The role of HIF1α in renal cell carcinoma tumorigenesis

The transcription factor HIF1 alpha is implicated in the development of clear cell renal cell carcinoma (ccRCC). Although HIF1 alpha was initially believed to be essential for ccRCC development, recent studies hypothesize an oncogenic role for HIF2 alpha in ccRCC, but a tumor suppressor role for HIF1 alpha [1], 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 HIF1 alpha and HIF2 alpha in the pathogenesis of ccRCC. We present a convergence of clinical and mechanistic data supporting an important role for HIF1 alpha in promoting tumorigenesis in a clinically important and large subset of ccRCC. This indicates that current understanding of the exact roles of HIF1 alpha and HIF2 alpha is incomplete and that further research is required to determine the diverse roles of HIF1 alpha and HIF2 alpha in ccRCC. The TRACK mouse ccRCC model with constitutively active HIF1 alpha but not HIF2 alpha expressed in proximal tubules develops RCC. HIF1 alpha protein is expressed in the majority of human ccRCC specimens. Elevated HIF1 alpha in ccRCC correlates with a worse prognosis. Many publications do not support a tumor suppressor role for HIF1 alpha in ccRCC. HIF1 alpha, but not HIF2 alpha, is expressed in some types of cancer stem cells.