Snail and Slug are major determinants of ovarian cancer invasiveness at the transcription level

Kurrey, Nawneet K.; Amit, K; Bapat, Sharmila A.

doi:10.1016/j.ygyno.2004.12.043

Cited by 225 publications

(168 citation statements)

References 27 publications

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“…Activity of this enhancer is associated with enrichment of H3 Lys (4) dimethylation and H3 acetylation of both the enhancer and promoter. Although hypoxia has been implicated in upregulation of Snail (19)(20)(21), no functional hypoxia-responsive element has been identified in the snail promoter.…”

Section: D a Bmentioning

confidence: 99%

“…GSK-3 is an endogenous inhibitor of Snail transcription (17) and GSK-3b mediated phosphorylation of Snail has been shown to facilitate its proteasomal degradation (18). Low oxygen induces Snail transcription (19)(20)(21)(22) and both the canonical HIF (22,23) and Notch (24,25) pathways have been implicated in hypoxia-induced EMT. However, Snail is yet to be identified as a direct HIF target gene.…”

Section: Introductionmentioning

confidence: 99%

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Mouse Snail Is a Target Gene for HIF

Luo

Wang

et al. 2011

Molecular Cancer Research

103

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The transcriptional inhibitor Snail is a critical regulator for epithelial-mesenchymal transition (EMT). Although low oxygen induces Snail transcription, thereby stimulating EMT, a direct role of hypoxia-inducible factor (HIF) in this process remains to be demonstrated. Here we show that hypoxia induces the expression of Snail via HIF. In silico analysis identified a potential hypoxia-response element (HRE) close to the minimal promoter of the human and mouse genome of the snail gene. Gel shift assays demonstrated that a specific hypoxiainducible complex is formed with the putative HRE and that the complex contains HIF proteins. ChIP assays confirmed the interaction of HIF proteins with the putative HRE in vivo. Reporter gene analyses showed that the putative HRE responds to hypoxia in its natural position as well as in front of a heterologous promoter and that the HRE is directly activated by HIF-1a or HIF-2a. HIF knockdown with siRNA at 2% oxygen and overexpression of an oxygen-insensitive HIF (HIF-DODD) mutant at 21% oxygen showed that HIF regulates Snail activation and subsequent cell migration. Our findings identify snail as a HIF target gene and provide novel insights into the regulation of snail and hypoxia-induced EMT. Mol Cancer Res; 9(2); 234-45. Ó2011 AACR.

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Section: D a Bmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mouse Snail Is a Target Gene for HIF

Luo

Wang

et al. 2011

Molecular Cancer Research

103

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“…In one of the first accounts, Kurrey et al described Snail and Slug activation of EMT, inactivation of p53-mediated apoptosis and de-repression of stemnessassociated genes under conditions of radiation-and druginduced stress. The authors proposed that the resulting CSCs were capable of escaping the unfavorable primary tumor niche, traveling to distant sites, and surviving/ colonizing the metastatic niche, leading to their characterization of Snail and Slug as critical determinants of ovarian cancer progression and resistance to therapy [150]. Using pancreatic epithelial cells derived from p53−/− mice that were also cultured under stress conditions, Pinho et al described similar EMT and stemness features mediated by the self-renewal factor Bmi1 [151].…”

Section: Inflammation-inducible Emt Drives Stemness and Contributes Tmentioning

confidence: 99%

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

Heinrich

Walser

Krysan

et al. 2011

Cancer Microenvironment

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The inflammatory tumor microenvironment (TME) has many roles in tumor progression and metastasis, including creation of a hypoxic environment, increased angiogenesis and invasion, changes in expression of microRNAs (miRNAs) and an increase in a stem cell phenotype. Each of these has an impact on epithelial mesenchymal transition (EMT), particularly through the downregulation of E-cadherin. Here we review seminal work and recent findings linking the role of inflammation in the TME, EMT and lung cancer initiation, progression and metastasis.Finally, we discuss the potential of targeting aspects of inflammation and EMT in cancer prevention and treatment.

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“…Elevated expression of several of these factors including Snail, Slug, SIP1 and Twist have been identified in EOC and associated with less favorable patient outcomes [72][73][74][75][76]. Ectopic expression of Snail, Slug or Twist in ovarian cancer cell lines results in repression of E-cadherin with accompanying EMT, enhanced motility, and invasiveness suggesting that transcriptional regulation of E-cadherin may be operational in EOC [72,75].On the other hand, it has been reported that reduced E-cadherin protein level in EOC did not correlate with its mRNA levels, suggesting post-transcriptional regulation of E-cadherin [19]. Post-translational mechanisms for modification of E-cadherin function, for example via altered trafficking or proteolytic processing, have received little attention in ovarian cancer.…”

mentioning

confidence: 99%

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

Hudson

Zeineldin

Stack

2008

Clin Exp Metastasis

165

172

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The mesodermally derived normal ovarian surface epithelium (OSE) displays both epithelial and mesenchymal characteristics and exhibits remarkable phenotypic plasticity during post-ovulatory repair. The majority of epithelial ovarian carcinomas (EOC) are derived from the OSE and represent the most lethal of all gynecological malignancies, as most patients (~70%) present at diagnosis with disseminated intra-abdominal metastasis. The predominant pattern of EOC metastasis involves pelvic dissemination rather than lymphatic or hematologic spread, distinguishing EOC from other solid tumors. Acquisition of the metastatic phenotype involves a complex series of interrelated cellular events leading to dissociation (shedding) and dispersal of malignant cells. A key event in this process is disruption of cell-cell contacts via modulation of intercellular junctional components. In contrast to most carcinomas that downregulate E-cadherin expression during tumor progression, an unique feature of primary well-differentiated ovarian cancers is a gain of epithelial features, characterized by an increase in expression of E-cadherin. Subsequent reacquisition of mesenchymal features is observed in more advanced tumors with concomitant loss of E-cadherin expression and/ or function during progression to metastasis. The functional consequences of this remarkable phenotypic plasticity are not fully understood, but may play a role in modulation of cell survival in suspension (ascites), chemoresistance, and intraperitoneal anchoring of metastatic lesions. Keywords ovarian cancer; epithelium; cadherin; keratin; vimentin; epithelial-mesenchymal transition; plasticity Ovarian Cancer-OverviewTumors arising from the ovarian epithelium account for ~90% of ovarian malignancies and epithelial ovarian carcinoma (EOC) is the leading cause of death from gynecologic malignancy, resulting in approximately 15,280 deaths in the United States alone in 2006 [1]. These distressing statistics are largely due to the low detection rate of disease confined to the ovary (stage 1) when 5-year survival is >90%. Approximately 75% of women are initially diagnosed with disseminated intra-abdominal disease (stage III-IV) and have a 5-year survival of <20%.Ovarian tumors are pathologically heterogeneous with four major histotypes: serous, endometroid, clear cell and mucinous. These classifications are histogenetically based on The early steps of EOC metastasis involve shedding of the cells from the primary tumor to form free floating cells or multi-cellular aggregates (MCAs) in ascites [ Fig. 1]. Cell-cell and cell-matrix adhesion molecules mediate interaction of metastasizing tumor cells with mesothelial cells lining the inner surface of the peritoneal cavity and the sub-mesothelial extracellular matrix (ECM). Localized proteolytic degradation of sub-mesothelial ECM components facilitates migration of tumor cells and anchoring of secondary lesions on adjacent pelvic organs, and at later stages, metastasis to distant organs [9,10]. However, the majority of wo...

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Snail and Slug are major determinants of ovarian cancer invasiveness at the transcription level

Cited by 225 publications

References 27 publications

Mouse Snail Is a Target Gene for HIF

Mouse Snail Is a Target Gene for HIF

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

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