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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocyte growth factor/scatter factor (HGF) exerts several functions in physiological and pathological processes, among them the induction of epithelial cell scattering and motility. Its pivotal role in angiogenesis, tumor progression, and metastasis is evident; however, the underlying molecular mechanisms are still poorly understood. Here, we demonstrate that HGF induces scattering of epithelial cells by upregulating the expression of Snail, a transcriptional repressor involved in epithelial-mesenchymal transition (EMT). Snail is required for HGF-induced cell scattering, since shRNA-mediated ablation of Snail expression prevents this process. HGF-induced upregulation of Snail transcription involves activation of the mitogen-activated protein kinase (MAPK) pathway and requires the activity of early growth response factor-1 (Egr-1). Upon induction by Egr-1, Snail represses the expression of E-cadherin and claudin-3 genes. It also binds to the Egr-1 promoter and represses Egr-1 transcription, thereby establishing a negative regulatory feedback loop. These findings indicate that Snail upregulation by HGF is mediated via the MAPK/Egr-1 signaling pathway and that both Snail and Egr-1 play a critical role in HGF-induced cell scattering, migration, and invasion.
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PMID:Hepatocyte growth factor induces cell scattering through MAPK/Egr-1-mediated upregulation of Snail. 1685 14

Zinc-finger protein 217 (ZNF217) is a Kruppel-like zinc-finger protein located at 20q13.2, within a region of recurrent maximal amplification. Here, we demonstrate that ZNF217 is a transcriptional repressor protein and report the purification and characterization of a ZNF217 complex. The purified ZNF217 complex consists of approximately six proteins and contains the transcriptional co-repressors CoREST, BHC110/LSD1, histone deacetylase (HDAC) 2 and C-terminal binding protein (CtBP1). The purified ZNF217 complex possesses deacetylase activity as well as lysine 4 histone H3-specific demethylase activity that is most likely mediated by the BHC110/LSD1 component. To determine if ZNF217 is a sequence-specific binding protein, we have made use of cyclic amplification and selection of targets (CAST) assay and identify for the first time a ZNF217 DNA consensus recognition sequence (CRS) that is highly conserved in the human E-cadherin promoter. Chromatin immunoprecipitation (ChIP) experiments demonstrate that ZNF217, as well as the other components of the ZNF217 complex, are found on the region of the proximal E-cadherin promoter that contains the identified ZNF217 CRS in vivo. Using a combination of transient transfections and small interfering RNA, we demonstrate that ZNF217 represses the E-cadherin promoter. Collectively, our results implicate ZNF217 and its associated proteins in a novel pathway that may have profound effects on cancer progression.
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PMID:Biochemical characterization of the zinc-finger protein 217 transcriptional repressor complex: identification of a ZNF217 consensus recognition sequence. 1713 Aug 29

Rac1b is a tumor-specific splice variant of the Rac1 GTPase that displays limited functional similarities to Rac1. We have shown previously a novel cross-talk between Rac1 and beta-catenin, which induces canonical Wnt pathway activation in colorectal cancer cells. This prompted us to investigate if Rac1b, frequently overexpressed in colon tumors, contributes to Wnt pathway dysregulation. We show that Rac1b overexpression stimulates Tcf-mediated gene transcription, whereas depletion of Rac1b results in decreased expression of the Wnt target gene cyclin D1. Reconstitution experiments revealed an important difference between Rac1 and Rac1b such that Rac1b was capable of functionally interacting with Dishevelled-3 (Dvl-3) but not beta-catenin to mediate synergistic induction of Wnt target genes. In agreement, Dvl-3 but not beta-catenin caused increased activation of Rac1b levels, which may explain the functional cooperativity displayed in transcription assays. Furthermore, we show that Rac1b negatively regulates E-cadherin expression and results in decreased adhesion of colorectal cancer cells. RNA interference-mediated suppression of Rac1b resulted in reduced expression of Slug, a specific transcriptional repressor of E-cadherin, and a concomitant increase in E-cadherin transcript levels was observed. Intriguingly, mutation of the polybasic region of Rac1b resulted in complete loss of Rac1b stimulatory effects on transcription and suppressive effects on adhesion, indicating the importance of nuclear and membrane localization of Rac1b. Our results suggest that Rac1b overexpression may facilitate tumor progression by enhancing Dvl-3-mediated Wnt pathway signaling and induction of Wnt target genes specifically involved in decreasing the adhesive properties of colorectal cancer cells.
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PMID:Activation of tumor-specific splice variant Rac1b by dishevelled promotes canonical Wnt signaling and decreased adhesion of colorectal cancer cells. 1736 64

The snail gene encodes a transcriptional repressor that functions during animal development and in cancer progression to promote epithelial-mesenchymal transitions. Strict spatial and temporal boundaries of Snail expression in development imply precise transcriptional control, which becomes inappropriately activated in many cancer subtypes. To gain insight into the molecular mechanism(s) governing transcriptional control of Snail, we analyze chromatin structural changes associated with Snail transcription in melanoma cells. Regardless of transcriptional status, the Snail promoter displays three constitutive DNase hypersensitive sites (HS) and a moderate level of histone H3 Lys(4) dimethylation. A robust HS is found in the 3' region of A375 melanoma cells, in which Snail is highly expressed, but is absent in cells not expressing Snail. This element is conserved throughout the mammalian lineage and strongly activates expression of a reporter in A375 and Colo829 melanoma cells, but not in keratinocytes or primary melanocytes. Activity of this enhancer is associated with enrichment of H3 Lys(4) dimethylation and H3 acetylation at both the enhancer and the promoter. Additionally, enhancer activity is associated with H3 Lys(4) trimethylation at the promoter. A physical interaction between the 3' enhancer and promoter was observed in Snail-expressing cells, demonstrating a direct role for the enhancer in Snail expression. These results suggest a model in which the Snail promoter is constitutively packaged in a poised chromatin structure that can be activated in melanoma cells by a tissue-specific enhancer, which physically contacts the promoter.
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PMID:A 3' enhancer controls snail expression in melanoma cells. 1761 67

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF growth factor family. Initially synthesized as a membrane-bound precursor (pro-HB-EGF), it is cleaved at the juxtamembrane domain to release the soluble form of HB-EGF (s-HB-EGF) by sheddases, including matrix metalloproteinases (MMP) and a disintegrin and metalloproteinases. This is a process referred to as ectodomain shedding and is implicated in the process of all ligands of the EGF receptor (EGFR) family. The tumorigenic potential of s-HB-EGF has been studied extensively; however, the role of pro-HB-EGF in tumor progression is unknown, despite the fact that a considerable amount of pro-HB-EGF remains on the cell membrane. Our data here clearly indicated the distinct role of pro-HB-EGF in the regulation of E-cadherin expression and the epithelial-mesenchymal transition. We showed here that the expression of pro-HB-EGF was associated with the differentiation status in pancreatic tumors and cell lines. Expression of noncleaved pro-HB-EGF in pancreatic cells resulted in the up-regulation of E-cadherin through suppression of ZEB1, which is a transcriptional repressor of E-cadherin. Inhibition of HB-EGF shedding using a MMP inhibitor, GM6001, also dramatically augmented the E-cadherin expression while suppressing the EGFR activation. Moreover, up-regulation of E-cadherin by pro-HB-EGF not only resulted in cellular morphologic change but also decreased cell motility and enhanced apoptotic sensitivity in response to gemcitabine-erlotinib treatment. Collectively, our data defined a distinct role of pro-HB-EGF in the regulation of E-cadherin, suggesting that inhibition of shedding may be a novel approach to suppress pancreatic metastasis and sensitize cells to cancer therapy.
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PMID:Membrane-bound heparin-binding epidermal growth factor like growth factor regulates E-cadherin expression in pancreatic carcinoma cells. 1787 87

Infection with HPV (human papillomavirus) 16 is the cause of 50% or more of cervical cancers in women. HPV16 infection, however, is very common in young sexually active women, but the majority mount an effective immune response and clear infection. Approx. 10% of individuals develop a persistent infection, and it is this cohort who are at risk of cancer progression, with the development of high-grade precursor lesions and eventually invasive carcinoma. Effective evasion of innate immune recognition seems to be the hallmark of HPV infections, since the infectious cycle is one in which viral replication and release is not associated with inflammation. Furthermore, HPV infections disrupt cytokine expression and signalling with the E6 and E7 oncoproteins particularly targeting the type I IFN (interferon) pathway. High doses of IFN can overcome the HPV-mediated abrogation of signalling, and this may be the basis for the therapeutic effects on HPV infections of immune-response modulators such as the imidazoquinolones that induce high levels of type I IFNs by activation of TLR (Toll-like receptor) 7. Using the unique W12 model of cervical carcinogenesis, some of these IFN-related interactions and their relevance in the selection of cells with integrated viral DNA in cancer progression have been investigated. Our data show that episome loss associated with induction of antiviral response genes is a key event in the spontaneous selection of cervical keratinocytes containing integrated HPV16. Exogenous IFN-beta treatment of W12 keratinocytes in which the majority of the population contain episomes results only in the rapid emergence of IFN-resistant cells, loss of episome-containing cells and a selection of cells containing integrated HPV16 in which the expression of the transcriptional repressor E2 is down-regulated, but in which E6 and E7 are up-regulated.
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PMID:HPV: from infection to cancer. 1803 Dec 45

The E-cadherin transcriptional repressor Snail is a prognostic marker for metastatic breast carcinoma, as well as a critical determinant of tumor growth and recurrence. We define a non-angiogenic, autocrine function for the vascular endothelial growth factor-A (VEGF-A) in regulating Snail expression in breast tumor cells. The transfection of well-differentiated breast tumor cells with VEGF-A increases Snail mRNA and protein levels, resulting in reduced E-cadherin expression. Conversely, reducing endogenous VEGF-A expression in poorly differentiated breast tumor cells by siRNA transfection decreases Snail levels. Our studies demonstrate that VEGF and the VEGF receptor Neuropilin-1 increase Snail expression by suppressing the Glycogen Synthase Kinase-3 (GSK-3), an established inhibitor of Snail transcription and protein stability. The VEGF-A neutralizing antibody Avastin was recently approved by the FDA for the treatment of metastatic breast cancer. We present the provocative finding that beyond its anti-angiogenic activity, Avastin can reduce Snail expression in breast tumor cells. Collectively, this work describes a novel autocrine function for VEGF in breast tumor cells in driving the expression of Snail, a breast tumor progression factor. Based on our demonstration that Avastin reduces Snail expression in breast tumor cells, we propose that the treatment of early stage breast cancer patients with Avastin may impede tumor progression.
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PMID:Vascular endothelial growth factor-A stimulates Snail expression in breast tumor cells: implications for tumor progression. 1855 84

Ovarian epithelial carcinomas (OECs) frequently exhibit amplifications at the 20q13 locus which is the site of several oncogenes, including the eukaryotic elongation factor EEF1A2 and the transcription factor ZNF217. We reported previously that overexpressed ZNF217 induces neoplastic characteristics in precursor cells of OEC. Unexpectedly, ZNF217, which is a transcriptional repressor, enhanced expression of eEF1A2. In our study, array comparative genomic hybridization, single nucleotide polymorphism and Affymetrix analysis of ZNF217-overexpressing cell lines confirmed consistently increased expression of eEF1A2 but not of other oncogenes, and revealed early changes in EEF1A2 gene copy numbers and increased expression at crisis during immortalization. We defined the influence of eEF1A2 overexpression on immortalized ovarian surface epithelial cells, and investigated interrelationships between effects of ZNF217 and eEF1A2 on cellular phenotypes. Lentivirally induced eEF1A2 overexpression caused delayed crisis, apoptosis resistance and increases in serum-independence, saturation densities and anchorage independence. siRNA to eEF1A2 reversed apoptosis resistance and reduced anchorage independence in eEF1A2-overexpressing lines. Remarkably, siRNA to eEF1A2 was equally efficient in inhibiting both anchorage independence and resistance to apoptosis conferred by ZNF217 overexpression. Our data define neoplastic properties that are caused by eEF1A2 in nontumorigenic ovarian cancer precursor cells, and suggest that eEF1A2 plays a role in mediating ZNF217-induced neoplastic progression.
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PMID:The eukaryotic translation elongation factor eEF1A2 induces neoplastic properties and mediates tumorigenic effects of ZNF217 in precursor cells of human ovarian carcinomas. 1866 15

Prostaglandin E(2) (PGE(2)) promotes cancer progression by modulating proliferation, apoptosis, angiogenesis, and the immune response. Enzymatic degradation of PGE(2) involves the NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Recent reports have shown a marked diminution of 15-PGDH expression in colorectal carcinomas (CRC). We report here that treatment of CRC cells with histone deacetylase (HDAC) inhibitors, including sodium butyrate and valproic acid, induces 15-PGDH expression. Additionally, we show that pretreatment of CRC cells with HDAC inhibitors can block epidermal growth factor-mediated or Snail-mediated transcriptional repression of 15-PGDH. We show an interaction between Snail and HDAC2 and the binding of HDAC2 to the 15-PGDH promoter. In vivo, we observe increased Hdac2 expression in Apc-deficient mouse adenomas, which inversely correlated with loss of 15-Pgdh expression. Finally, in human colon cancers, elevated HDAC expression correlated with down-regulation of 15-PGDH. These data suggest that class I HDACs, specifically HDAC2, and the transcriptional repressor Snail play a central role in the suppression of 15-PGDH expression. These results also provide a cyclooxygenase-2-independent mechanism to explain increased PGE(2) levels that contribute to progression of CRC.
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PMID:Repression of 15-hydroxyprostaglandin dehydrogenase involves histone deacetylase 2 and snail in colorectal cancer. 1901 Sep 7

MTA (metastasis-associated gene) is a newly discovered family of cancer progression-related genes and their encoded products. MTA1, the first gene found in this family, has been repeatedly reported to be overexpressed along with its protein product MTA1 in a wide range of human cancers. In addition, the expression of MTA1/MTA1 correlates with the clinicopathological properties (malignant properties) of human cancers. MTA proteins are transcriptional co-repressors that function in histone deacetylation and are involved in the NuRD complex, which contains nucleosome remodeling and histone deacetylating molecules. MTA1 expression correlates with tumor formation in the mammary gland. In addition, MTA1 converts breast cancer cells to a more aggressive phenotype by repression of the estrogen receptor (ER) alpha trans-activation function through deacetylation of the chromatin in the ER-responsive element of ER-responsive genes. Furthermore, MTA1 plays an essential role in c-MYC-mediated cell transformation. Another member of this family, MTA3, is induced by estrogen and represses the expression of the transcriptional repressor Snail, a master regulator of "epithelial to mesenchymal transitions", resulting in the expression of the cell adhesion molecule E-cadherin and maintenance of a differentiated, normal epithelial phenotype in breast cells. In addition, tumor suppressor p53 protein is deacetylated and inactivated by both MTA1 and MTA2, leading to inhibition of growth arrest and apoptosis. Moreover, a hypoxia-inducible factor-1alpha (HIF-1alpha) is also deacetylated and stabilized by MTA1, resulting in angiogenesis. Thus, MTA proteins, especially MTA1, represent a possible set of master co-regulatory molecules involved in the carcinogenesis and progression of various malignant tumors. MTA proteins are proposed to be important new tools for clinical application in cancer diagnosis and treatment.
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PMID:The role of the MTA family and their encoded proteins in human cancers: molecular functions and clinical implications. 1911 62


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