The role of MXI1 in VHL deficient tumorigenesis

摘要

The von Hippel-Lindau (VHL) gene plays a central role in the pathogenesis of both hereditary and sporadic renal cell carcinoma (RCC). VHL encodes a component of an E3 ubiquitin ligase complex that degrades hypoxia inducible transcription factors (HIFs) HIF-1alpha and HIF-2alpha in an oxygen-dependent manner. The loss of VHL therefore results in aberrant HIF stabilization under normal oxygen tension. HIF-2alpha stabilization is a key step in the pathogenesis of renal cell carcinoma; however, the range of downstream target genes responsible for HIF dependent tumorigenesis remains to be fully elucidated. HIF targets that have been implicated in renal cancer include angiogenic factors (VEGF, PDGF), mitogens (EGF-R and its ligand TGFalpha), as well as glycolytic enzymes (GLUT1, LDH-A). Identification of these downstream targets has led to the emergence of targeted therapy for treating advanced RCC, including the use of sorafenib, sunitinib and bevacizumab to block VEGF signaling, and sirolimus to inhibit the mTOR pathway.