HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice

Mutational inactivation of VHL is the earliest genetic event in the majority of clear cell renal cell carcinomas (ccRCC), leading to accumulation of the HIF-1 alpha and HIF-2 alpha transcription factors. While correlative studies of human ccRCC and functional studies using human ccRCC cell lines have implicated HIF-1 alpha as an inhibitor and HIF-2 alpha as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Herein we show using an autochthonous ccRCC model that Hif1a is essential for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth. Both HIF-1 alpha and HIF-2 alpha are required for the clear cell phenotype. Transcriptomic and proteomic analyses reveal that HIF-1 alpha regulates glycolysis while HIF-2 alpha regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. HIF-2 alpha -deficient tumours are characterised by increased antigen presentation, interferon signalling and CD8(+) T cell infiltration and activation. Single copy loss of HIF1A or high levels of HIF2A mRNA expression correlate with altered immune microenvironments in human ccRCC. These studies reveal an oncogenic role of HIF-1 alpha in ccRCC initiation and suggest that alterations in the balance of HIF-1 alpha and HIF-2 alpha activities can affect different aspects of ccRCC biology and disease aggressiveness. Genetic inactivation of VHL leads to stabilization of HIF-1 alpha /HIF-2 alpha and is associated with clear cell renal cell carcinoma (ccRCC) initiation and progression. Using an autochthonous mouse model of ccRCC with Vhl deletion, here the authors show that HIF-1 alpha is necessary for tumor formation, while HIF-2 alpha deletion has only a moderate effect.