A knockout of factor inhibiting HIF in the colon epithelium did not affect tumor growth but significantly reduced recruitment of inflammatory cells and disease progress in DSS-induced chronic colitis.

BACKGROUND AND AIMS: Inflammatory bowel disease such as chronic colitis promotes colorectal cancer which is the fourth most common cause of cancer mortality worldwide. Hypoxia is a characteristic of inflammation as well as of solid tumors and enforces a gene expression response controlled by transcription factors called hypoxia-inducible factors (HIFs). While HIF activity is known to promote cancer development, both prolyl hydroxylases and an asparaginyl hydroxylase termed factor-inhibiting HIF (FIH) negatively regulate it. Thus, FIH may act as a tumor suppressor in colorectal cancer development by repressing the HIF-1 pathway. Herein, we studied the role of colon epithelial FIH in a mouse model of colitis-induced colorectal cancer.METHODS: We recapitulated colitis-associated colorectal cancer development in mice using the azoxymethane/dextran sodium sulfate model in Vil1-Cre/FIH +f/+f and wildtype siblings. Animals were treated with two intraperitoneal injections of azoxymethane and with two 5-day/one 4-day cycle of 1.5% dextran sodium sulfate in drinking water. Colon samples were analyzed regarding RNA and protein expression and histology.RESULTS: Vil1-Cre/FIH+f/+f mice showed a less severe colitis progress compared to FIH+f/+f animals and a lower number of infiltrating macrophages in the inflamed tissue. RNA-Seq analyses of colon tissue revealed a lower expression of genes associated with the immune response in Vil1-Cre/FIH+f/+f mice. However, tumor occurrence did not significantly differ between Vil1-Cre/FIH+f/+f and wildtype mice. CONCLUSION: FIH knockout in colon epithelial cells did not modulate colorectal cancer development but reduced the inflammatory response in chronic colitis.