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

  • Hoefflin R Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Harlander S Institute of Physiology, University of Zurich, Zurich, Switzerland.
  • Schäfer S Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Metzger P Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • Kuo F Immunogenomics & Precision Oncology Platform (IPOP), Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Schönenberger D Institute of Physiology, University of Zurich, Zurich, Switzerland.
  • Adlesic M Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Peighambari A Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Seidel P Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Chen CY Institute for Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Consenza-Contreras M Institute for Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Jud A Department of General and Visceral Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Lahrmann B Hamamatsu Tissue Imaging and Analysis (TIGA) Center, BioQuant, University of Heidelberg, Heidelberg, Germany.
  • Grabe N Hamamatsu Tissue Imaging and Analysis (TIGA) Center, BioQuant, University of Heidelberg, Heidelberg, Germany.
  • Heide D Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Uhl FM Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Chan TA Immunogenomics & Precision Oncology Platform (IPOP), Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Duyster J Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Zeiser R Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Schell C Institute for Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Heikenwalder M Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Schilling O Institute for Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Hakimi AA Immunogenomics & Precision Oncology Platform (IPOP), Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Boerries M Institute of Medical Bioinformatics and Systems Medicine, Medical Centre-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Frew IJ Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. ian.frew@uniklinik-freiburg.de.
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  • 2020-08-19
Published in:
  • Nature communications. - 2020
3T3 Cells
Animals
Basic Helix-Loop-Helix Transcription Factors
Blotting, Western
CD8-Positive T-Lymphocytes
Carcinoma, Renal Cell
Cell Line, Tumor
Cell Proliferation
Gene Expression Regulation, Neoplastic
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
Immunohistochemistry
Inflammation
Kidney Neoplasms
Mass Spectrometry
Mice
Proteomics
Real-Time Polymerase Chain Reaction
Sequence Analysis, RNA
Tumor Microenvironment
English 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.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/260858
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