| NF-kappaB-dependent plasticity of the epithelial to mesenchymal transition induced by Von Hippel-Lindau inactivation in renal cell carcinomas. | |
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MedLine Citation:
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PMID: 20068166 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The critical downstream signaling consequences contributing to renal cancer as a result of loss of the tumor suppressor gene von Hippel-Lindau (VHL) have yet to be fully elucidated. Here, we report that VHL loss results in an epithelial to mesenchymal transition (EMT). In studies of paired isogenic cell lines, VHL silencing increased the levels of N-cadherin and vimentin and reduced the levels of E-cadherin relative to the parental VHL(+) cell line, which displayed the opposite profile. VHL(+) cells grew as clusters of cuboidal and rhomboid cells, whereas VHL-silenced cells took on an elongated, fibroblastoid morphology associated with a more highly invasive character in Matrigel chamber assays. Based on earlier evidence that VHL loss can activate NF-kappaB, a known mediator of EMT, we tested whether NF-kappaB contributed to VHL-mediated effects on EMT. On pharmacologic or molecular inhibition of NF-kappaB, VHL-silenced cells regained expression of E-cadherin, lost expression of N-cadherin, and reversed their highly invasive phenotype. Introducing a pVHL-resistant hypoxia-inducible factor 1alpha (HIF1alpha) mutant (HIFalpha(M)) into VHL(+) cells heightened NF-kappaB activity, phenocopying EMT effects produced by VHL silencing. Conversely, inhibiting the heightened NF-kappaB activity in this setting reversed the EMT phenotype. Taken together, these results suggest that VHL loss induces an EMT that is largely dependent on HIFalpha-induced NF-kappaB. Our findings rationalize targeting the NF-kappaB pathway as a therapeutic strategy to treat renal tumors characterized by biallelic VHL inactivation. |
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Authors:
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Allan J Pantuck; Jiabin An; Huiren Liu; Matthew B Rettig |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-01-12 |
Journal Detail:
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Title: Cancer research Volume: 70 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2010 Jan |
Date Detail:
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Created Date: 2010-01-15 Completed Date: 2010-03-09 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 752-61 Citation Subset: IM |
Affiliation:
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Department of Urology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-1738, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Carcinoma, Renal Cell
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genetics,
metabolism,
pathology* Epithelial Cells / pathology Gene Expression Regulation, Neoplastic Gene Silencing Humans Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis Kidney Neoplasms / genetics, metabolism, pathology* Mesoderm / pathology NF-kappa B / antagonists & inhibitors, metabolism* Nuclear Proteins / biosynthesis Transcription Factors / biosynthesis Twist Transcription Factor / biosynthesis Up-Regulation Von Hippel-Lindau Tumor Suppressor Protein / genetics*, metabolism |
| Chemical | |
Reg. No./Substance:
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0/HIF1A protein, human; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/NF-kappa B; 0/Nuclear Proteins; 0/TWIST1 protein, human; 0/Transcription Factors; 0/Twist Transcription Factor; 0/snail family transcription factors; EC 6.3.2.19/VHL protein, human; EC 6.3.2.19/Von Hippel-Lindau Tumor Suppressor Protein |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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