UNLABELLED: The transcription factor HIF1α is implicated in the development of clear cell renal cell carcinoma (ccRCC). Although HIF1α was initially believed to be essential for ccRCC development, recent studies hypothesize an oncogenic role for HIF2α in ccRCC, but a tumor suppressor role for HIF1α, leading to uncertainty as to the precise roles of the different HIF transcription factors in this disease. Using evidence available from studies with human ccRCC cell lines, mouse xenografts, murine models of ccRCC, and human ccRCC specimens, we evaluate the roles of HIF1α and HIF2α in the pathogenesis of ccRCC. We present a convergence of clinical and mechanistic data supporting an important role for HIF1α in promoting tumorigenesis in a clinically important and large subset of ccRCC. This indicates that current understanding of the exact roles of HIF1α and HIF2α is incomplete and that further research is required to determine the diverse roles of HIF1α and HIF2α in ccRCC.

KEY MESSAGES: The TRACK mouse ccRCC model with constitutively active HIF1α but not HIF2α expressed in proximal tubules develops RCC. HIF1α protein is expressed in the majority of human ccRCC specimens. Elevated HIF1α in ccRCC correlates with a worse prognosis. Many publications do not support a tumor suppressor role for HIF1α in ccRCC. HIF1α, but not HIF2α, is expressed in some types of cancer stem cells.