HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice.
3T3 Cells
Animals
Basic Helix-Loop-Helix Transcription Factors
/ genetics
Blotting, Western
CD8-Positive T-Lymphocytes
/ metabolism
Carcinoma, Renal Cell
/ genetics
Cell Line, Tumor
Cell Proliferation
/ genetics
Gene Expression Regulation, Neoplastic
/ genetics
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
/ genetics
Immunohistochemistry
Inflammation
/ genetics
Kidney Neoplasms
/ genetics
Mass Spectrometry
Mice
Proteomics
/ methods
Real-Time Polymerase Chain Reaction
Sequence Analysis, RNA
Tumor Microenvironment
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 08 2020
17 08 2020
Historique:
received:
27
01
2020
accepted:
21
07
2020
entrez:
19
8
2020
pubmed:
19
8
2020
medline:
9
9
2020
Statut:
epublish
Résumé
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
Identifiants
pubmed: 32807776
doi: 10.1038/s41467-020-17873-3
pii: 10.1038/s41467-020-17873-3
pmc: PMC7431415
doi:
Substances chimiques
Basic Helix-Loop-Helix Transcription Factors
0
Hypoxia-Inducible Factor 1, alpha Subunit
0
endothelial PAS domain-containing protein 1
1B37H0967P
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4111Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
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