VHL loss of function and its impact on oncogenic signaling networks in clear cell renal cell carcinoma

Abstract

Loss of von Hippel-Lindau tumor suppressor gene function occurs in familial and most sporadic clear cell renal cell carcinoma, resulting in the aberrant expression of genes that control cell proliferation, metabolism, invasion and angiogenesis. The molecular mechanisms by which loss of function leads to tumorigenesis are not yet fully defined. The von Hippel-Lindau gene product is part of an ubiquitin ligase complex that targets hypoxia inducible factors for polyubiquitination and proteasomal degradation, linking hypoxia response genes to renal cell carcinoma oncogenesis. Loss von Hippel-Lindau gene function also promotes cell invasiveness in response to hepatocyte growth factor, an important regulator of kidney development and renal homeostasis. Increased cell invasiveness is mediated by another ubiquitin ligase target with relevance to the molecular pathogenesis of renal cell carcinoma: beta-catenin. This discovery and other recent insights into kidney cancer oncogenesis implicate convergent developmental and homeostatic signaling pathways in tumorigenesis, tumor invasiveness and metastasis.

Figure 1. Hypothetical model of HGF and Wnt signaling in kidney development and adulthood

During development, HGF-Met binding promotes receptor kinase activation and tyrosyl phosphorylation of junctional β-catenin, resulting in its dissociation from E-cadherin and cytoplasmic accumulation. Wnt binding to Fzd and LRP5/6 induces Fzd activation, which stabilizes cytoplasmic β-catenin by protecting it from constitutive degradation. Cytoplasmic β-catenin from either pathway translocates to the nucleus, where it associates with members of TCF/LEF transcription factor family and promotes the expression of genes controlling cell motility, proliferation and matrix remodeling. In adult, fully differentiated renal epithelial cells, pVHL targets cytosolic β-catenin for degradation and balanced expression of Wnts and the negative regulators DKKs and sFRPs keeps Fzd activation, and thus cytosolic β-catenin, to a minimum.

Figure 2. Convergence of HIF and β-catenin signaling networks at multiple levels in ccRCC

Wnt-Fzd-LRP5/6 and HGF-Met interactions promote increases in cytosolic β-catenin normally kept in check by sFRPs, DKKs and pVHL. The loss of these negative regulators in ccRCC, as well as hypoxia during tumor progression, results in the aberrant accumulation of cytoplasmic and nuclear β-catenin and HIF through multiple pathways, with compounding effects on target gene expression. Nuclear β-catenin interacts either with HIF or TCF/LEF to promote the expression of overlapping sets of genes, contributing to tumorigenesis, tumor angiogenesis and metastasis.