title: Formation of Renal Cysts and Tumors in Vhl/Trp53-Deficient Mice Requires HIF1α and HIF2α.
abstract: The von Hippel-Lindau (VHL) tumor suppressor gene is inactivated in the majority of clear cell renal cell carcinomas (ccRCC), but genetic ablation of Vhl alone in mouse models is insufficient to recapitulate human tumorigenesis. One function of pVHL is to regulate the stability of the hypoxia-inducible factors (HIF), which become constitutively activated in the absence of pVHL. In established ccRCC, HIF1α has been implicated as a renal tumor suppressor, whereas HIF2α is considered an oncoprotein. In this study, we investigated the contributions of HIF1α and HIF2α to ccRCC initiation in the context of Vhl deficiency. We found that deleting Vhl plus Hif1a or Hif2a specifically in the renal epithelium did not induce tumor formation. However, HIF1α and HIF2α differentially regulated cell proliferation, mitochondrial abundance and oxidative capacity, glycogen accumulation, and acquisition of a clear cell phenotype in Vhl-deficient renal epithelial cells. HIF1α, but not HIF2α, induced Warburg-like metabolism characterized by increased glycolysis, decreased oxygen consumption, and decreased ATP production in mouse embryonic fibroblasts, providing insights into the cellular changes potentially occurring in Vhl mutant renal cells before ccRCC formation. Importantly, deletion of either Hif1a or Hif2a completely prevented the formation of renal cysts and tumors in Vhl/Trp53 mutant mice. These findings argue that both HIF1α and HIF2α exert protumorigenic functions during the earliest stages of cyst and tumor formation in the kidney. Cancer Res; 76(7); 2025-36. ©2016 AACR.
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Désirée
authors.initials: D
authors.lastname: Schönenberger
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Harlander
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Michal
authors.initials: M
authors.lastname: Rajski
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. Health and Physical Education, School of Teaching and Learning, Western Carolina University, Cullowhee, North Carolina.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Jacobs
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Anne-Kristine
authors.initials: AK
authors.lastname: Lundby
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Mojca
authors.initials: M
authors.lastname: Adlesic
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Tomas
authors.initials: T
authors.lastname: Hejhal
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Carsten
authors.initials: C
authors.lastname: Lundby
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. ian.frew@access.uzh.ch.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Frew
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497446:VHL protein, human