Schoenenberger 2016 Cancer Res
| SchΓΆnenberger D, Harlander S, Rajski M, Jacobs RA, Lundby AK, Adlesic M, Hejhal T, Wild PJ, Lundby C, Frew IJ (2016) Formation of renal cysts and tumors in Vhl/Trp53-deficient mice requires HIF1Ξ± and HIF2Ξ±. Cancer Res 76:2025-36. |
Schoenenberger D, Harlander S, Rajski M, Jacobs RA, Lundby AK, Adlesic M, Hejhal T, Wild PJ, Lundby C, Frew IJ (2016) Cancer Res
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, HIF1Ξ± has been implicated as a renal tumor suppressor, whereas HIF2Ξ± is considered an oncoprotein. In this study, we investigated the contributions of HIF1Ξ± and HIF2Ξ± 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, HIF1Ξ± and HIF2Ξ± differentially regulated cell proliferation, mitochondrial abundance and oxidative capacity, glycogen accumulation, and acquisition of a clear cell phenotype in Vhl-deficient renal epithelial cells. HIF1Ξ±, but not HIF2Ξ±, 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 HIF1Ξ± and HIF2Ξ± exert protumorigenic functions during the earliest stages of cyst and tumor formation in the kidney.
Β©2016 American Association for Cancer Research.
Labels: MiParea: Respiration, nDNA;cell genetics
Pathology: Cancer
Organism: Mouse
Regulation: ATP production
HRR: Oxygraph-2k
Labels, 2016-09, noPDF
