Downstream Targets of VHL/HIF-α Signaling in Renal Clear Cell Carcinoma Progression: Mechanisms and Therapeutic Relevance

SIMPLE SUMMARY: Clear cell renal cell carcinoma (ccRCC) progression, which is the most common form of kidney cancer, is associated with the loss of the Von Hippel-Lindau (VHL) gene in renal epithelium. VHL promotes proteasomal degradation of Hypoxia Inducible Factor alpha (HIF-α) thereby inhibiting the transcription of genes that are required for cell growth and proliferation during hypoxia (lack of oxygen). Accumulation of HIF-α consequent to VHL loss results in the activation of HIF target genes irrespective of oxygen availability which initiates tumorigenesis in the kidney. In this review, we discuss which signaling networks and genes are upregulated in response to HIF-α activation and how they drive ccRCC progression. We also highlight the potential therapies available to treat ccRCC patients as well as several medical and scientific challenges that impede the scientific investigation in this field. ABSTRACT: The clear cell variant of renal cell carcinoma (ccRCC) is the most common renal epithelial malignancy and responsible for most of the deaths from kidney cancer. Patients carrying inactivating mutations in the Von Hippel-Lindau (VHL) gene have an increased proclivity to develop several types of tumors including ccRCC. Normally, the Hypoxia Inducible Factor alpha (HIF-α) subunits of the HIF heterodimeric transcription factor complex are regulated by oxygen-dependent prolyl-hydroxylation, VHL-mediated ubiquitination and proteasomal degradation. Loss of pVHL function results in elevated levels of HIF-α due to increased stability, leading to RCC progression. While HIF-1α acts as a tumor suppressor, HIF-2α promotes oncogenic potential by driving tumor progression and metastasis through activation of hypoxia-sensitive signaling pathways and overexpression of HIF-2α target genes. One strategy to suppress ccRCC aggressiveness is directed at inhibition of HIF-2α and the associated molecular pathways leading to cell proliferation, angiogenesis, and metastasis. Indeed, clinical and pre-clinical data demonstrated the effectiveness of HIF-2α targeted therapy in attenuating ccRCC progression. This review focuses on the signaling pathways and the involved genes (cyclin D, c-Myc, VEGF-a, EGFR, TGF-α, GLUT-1) that confer oncogenic potential downstream of the VHL-HIF-2α signaling axis in ccRCC. Discussed as well are current treatment options (including receptor tyrosine kinase inhibitors such as sunitinib), the medical challenges (high prevalence of metastasis at the time of diagnosis, refractory nature of advanced disease to current treatment options), scientific challenges and future directions.