Abstract
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-1α and HIF-2α transcription factors. While correlative studies of human ccRCC and functional studies using human ccRCC cell lines have implicated HIF-1α as an inhibitor and HIF-2α 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-1α and HIF-2α are required for the clear cell phenotype. Transcriptomic and proteomic analyses reveal that HIF-1α regulates glycolysis while HIF-2α regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. HIF-2α-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-1α in ccRCC initiation and suggest that alterations in the balance of HIF-1α and HIF-2α activities can affect different aspects of ccRCC biology and disease aggressiveness.
Highlights
Mutational inactivation of von Hippel–Lindau (VHL) is the earliest genetic event in the majority of clear cell renal cell carcinomas, leading to accumulation of the HIF-1α and HIF-2α transcription factors
Metastases were not observed in any of the genotypes. These data indicate that HIF-1α is very important for the efficient evolution and growth of Vhl mutant clear cell renal cell carcinomas (ccRCC), while HIF-2α is only partly required and many tumours still develop in the Vhl/Trp53/Rb1/ Hif2a quadruple mutant background
We focused analyses on genes that were differentially expressed between VhlΔ/ΔTrp53Δ/ΔRb1Δ/Δ tumours and the VhlΔ/Δ Trp53Δ/ΔRb1Δ/ΔHif1aΔ/Δ and VhlΔ/ΔTrp53Δ/ΔRb1Δ/ΔHif2aΔ/Δ tumour genotypes and identified 396 differentially expressed genes that are dependent on HIF-1α (Supplementary Fig. 7a), 804 differentially expressed genes that are dependent on HIF-2α (Supplementary Fig. 7b) and 131 differentially expressed genes that are dependent on both HIF-1α and HIF-2α (Supplementary Fig. 7c)
Summary
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-1α and HIF-2α transcription factors. 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-1α and HIF-2α are required for the clear cell phenotype. 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-1α in ccRCC initiation and suggest that alterations in the balance of HIF-1α and HIF-2α activities can affect different aspects of ccRCC biology and disease aggressiveness. Numerous mouse models have supported this notion of genetic cooperation by showing that renal epithelial cell-specific inactivation of different combinations of Vhl together with Pten[10], Tsc[111], Pbrm[111–13], Bap[111,14], Trp5315, Trp53/Rb116, Cdkn2a17, or with Myc[17] overexpression causes the formation of cystic and solid precursor lesions or ccRCC tumours
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