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

Rouven Hoefflin, Sabine Harlander, Silvia Schäfer, Patrick Metzger, Fengshen Kuo, Désirée Schönenberger, Mojca Adlesic, Asin Peighambari, Philipp Seidel, Chia-yi Chen, Miguel Consenza-Contreras, Andreas Jud, Bernd Lahrmann, Niels Grabe, Danijela Heide, Franziska M. Uhl, Timothy A. Chan, Justus Duyster, Robert Zeiser, Christoph Schell, Mathias Heikenwalder, Oliver Schilling, A. Ari Hakimi, Melanie Boerries and Ian J. Frew ()
Additional contact information
Rouven Hoefflin: Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg
Sabine Harlander: University of Zurich
Silvia Schäfer: Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg
Patrick Metzger: University of Freiburg
Fengshen Kuo: Immunogenomics & Precision Oncology Platform (IPOP), Memorial Sloan Kettering Cancer Center
Désirée Schönenberger: University of Zurich
Mojca Adlesic: Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg
Asin Peighambari: Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg
Philipp Seidel: Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg
Chia-yi Chen: Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg
Miguel Consenza-Contreras: Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg
Andreas Jud: Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg
Bernd Lahrmann: University of Heidelberg
Niels Grabe: University of Heidelberg
Danijela Heide: German Cancer Research Center (DKFZ)
Franziska M. Uhl: Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg
Timothy A. Chan: Immunogenomics & Precision Oncology Platform (IPOP), Memorial Sloan Kettering Cancer Center
Justus Duyster: Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg
Robert Zeiser: Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg
Christoph Schell: Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg
Mathias Heikenwalder: German Cancer Research Center (DKFZ)
Oliver Schilling: Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg
A. Ari Hakimi: Immunogenomics & Precision Oncology Platform (IPOP), Memorial Sloan Kettering Cancer Center
Melanie Boerries: Medical Centre—University of Freiburg, Faculty of Medicine, University of Freiburg
Ian J. Frew: Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg

Nature Communications, 2020, vol. 11, issue 1, 1-21

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-020-17873-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17873-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-17873-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().