Pharmacological inhibition of IRAK1 attenuates colitis‐induced tumorigenesis in mice by inhibiting the inflammatory response and epithelial–mesenchymal transition

Colorectal cancer (CRC) is the third most common type of cancer. Here, we studied the inhibitory effect of IRAK1 and IRAK4 as a preventive strategy using a colitis-induced tumorigenesis mouse model. CRC clinical data were obtained from the Gene Expression Omnibus (GEO). An experimental inflammation-dependent CRC model was induced by treatment with azoxymethane (AOM) and then dextran sodium sulfate (DSS) in C57BL/6 mice. Mice were administered an IRAK1/4 inhibitor by intraperitoneal injection at 3 mg/kg twice each week for 9 weeks. The IRAK1/4 inhibitor attenuated histological changes and prevented tumor growth. Tumor-associated proteins, including p65 and Ki-67, were downregulated by the IRAK1/4 inhibitor in AOM/DSS-treated mice. Additionally, IRAK1/4 inhibitor administration effectively decreased the expression of inflammatory cytokines. Furthermore, we observed that IRAK1/4 inhibitor treatment attenuated colitis-induced tumorigenesis by inhibiting epithelial-mesenchymal transition. These observations indicate that inhibition of IRAK1 and IRAK4 may suppress experimental colitis-induced tumorigenesis by inhibiting inflammatory responses and epithelial-mesenchymal transition.