The Transcription Factor IRF9 Promotes Colorectal Cancer via Modulating the IL-6/STAT3 Signaling Axis

SIMPLE SUMMARY: Colorectal cancer (CRC) is the second most common cause of cancer-related death worldwide. While the exact causes and prognosis of CRC are complex, colonic inflammation is the major predisposing factor for the development of CRC. The aim of our study was to investigate the physiological function of interferon regulatory factor 9 (IRF9) in CRC. We found that mice deficient in IRF9 developed fewer tumors compared with their corresponding WT littermates in mouse models of CRC. Mechanistically, IRF9 was required for IL-6 production which drove the activation of STAT3, leading to the development of tumors in the colon. Overall, these findings will be important to inform the development of therapeutic strategies to improve outcomes for patients with this deadly cancer and other diseases where the IRF9-mediated production of IL-6 can be therapeutically modulated. ABSTRACT: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, and innate immune responses and inflammation are known to affect the course of disease. Interferon (IFN) signaling in particular is critical for modulating inflammation-associated diseases including CRC. While the effects of IFN signaling in CRC have been studied, results have been conflicting. Furthermore, individual molecules in the IFN pathway that could be therapeutically targeted have distinct functions, with many of their diverse roles in CRC remaining unclear. Here, we found that IRF9 had an oncogenic effect in CRC; loss of IRF9 reduced tumorigenesis in both azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced and spontaneous CRC models. IRF9 also reduced DSS-induced colitis and inflammation in the colon, but it had no effect on the NF-κB and MAPK signaling activation. Instead, IRF9 enhanced the transcription and production of the inflammatory cytokine IL-6. By promoting IL-6 release, IRF9 drove the activation of pro-oncogenic STAT3 signaling in the colon. Overall, our study found that IRF9 promoted the development of CRC via modulation of the IL-6/STAT3 signaling axis, identifying multiple potential targets and suggesting new therapeutic strategies for the treatment of CRC.