| First Author | Hoefflin R | Year | 2020 |
| Journal | Nat Commun | Volume | 11 |
| Issue | 1 | Pages | 4111 |
| PubMed ID | 32807776 | Mgi Jnum | J:303341 |
| Mgi Id | MGI:6471304 | Doi | 10.1038/s41467-020-17873-3 |
| Citation | Hoefflin R, et al. (2020) HIF-1alpha and HIF-2alpha differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice. Nat Commun 11(1):4111 |
| abstractText | 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-1alpha and HIF-2alpha transcription factors. While correlative studies of human ccRCC and functional studies using human ccRCC cell lines have implicated HIF-1alpha as an inhibitor and HIF-2alpha 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-1alpha and HIF-2alpha are required for the clear cell phenotype. Transcriptomic and proteomic analyses reveal that HIF-1alpha regulates glycolysis while HIF-2alpha regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. HIF-2alpha-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-1alpha in ccRCC initiation and suggest that alterations in the balance of HIF-1alpha and HIF-2alpha activities can affect different aspects of ccRCC biology and disease aggressiveness. |
