Hypoxia‐inducible factor‐2α regulates intestinal inflammation and colon cancer

Abstract

A combination of a disturbed function of the intestinal epithelial barrier and a dysregulation of the mucosal immune system are critical in the pathogenesis of Inflammatory bowel disease (IBD). Moreover, IBD is a major risk factor for colorectal cancer. Significant increases in focal hypoxia and its associated transcription factors have been observed during the pathogenesis of colitis and colon cancer. Regulation of hypoxia‐mediated genes is dependent on the nuclear transcription factor, hypoxia‐inducible factor (HIF)1α and HIF2α. HIF1α has been shown to be critical in maintaining the integrity of intestinal epithelial barrier during the pathogenesis of colitis. However, the role of HIF2α in inflammatory lesions in the intestine and colorectal cancer remains less clear. Here we developed novel mouse models with intestine‐specific gain‐of‐function and loss‐of‐function of HIF2α to investigate the role of HIF2α in experimental colitis and colon tumorigenesis. Activation of HIF2α potentiated inflammation, whereas deletion of HIF2α attenuated inflammation in an acute model of colitis. Moreover, HIF2α was critical in the apoptotic response following tissue injury. Since, chronic inflammation is major risk factor for colon cancer and HIF2α was shown to be critical in intestinal inflammation and apoptosis, studies assessing the role of HIF2α in colon carcinogenesis were also performed. The data demonstrated that activation of HIF2α increases colon tumor multiplicity, incidence, and progression. Together, our data suggest an important role of HIF2α as a molecular link between intestinal inflammation and cancer.