Activation of HIF2 alpha in Kidney Proximal Tubule Cells Causes Abnormal Glycogen Deposition but not Tumorigenesis

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-1 alpha (HIF1 alpha) and HIF2 alpha 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 HIF2 alpha (P405A, P530A, and N851A, named as HIF2 alpha M3) in the proximal tubules of mice is not sufficient to promote ccRCC by itself, nor does it enhance HIF1 alpha M3 oncogenesis when coexpressed with constitutively active HIF1 alpha M3. Neoplastic transformation in kidneys was not detected at up to 33 months of age, nor was increased expression of Ki67 (MKI67), gH2AX (H2AFX), or CD70 observed. Furthermore, the genome-wide transcriptome of the transgenic kidneys does not resemble human ccRCC. We conclude that a constitutively active HIF2 alpha is not sufficient to cause neoplastic transformation of proximal tubules, arguing against the idea that HIF2 alpha activation is critical for ccRCC tumorigenesis. (C) 2013 AACR.