HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice Journal Article
| Authors: | Hoefflin, R.; Harlander, S.; Schäfer, S.; Metzger, P.; Kuo, F.; Schönenberger, D.; Adlesic, M.; Peighambari, A.; Seidel, P.; Chen, C. Y.; Consenza-Contreras, M.; Jud, A.; Lahrmann, B.; Grabe, N.; Heide, D.; Uhl, F. M.; Chan, T. A.; Duyster, J.; Zeiser, R.; Schell, C.; Heikenwalder, M.; Schilling, O.; Hakimi, A. A.; Boerries, M.; Frew, I. J. |
| Article Title: | HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice |
| 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. © 2020, The Author(s). |
| Keywords: | immunohistochemistry; allograft; gene deletion; mutation; nonhuman; cd3 antigen; cd8 antigen; cd8+ t lymphocyte; cell proliferation; mass spectrometry; animal cell; mouse; phenotype; mus; dna repair; gene expression; cell infiltration; tumor volume; animal experiment; animal model; inflammation; cohort analysis; genotype; proteomics; transcriptomics; protein p53; renal cell carcinoma; carcinogenesis; oncogene; antigen presentation; gamma interferon; messenger rna; cd4+ t lymphocyte; western blotting; tamoxifen; down regulation; real time polymerase chain reaction; upregulation; oxidative stress; rodent; cd4 antigen; tumor growth; tumor; cell suspension; hypoxia inducible factor 1alpha; glycolysis; retrovirus infection; von hippel lindau protein; genomic dna; biogenesis; carcinogen; cell; tumor microenvironment; ribosome; mammalian target of rapamycin complex 1; aggressiveness; gene ontology; hypoxia inducible factor 2alpha; article; rna sequencing; lipoprotein metabolism; lentivirus infection; cell proliferation assay |
| Journal Title: | Nature Communications |
| Volume: | 11 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2020-08-17 |
| Start Page: | 4111 |
| Language: | English |
| DOI: | 10.1038/s41467-020-17873-3 |
| PUBMED: | 32807776 |
| PROVIDER: | scopus |
| PMCID: | PMC7431415 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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