title: NF-kappaB-dependent plasticity of the epithelial to mesenchymal transition induced by Von Hippel-Lindau inactivation in renal cell carcinomas.
abstract: 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.
authors.affiliation: Department of Urology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-1738, USA.
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Pantuck
authors.forename: Jiabin
authors.initials: J
authors.lastname: An
authors.forename: Huiren
authors.initials: H
authors.lastname: Liu
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Rettig
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004847:Epithelial Cells / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008648:Mesoderm / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis; D051879:Twist-Related Protein 1 / Q000096:biosynthesis; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D009687:Nuclear Proteins; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human