situ hybridization analysis of the gene APC underlined that a somatic UPD event might represent the second hit to achieve biallelic inactivation of this TSG in colorectal tumors. In summary, our data define a profile of somatic UPDs/UPPs in sporadic CRC and highlights the importance of these events as a mechanism to achieve the inactivation of TSGs. PMID:26243311

  5. Effect of cytostatic proline rich polypeptide-1 on tumor suppressors of inflammation pathway signaling in chondrosarcoma

    PubMed Central

    Galoian, Karina; Luo, Shihua; Qureshi, Amir; Patel, Parthik; Price, Rachel; Morse, Ashlyn S.; Chailyan, Gor; Abrahamyan, Silva; Temple, H. T.

    2016-01-01

    Cytokines produced in the tumour microenvironment exert an important role in cancer pathogenesis and in the inhibition of disease progression. Cancer of the cartilage is termed metastatic chondrosarcoma; however, the signaling events resulting in mesenchymal cell transformation to sarcoma have yet to be fully elucidated. The present study aimed to characterize the cytokine expression profile in the human JJ012 chondrosarcoma cell line, as well as the effect of cytostatic proline-rich polypeptide-1 (PRP-1). Western blot experiments demonstrated that the levels of suppressor of cytokine signaling 3 (SOCS3) were upregulated in chondrocytes compared with chondrosarcoma cells. Addition of PRP-1 restored the expression of the tumor suppressors, SOCS3 and ten-eleven-translocation methylcytosine dioxygenase 1 and 2 (TET1/2), in a dose-responsive manner. It is known that methylation of histone H3K9 was eliminated from the promoters of the inflammation-associated genes. PRP-1 inhibited H3K9 demethylase activity with an IC50 (concentration required to give half-maximal inhibition) value of 3.72 µg/ml in the chondrosarcoma cell line. Data obtained from ELISA experiments indicated that the expression of interleukin-6 (IL-6) in chondrosarcoma cells was 86-fold lower compared with that in C28 chondrocytes. In the present study, a 53-fold downregulation of IL-6 expression in co-culture of chondrosarcoma cells and C28 chondrocytes was identified as well. Downregulation of IL-6 expression has been documented in numerous other tumor types, although the reasons for this have not been fully established. In chondrosarcoma, IL-6 manifests itself as an anti-inflammatory agent and, possibly, as an anti-tumorigenic factor. To explore protein-DNA interactions leading to such differences, a gel-shift chemiluminescent assay was performed. Gel shifts were observed for chondrosarcoma and chondrocytes in the lanes that contained nuclear cell extract and oligo-IL-6 DNA. Notably, the DNA

  6. A single-copy Sleeping Beauty transposon mutagenesis screen identifies new PTEN-cooperating tumor suppressor genes

    PubMed Central

    de la Rosa, Jorge; Weber, Julia; Friedrich, Mathias Josef; Li, Yilong; Rad, Lena; Ponstingl, Hannes; Liang, Qi; de Quirós, Sandra Bernaldo; Noorani, Imran; Metzakopian, Emmanouil; Strong, Alexander; Li, Meng Amy; Astudillo, Aurora; Fernández-García, María Teresa; Fernández-García, María Soledad; Hoffman, Gary J.; Fuente, Rocío; Vassiliou, George S.; Rad, Roland; López-Otín, Carlos; Bradley, Allan; Cadiñanos, Juan

    2017-01-01

    The overwhelming amount of genetic alterations identified through cancer genome sequencing requires complementary approaches to interpret their significance and interactions. We developed a novel whole-body insertional mutagenesis screen in mice, designed for the discovery of Pten-cooperating tumor suppressors, in which mobilization of a single-copy inactivating Sleeping Beauty transposon is coupled to Pten disruption within the same genome. The analysis of 278 transposition-induced prostate, breast and skin tumors detected tissue-specific and shared datasets of known and candidate cancer genes. We validated ZBTB20, CELF2, PARD3, AKAP13 and WAC, identified by our screens in multiple cancer types, as new tumor suppressors in prostate cancer: we demonstrated their synergy with PTEN for preventing invasion in vitro and confirmed their clinical relevance. Further characterization of Wac in vivo revealed obligate haploinsufficiency for this autophagy-regulating gene in a Pten-deficient context. Our study identifies complex PTEN-cooperating tumor suppressor networks in different cancer types with potential clinical implications. PMID:28319090

  7. A single-copy Sleeping Beauty transposon mutagenesis screen identifies new PTEN-cooperating tumor suppressor genes.

    PubMed

    de la Rosa, Jorge; Weber, Julia; Friedrich, Mathias Josef; Li, Yilong; Rad, Lena; Ponstingl, Hannes; Liang, Qi; de Quirós, Sandra Bernaldo; Noorani, Imran; Metzakopian, Emmanouil; Strong, Alexander; Li, Meng Amy; Astudillo, Aurora; Fernández-García, María Teresa; Fernández-García, María Soledad; Hoffman, Gary J; Fuente, Rocío; Vassiliou, George S; Rad, Roland; López-Otín, Carlos; Bradley, Allan; Cadiñanos, Juan

    2017-03-20

    The overwhelming number of genetic alterations identified through cancer genome sequencing requires complementary approaches to interpret their significance and interactions. Here we developed a novel whole-body insertional mutagenesis screen in mice, which was designed for the discovery of Pten-cooperating tumor suppressors. Toward this aim, we coupled mobilization of a single-copy inactivating Sleeping Beauty transposon to Pten disruption within the same genome. The analysis of 278 transposition-induced prostate, breast and skin tumors detected tissue-specific and shared data sets of known and candidate genes involved in cancer. We validated ZBTB20, CELF2, PARD3, AKAP13 and WAC, which were identified by our screens in multiple cancer types, as new tumor suppressor genes in prostate cancer. We demonstrated their synergy with PTEN in preventing invasion in vitro and confirmed their clinical relevance. Further characterization of Wac in vivo showed obligate haploinsufficiency for this gene (which encodes an autophagy-regulating factor) in a Pten-deficient context. Our study identified complex PTEN-cooperating tumor suppressor networks in different cancer types, with potential clinical implications.

  8. Hypermethylation of the tumor suppressor gene PRDM1/Blimp-1 supports a pathogenetic role in EBV-positive Burkitt lymphoma.

    PubMed

    Zhang, T; Ma, J; Nie, K; Yan, J; Liu, Y; Bacchi, C E; Queiroga, E M; Gualco, G; Sample, J T; Orazi, A; Knowles, D M; Tam, W

    2014-11-07

    PRDM1/Blimp-1 is a tumor suppressor gene in the activated B-cell subtype of diffuse large B-cell lymphomas. Its inactivation contributes to pathogenesis in this setting by impairing terminal B-cell differentiation induced by constitutive nuclear factor-κB activation. The role of PRDM1 in Burkitt lymphoma (BL) lymphomagenesis is not known. Here we identified hypermethylation of the promoter region and exon 1 of PRDM1 in all six Epstein-Barr virus (EBV)-positive BL cell lines and 12 of 23 (52%) primary EBV-positive BL or BL-related cases examined, but in none of the EBV-negative BL cell lines or primary tumors that we assessed, implying a tumor suppressor role for PRDM1 specifically in EBV-associated BL. A direct induction of PRDM1 hypermethylation by EBV is unlikely, as PRDM1 hypermethylation was not observed in EBV-immortalized B lymphoblastoid cell lines. Treatment of EBV-positive BL cells with 5' azacytidine resulted in PRDM1 induction associated with PRDM1 demethylation, consistent with transcriptional silencing of PRDM1 as a result of DNA methylation. Overexpression of PRDM1 in EBV-positive BL cell lines resulted in cell cycle arrest. Our results expand the spectrum of lymphoid malignancies in which PRDM1 may have a tumor suppressor role and identify an epigenetic event that likely contributes to the pathogenesis of BL.

  9. Hypermethylation of the tumor suppressor gene PRDM1/Blimp-1 supports a pathogenetic role in EBV-positive Burkitt lymphoma

    PubMed Central

    Zhang, T; Ma, J; Nie, K; Yan, J; Liu, Y; Bacchi, C E; Queiroga, E M; Gualco, G; Sample, J T; Orazi, A; Knowles, D M; Tam, W

    2014-01-01

    PRDM1/Blimp-1 is a tumor suppressor gene in the activated B-cell subtype of diffuse large B-cell lymphomas. Its inactivation contributes to pathogenesis in this setting by impairing terminal B-cell differentiation induced by constitutive nuclear factor-κB activation. The role of PRDM1 in Burkitt lymphoma (BL) lymphomagenesis is not known. Here we identified hypermethylation of the promoter region and exon 1 of PRDM1 in all six Epstein–Barr virus (EBV)-positive BL cell lines and 12 of 23 (52%) primary EBV-positive BL or BL-related cases examined, but in none of the EBV-negative BL cell lines or primary tumors that we assessed, implying a tumor suppressor role for PRDM1 specifically in EBV-associated BL. A direct induction of PRDM1 hypermethylation by EBV is unlikely, as PRDM1 hypermethylation was not observed in EBV-immortalized B lymphoblastoid cell lines. Treatment of EBV-positive BL cells with 5′ azacytidine resulted in PRDM1 induction associated with PRDM1 demethylation, consistent with transcriptional silencing of PRDM1 as a result of DNA methylation. Overexpression of PRDM1 in EBV-positive BL cell lines resulted in cell cycle arrest. Our results expand the spectrum of lymphoid malignancies in which PRDM1 may have a tumor suppressor role and identify an epigenetic event that likely contributes to the pathogenesis of BL. PMID:25382611

  10. PERK Is a Haploinsufficient Tumor Suppressor: Gene Dose Determines Tumor-Suppressive Versus Tumor Promoting Properties of PERK in Melanoma

    PubMed Central

    Mackiewicz, Katarzyna; Katlinskaya, Yuliya V.; Staschke, Kirk A.; Paredes, Maria C. G.; Yoshida, Akihiro; Qie, Shuo; Zhang, Gao; Chajewski, Olga S.; Majsterek, Ireneusz; Herlyn, Meenhard; Fuchs, Serge Y.; Diehl, J. Alan

    2016-01-01

    The unfolded protein response (UPR) regulates cell fate following exposure of cells to endoplasmic reticulum stresses. PERK, a UPR protein kinase, regulates protein synthesis and while linked with cell survival, exhibits activities associated with both tumor progression and tumor suppression. For example, while cells lacking PERK are sensitive to UPR-dependent cell death, acute activation of PERK triggers both apoptosis and cell cycle arrest, which would be expected to contribute tumor suppressive activity. We have evaluated these activities in the BRAF-dependent melanoma and provide evidence revealing a complex role for PERK in melanoma where a 50% reduction is permissive for BrafV600E-dependent transformation, while complete inhibition is tumor suppressive. Consistently, PERK mutants identified in human melanoma are hypomorphic with dominant inhibitory function. Strikingly, we demonstrate that small molecule PERK inhibitors exhibit single agent efficacy against BrafV600E-dependent tumors highlighting the clinical value of targeting PERK. PMID:27977682

  11. PERK Is a Haploinsufficient Tumor Suppressor: Gene Dose Determines Tumor-Suppressive Versus Tumor Promoting Properties of PERK in Melanoma.

    PubMed

    Pytel, Dariusz; Gao, Yan; Mackiewicz, Katarzyna; Katlinskaya, Yuliya V; Staschke, Kirk A; Paredes, Maria C G; Yoshida, Akihiro; Qie, Shuo; Zhang, Gao; Chajewski, Olga S; Wu, Lawrence; Majsterek, Ireneusz; Herlyn, Meenhard; Fuchs, Serge Y; Diehl, J Alan

    2016-12-01

    The unfolded protein response (UPR) regulates cell fate following exposure of cells to endoplasmic reticulum stresses. PERK, a UPR protein kinase, regulates protein synthesis and while linked with cell survival, exhibits activities associated with both tumor progression and tumor suppression. For example, while cells lacking PERK are sensitive to UPR-dependent cell death, acute activation of PERK triggers both apoptosis and cell cycle arrest, which would be expected to contribute tumor suppressive activity. We have evaluated these activities in the BRAF-dependent melanoma and provide evidence revealing a complex role for PERK in melanoma where a 50% reduction is permissive for BrafV600E-dependent transformation, while complete inhibition is tumor suppressive. Consistently, PERK mutants identified in human melanoma are hypomorphic with dominant inhibitory function. Strikingly, we demonstrate that small molecule PERK inhibitors exhibit single agent efficacy against BrafV600E-dependent tumors highlighting the clinical value of targeting PERK.

  12. Modulation of Cell Migration and Invasiveness by Tumor Suppressor TSC2 in Lymphangioleiomyomatosis

    PubMed Central

    Goncharova, Elena A.; Goncharov, Dmitriy A.; Lim, Poay N.; Noonan, Daniel; Krymskaya, Vera P.

    2006-01-01

    The loss of TSC2 function is associated with the pathobiology of lymphangioleiomyomatosis (LAM), which is characterized by the abnormal proliferation, migration, and differentiation of smooth muscle–like cells within the lungs. Although the etiology of LAM remains unknown, clinical and genetic evidence provides support for the neoplastic nature of LAM. The goal of this study was to determine the role of tumor suppressor TSC2 in the neoplastic potential of LAM cells. We show that primary cultures of human LAM cells exhibit increased migratory activity and invasiveness, which is abolished by TSC2 re-expression. We found that TSC2 also inhibits cell migration through its N-terminus, independent of its GTPase-activating protein activity. LAM cells show increased stress fiber and focal adhesion formation, which is attenuated by TSC2 re-expression. The small GTPase RhoA is activated in LAM cells compared with normal human mesenchymal cells. Pharmacologic inhibition of Rho activity abrogates LAM cell migration; RhoA activity was also abolished by TSC2 re-expression or TSC1 knockdown with specific siRNA. These data demonstrate that TSC2 controls cell migration through its N-terminus by associating with TSC1 and regulating RhoA activity, suggesting that TSC2 may play a critical role in modulating cell migration and invasiveness, which contributes to the pathobiology of LAM. PMID:16388022

  13. Frequent Down Regulation of the Tumor Suppressor Gene A20 in Multiple Myeloma

    PubMed Central

    Lassnig, Markus; Pursche, Beata; Steinbauer, Elisabeth; Wiltgen, Marco; Zulus, Barbara; Renner, Wilfried; Beham-Schmid, Christine

    2015-01-01

    Multiple myeloma (MM) is a malignant clonal expansion of plasma cells in the bone marrow and belongs to the mature B-cell neoplams. The pathogenesis of MM is associated with constitutive NF-κB activation. However, genetic alterations causing constitutive NF-κB activation are still incompletely understood. Since A20 (TNFAIP3) is a suppressor of the NF-κB pathway and is frequently inactivated in various lymphoid malignancies, we investigated the genetic and epigenetic properties of A20 in MM. In total, of 46 patient specimens analyzed, 3 single base pair exchanges, 2 synonymous mutations and one missense mutation were detected by direct sequencing. Gene copy number analysis revealed a reduced A20 gene copy number in 8 of 45 (17.7%) patients. Furthermore, immunohistochemical staining confirmed that A20 expression correlates with the reduction of A20 gene copy number. These data suggest that A20 contributes to tumor formation in a significant fraction of myeloma patients. PMID:25856582

  14. Characterizing WW Domain Interactions of Tumor Suppressor WWOX Reveals Its Association with Multiprotein Networks*

    PubMed Central

    Abu-Odeh, Mohammad; Bar-Mag, Tomer; Huang, Haiming; Kim, TaeHyung; Salah, Zaidoun; Abdeen, Suhaib K.; Sudol, Marius; Reichmann, Dana; Sidhu, Sachdev; Kim, Philip M.; Aqeilan, Rami I.

    2014-01-01

    WW domains are small modules present in regulatory and signaling proteins that mediate specific protein-protein interactions. The WW domain-containing oxidoreductase (WWOX) encodes a 46-kDa tumor suppressor that contains two N-terminal WW domains and a central short-chain dehydrogenase/reductase domain. Based on its ligand recognition motifs, the WW domain family is classified into four groups. The largest one, to which WWOX belongs, recognizes ligands with a PPXY motif. To pursue the functional properties of the WW domains of WWOX, we employed mass spectrometry and phage display experiments to identify putative WWOX-interacting partners. Our analysis revealed that the first WW (WW1) domain of WWOX is the main functional interacting domain. Furthermore, our study uncovered well known and new PPXY-WW1-interacting partners and shed light on novel LPXY-WW1-interacting partners of WWOX. Many of these proteins are components of multiprotein complexes involved in molecular processes, including transcription, RNA processing, tight junction, and metabolism. By utilizing GST pull-down and immunoprecipitation assays, we validated that WWOX is a substrate of the E3 ubiquitin ligase ITCH, which contains two LPXY motifs. We found that ITCH mediates Lys-63-linked polyubiquitination of WWOX, leading to its nuclear localization and increased cell death. Our data suggest that the WW1 domain of WWOX provides a versatile platform that links WWOX with individual proteins associated with physiologically important networks. PMID:24550385

  15. Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair

    PubMed Central

    Yu, Helen; Pak, Helen; Hammond-Martel, Ian; Ghram, Mehdi; Rodrigue, Amélie; Daou, Salima; Barbour, Haithem; Corbeil, Luc; Hébert, Josée; Drobetsky, Elliot; Masson, Jean Yves; Di Noia, Javier M.; Affar, El Bachir

    2014-01-01

    The cellular response to highly genotoxic DNA double-strand breaks (DSBs) involves the exquisite coordination of multiple signaling and repair factors. Here, we conducted a functional RNAi screen and identified BAP1 as a deubiquitinase required for efficient assembly of the homologous recombination (HR) factors BRCA1 and RAD51 at ionizing radiation (IR) -induced foci. BAP1 is a chromatin-associated protein frequently inactivated in cancers of various tissues. To further investigate the role of BAP1 in DSB repair, we used a gene targeting approach to knockout (KO) this deubiquitinase in chicken DT40 cells. We show that BAP1-deficient cells are (i) sensitive to IR and other agents that induce DSBs, (ii) defective in HR-mediated immunoglobulin gene conversion, and (iii) exhibit an increased frequency of chromosomal breaks after IR treatment. We also show that BAP1 is recruited to chromatin in the proximity of a single site-specific I-SceI–induced DSB. Finally, we identified six IR-induced phosphorylation sites in BAP1 and showed that mutation of these residues inhibits BAP1 recruitment to DSB sites. We also found that both BAP1 catalytic activity and its phosphorylation are critical for promoting DNA repair and cellular recovery from DNA damage. Our data reveal an important role for BAP1 in DSB repair by HR, thereby providing a possible molecular basis for its tumor suppressor function. PMID:24347639

  16. The ARF tumor suppressor controls Drosha translation to prevent Ras-driven transformation

    PubMed Central

    Kuchenreuther, Michael J.; Weber, Jason D.

    2014-01-01

    ARF is a multifunctional tumor suppressor that acts as both a sensor of oncogenic stimuli and as a key regulator of ribosome biogenesis. Recently, our group established the DEAD-box RNA helicase and microRNA (miRNA) microprocessor accessory subunit, DDX5, as a critical target of basal ARF function. To identify other molecular targets of ARF, we focused on known interacting proteins of DDX5 in the microprocessor complex. Drosha, the catalytic core of the microprocessor complex, plays a critical role in the maturation of specific non-coding RNAs, including miRNAs and rRNAs. Here, we report that chronic or acute loss of Arf enhanced Drosha protein expression. This induction did not involve Drosha mRNA transcription or protein stability but rather relied on the increased translation of existing Drosha mRNAs. Enhanced Drosha expression did not alter global miRNA production, but rather modified expression of a subset of miRNAs in the absence of Arf. Elevated Drosha protein levels were required to maintain the increased rRNA synthesis and cellular proliferation observed in the absence of Arf. Arf-deficient cells transformed by oncogenic RasV12 were dependent on increased Drosha expression as Drosha knockdown was sufficient to inhibit Ras-dependent cellular transformation. Thus, we propose that ARF regulates Drosha mRNA translation to prevent aberrant cell proliferation and Ras-dependent transformation. PMID:23318441

  17. Control of apoptosis in hematopoiesis and leukemia by cytokines, tumor suppressor and oncogenes.

    PubMed

    Lotem, J; Sachs, L

    1996-06-01

    Hematopoietic cells require certain cytokines including colony-stimulating factors and interleukins to maintain viability. Without these cytokines the program of apoptotic cell death is activated. Cells from many myeloid leukemias require cytokines for viability, and apoptosis is also activated in these leukemic cells after cytokine withdrawal resulting in reduced leukemogenicity. The same cytokines protect normal and leukemic cells from induction of apoptosis by irradiation and cytotoxic chemotherapeutic compounds. This suggests that decreasing the levels of viability inducing cytokines may increase the effectiveness of cytotoxic anti-cancer therapy. The susceptibility of normal and cancer cells to induction of apoptosis is also regulated by the balance between apoptosis-inducing genes such as the tumor suppressor wild-type p53, and c-myc and bax, and apoptosis-suppressing genes such as the oncogene mutant p53, and bcl-2 and bcl-XL. Cell susceptibility to induction of apoptosis in leukemic cells could be enhanced by increased expression of apoptosis-inducing genes and/or decreased expression of apoptosis-suppressing genes. Modulation of expression of apoptosis-regulating genes should thus also be useful for improvement of anti-cancer therapy.

  18. Familial melanoma-associated mutations in p16 uncouple its tumor suppressor functions

    PubMed Central

    Jenkins, Noah C.; Jung, Jae; Liu, Tong; Wilde, Megan; Holmen, Sheri L.; Grossman, Douglas

    2012-01-01

    Familial melanoma is associated with point mutations in the cyclin-dependent kinase (CDK) inhibitor p16INK4A (p16). We recently reported that p16 regulates intracellular oxidative stress in a cell cycle-independent manner. Here, we constructed 12 different familial melanoma-associated point mutants spanning the p16 coding region and analyzed their capacity to regulate cell-cycle phase and suppress reactive oxygen species (ROS). Compared to wild-type p16 which fully restored both functions in p16-deficient fibroblasts, various p16 mutants differed in their capacity to normalize ROS and cell cycle profiles. While some mutations did not impair either function, others impaired both. Interestingly, several impaired cell-cycle (R24Q, R99P, V126D) or oxidative function (A36P, A57V, P114S) selectively, indicating that these two functions of p16 can be uncoupled. Similar activities were confirmed with selected mutants in human melanoma cells. Many mutations impairing both cell-cycle and oxidative functions, or only cell cycle function, localize to the third ankyrin repeat of the p16 molecule. Alternatively, most mutations impairing oxidative but not cell-cycle function, or those not impairing either function, lie outside this region. These results demonstrate that particular familial melanoma-associated mutations in p16 can selectively compromise these two independent tumor-suppressor functions, which may be mediated by distinct regions of the protein. PMID:23190892

  19. The tumor suppressor PTEN and the PDK1 kinase regulate formation of the columnar neural epithelium

    PubMed Central

    Grego-Bessa, Joaquim; Bloomekatz, Joshua; Castel, Pau; Omelchenko, Tatiana; Baselga, José; Anderson, Kathryn V

    2016-01-01

    Epithelial morphogenesis and stability are essential for normal development and organ homeostasis. The mouse neural plate is a cuboidal epithelium that remodels into a columnar pseudostratified epithelium over the course of 24 hr. Here we show that the transition to a columnar epithelium fails in mutant embryos that lack the tumor suppressor PTEN, although proliferation, patterning and apical-basal polarity markers are normal in the mutants. The Pten phenotype is mimicked by constitutive activation of PI3 kinase and is rescued by the removal of PDK1 (PDPK1), but does not depend on the downstream kinases AKT and mTORC1. High resolution imaging shows that PTEN is required for stabilization of planar cell packing in the neural plate and for the formation of stable apical-basal microtubule arrays. The data suggest that appropriate levels of membrane-associated PDPK1 are required for stabilization of apical junctions, which promotes cell elongation, during epithelial morphogenesis. DOI: http://dx.doi.org/10.7554/eLife.12034.001 PMID:26809587

  20. The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia.

    PubMed

    Thompson, Benjamin J; Buonamici, Silvia; Sulis, Maria Luisa; Palomero, Teresa; Vilimas, Tomas; Basso, Giuseppe; Ferrando, Adolfo; Aifantis, Iannis

    2007-08-06

    Recent studies have shown that activating mutations of NOTCH1 are responsible for the majority of T cell acute lymphoblastic leukemia (T-ALL) cases. Most of these mutations truncate its C-terminal domain, a region that is important for the NOTCH1 proteasome-mediated degradation. We report that the E3 ligase FBW7 targets NOTCH1 for ubiquitination and degradation. Our studies map in detail the amino acid degron sequence required for NOTCH1-FBW7 interaction. Furthermore, we identify inactivating FBW7 mutations in a large fraction of human T-ALL lines and primary leukemias. These mutations abrogate the binding of FBW7 not only to NOTCH1 but also to the two other characterized targets, c-Myc and cyclin E. The majority of the FBW7 mutations were present during relapse, and they were associated with NOTCH1 HD mutations. Interestingly, most of the T-ALL lines harboring FBW7 mutations were resistant to gamma-secretase inhibitor treatment and this resistance appeared to be related to the stabilization of the c-Myc protein. Our data suggest that FBW7 is a novel tumor suppressor in T cell leukemia, and implicate the loss of FBW7 function as a potential mechanism of drug resistance in T-ALL.

  1. Identification of a tumor suppressor network in T-cell leukemia.

    PubMed

    Nagel, Stefan; Pommerenke, Claudia; Meyer, Corinna; Kaufmann, Maren; MacLeod, Roderick A F; Drexler, Hans G

    2017-09-01

    To identify novel cancer-related genes targeted by copy number alterations, we performed genomic profiling of T-cell acute lymphoblastic leukemia (T-ALL) cell lines. In 3/8, we identified a shared deletion at chromosomal position 2p16.3-p21. Within the minimally deleted region, we recognized several candidate tumor suppressor (TS) genes, including FBXO11 and FOXN2. An additional deletion at chromosome 14q23.2-q32.11 included FOXN3, highlighting this class of FOX genes as potential TS. Quantitative expression analyses of FBXO11, FOXN2, and FOXN3 confirmed reduced transcript levels in the identified cell lines. Moreover, reduced expression of these genes was also observed in about 7% of T-ALL patients, showing their clinical relevance in this malignancy. Bioinformatic analyses revealed concurrent reduction of FOXN2 and/or FOXN3 together with homeobox gene ZHX1. Consistently, experiments demonstrated that both FOXN2 and FOXN3 directly activated transcription of ZHX1. Taken together, we identified novel TS genes forming a regulatory network in T-cell development and leukemogenesis.

  2. Genomic characterization of Wilms' tumor suppressor 1 targets in nephron progenitor cells during kidney development

    PubMed Central

    Hartwig, Sunny; Ho, Jacqueline; Pandey, Priyanka; MacIsaac, Kenzie; Taglienti, Mary; Xiang, Michael; Alterovitz, Gil; Ramoni, Marco; Fraenkel, Ernest; Kreidberg, Jordan A.

    2010-01-01

    Summary The Wilms' tumor suppressor 1 (WT1) gene encodes a DNA- and RNA-binding protein that plays an essential role in nephron progenitor differentiation during renal development. To identify WT1 target genes that might regulate nephron progenitor differentiation in vivo, we performed chromatin immunoprecipitation (ChIP) coupled to mouse promoter microarray (ChIP-chip) using chromatin prepared from embryonic mouse kidney tissue. We identified 1663 genes bound by WT1, 86% of which contain a previously identified, conserved, high-affinity WT1 binding site. To investigate functional interactions between WT1 and candidate target genes in nephron progenitors, we used a novel, modified WT1 morpholino loss-of-function model in embryonic mouse kidney explants to knock down WT1 expression in nephron progenitors ex vivo. Low doses of WT1 morpholino resulted in reduced WT1 target gene expression specifically in nephron progenitors, whereas high doses of WT1 morpholino arrested kidney explant development and were associated with increased nephron progenitor cell apoptosis, reminiscent of the phenotype observed in Wt1−/− embryos. Collectively, our results provide a comprehensive description of endogenous WT1 target genes in nephron progenitor cells in vivo, as well as insights into the transcriptional signaling networks controlled by WT1 that might direct nephron progenitor fate during renal development. PMID:20215353

  3. Methylation of HPV and a tumor suppressor gene reveals anal cancer and precursor lesions

    PubMed Central

    Lorincz, Attila T.; Nathan, Mayura; Reuter, Caroline; Warman, Rhian; Thaha, Mohamed A.; Sheaff, Michael; Vasiljevic, Natasa; Ahmad, Amar; Cuzick, Jack;