The VHL tumour-suppressor gene (TSG) has a critical 'gatekeeper' role in regulating growth and differentiation of human kidney cells, and inactivation of the VHL gene is the most frequent genetic event in human kidney cancer.
pVHL, the product of the VHL tumor suppressor gene, plays an important role in the regulation of cell growth and differentiation of human kidney cells, and inactivation of the VHL gene is the most frequent genetic event in human kidney cancer.
In this study, we collected 35 archived Swedish sporadic RCCs identified from an epidemiological study on occupational exposure and kidney cancer to test how well stored pathological specimens could be retrieved and analyzed for VHL mutations.
Recent identification of VHL, c-met and TSC as candidate genes mutated in various types of renal carcinomas has greatly enhanced our understanding of the pathogenesis of renal carcinomas and has provided novel therapeutic options for patients with renal cancer.
In conclusion, unlike other hereditary kidney cancer-related genes (i.e., VHL and MET), which are cell type-specific, BHD is involved in the entire spectrum of histological types of renal tumors, suggesting its major role in kidney cancer tumorigenesis.
In addition to VHL, which is associated with clear cell carcinoma, one can now list HPRC (associated with type I papillary renal cancer) and HLRCC (associated with type II papillary renal cancer).
This review summarizes the current knowledge of the molecular pathogenesis of von Hippel-Lindau disease and the role of the VHL gene product (pVHL) in kidney cancer and the mammalian oxygen sensing pathway.
The von Hippel-Lindau tumor suppressor protein (pVHL) is frequently mutated in kidney cancer and is part of the ubiquitin ligase complex that targets prolyl hydroxylated HIFalpha for destruction.
Most of what is known about the genetic basis of kidney cancer has been learned from study of the inherited forms of kidney cancer: von Hippel Lindau (VHL gene), hereditary papillary renal carcinoma (c-Met gene), Birt Hogg Dubé (BHD gene), and hereditary leiomyomatosis renal cell cancer (fumarate hydratase gene).
The VHL gene product, pVHL, has multiple functions, but the best documented, and the one most clearly linked to tumor development, relates to its role as the substrate recognition module of a ubiquitin ligase complex that targets hypoxia-inducible factor (HIF) for destruction. pVHL function is often compromised in sporadic kidney cancers, and inhibitors of the HIF-responsive growth factor (vascular endothelial growth factor) are active against this disease. pVHL, by inhibiting atypical protein kinase C and hence JunB, also affects neuronal survival, as do the products of the other genes linked to familial pheochromocytoma or paraganglioma (NF1, RET, SDHB, SDHC, and SDHD).
Clear-cell renal cell carcinoma (RCC) is the most prevalent form of kidney cancer and is frequently associated with loss of von Hippel-Lindau (VHL) gene function, resulting in the aberrant transcriptional activation of genes that contribute to tumor growth and metastasis, including transforming growth factor-alpha (TGF-alpha), a ligand of the epidermal growth factor receptor (EGFR) tyrosine kinase.
Loss of VHL function causes the overexpression of transforming growth factor (TGF)-alpha, leading us to hypothesize that TGF-alpha could be a potential TAA for immunotherapy of kidney cancer, which was evaluated in this study.
The VHL gene is the gene for the hereditary cancer syndrome, von Hippel-Lindau, as well as for the common form of sporadic, noninherited, clear cell kidney cancer.