title: Activation of HIF2α in kidney proximal tubule cells causes abnormal glycogen deposition but not tumorigenesis.
abstract: Renal cell carcinoma (RCC) is the most common primary cancer arising from the kidney in adults, with clear cell renal cell carcinoma (ccRCC) representing approximately 75% of all RCCs. Increased expression of the hypoxia-induced factors-1α (HIF1α) and HIF2α has been suggested as a pivotal step in ccRCC carcinogenesis, but this has not been thoroughly tested. Here, we report that expression of a constitutively activated form of HIF2α (P405A, P530A, and N851A, named as HIF2αM3) in the proximal tubules of mice is not sufficient to promote ccRCC by itself, nor does it enhance HIF1αM3 oncogenesis when coexpressed with constitutively active HIF1αM3. Neoplastic transformation in kidneys was not detected at up to 33 months of age, nor was increased expression of Ki67 (MKI67), γH2AX (H2AFX), or CD70 observed. Furthermore, the genome-wide transcriptome of the transgenic kidneys does not resemble human ccRCC. We conclude that a constitutively active HIF2α is not sufficient to cause neoplastic transformation of proximal tubules, arguing against the idea that HIF2α activation is critical for ccRCC tumorigenesis.
authors: Department of Pharmacology and Pathology, Weill Cornell Medical College, Cornell University, New York, New York 10065, USA.
authors: Leiping
authors: L
authors: Fu
authors: Gang
authors: G
authors: Wang
authors: Maria M
authors: MM
authors: Shevchuk
authors: David M
authors: DM
authors: Nanus
authors: Lorraine J
authors: LJ
authors: Gudas
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic; D006003:Glycogen / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D007680:Kidney Neoplasms / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D006003:Glycogen; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse