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Regulation of E-cadherin expression by VHL and hypoxia-inducible factor

Esteban, MA; Tran, MGB; Harten, SK; Hill, P; Castellanos, MC; Chandra, A; ... Maxwell, PH; + view all (2006) Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. CANCER RES , 66 (7) 3567 - 3575. 10.1158/0008-5472.CAN-05-2670.

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Abstract

Mutations in von Hippel-Lindau tumor suppressor gene (VHL) underlie the VHL hereditary cancer syndrome and also occur in most sporadic clear cell renal cell cancers (CCRCC). Currently, the mechanism(s) by which VHL, loss of function promotes tumor development in the kidney are not fully elucidated. Here, we show filial. VHL. inactivation in precancerous lesions in kidneys from patients with VHL disease correlates with marked down-regulation of the intercellular adhesion molecule E-cadherin. Moreover, in VHL-defective cell lines (RCC4 and RCC 10) derived from sporadic CCRCC, reexpression of VHL, was found to restore E-cadherin expression.The product of the VHL gene has multiple reported functions, the best characterized of which is its role as the recognition component of an ubiquitin E3 ligase complex responsible for mediating oxygen-dependent destruction of hypoxia-inducible factor-alpha (HIF-alpha) subunits. We show that HIP activation is necessary and sufficient to suppress E-cadherin in renal cancer cells. Given the fundamental role of E-cadherin in controlling epithelial behavior, our findings give insight into how VHL inactivation/HIF activation may lead to kidney cancer and also indicate a mechanism by which reduced oxygenation could alter E-cadherin expression in other cancers and influence normal homeostasis in other epithelia.

Type:Article
Title:Regulation of E-cadherin expression by VHL and hypoxia-inducible factor
DOI:10.1158/0008-5472.CAN-05-2670
Keywords:LINDAU TUMOR-SUPPRESSOR, EPITHELIAL-MESENCHYMAL TRANSITIONS, TRANSCRIPTION FACTOR SNAIL, RENAL-CELL CARCINOMA, UP-REGULATION, PROTEIN, CANCER, GENE, HIF, ADHESION
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)

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