The role of VHL gene and its mutation in the pathogenesis of renal clear cell carcinoma

Abstract

The Von Hippel–Lindau (VHL) is an inherited neoplasia syndrome caused by the inactivation of VHL tumor suppressor gene, and somatic mutation of this gene has been related to the development of sporadic clear cell renal carcinoma.The VHL gene protein has multiple functions that are linked to tumor suppression, but the best recognized and evidently linked to the development of renal cell carcinoma (RCC) is inhibition of hypoxia-inducible factor (HIF), as well as plays a role in targeting HIF for ubiquitin-mediated degradation.Aberrations in VHL's function, either through mutation or promoter hypermethylation, lead to the accumulation of HIF, which will transcriptionally upregulate a sequence of hypoxia responsive genes, including epidermal growth factor, vascular endothelial growth factor, platelet-derived growth factor, and other proangiogenic factors, resulting in upregulated blood vessel growth, one of the prerequisites of a tumor.The missense mutations may more specifically affect the binding ability of pVHL to its partner and affect the corresponding signaling pathways, and may further provide a predictive trail of treatmentas compared to nonsense and frameshift mutations. Key words: Von Hippel-Linda; Hypoxia-inducible factor; Renal cell carcinoma; VHL missense mutations