IRF3 prevents colorectal tumorigenesis via inhibiting the nuclear translocation of β-catenin

Occurrence of Colorectal cancer（CRC）is relevant with gut microbiota. However, role of IRF3, a key signaling mediator in innate immune sensing, has been barely investigated in CRC. Here, we unexpectedly found that the IRF3 deficient mice are hyper-susceptible to the development of intestinal tumor in AOM/DSS and Apcmin/+ models. Genetic ablation of IRF3 profoundly promotes the proliferation of intestinal epithelial cells via aberrantly activating Wnt signaling. Mechanically, IRF3 in resting state robustly associates with the active β-catenin in the cytoplasm, thus preventing its nuclear translocation and cell proliferation, which can be relieved upon microbe-induced activation of IRF3. In accordance, the survival of CRC is clinically correlated with the expression level of IRF3. Therefore, our study identifies IRF3 as a negative regulator of the Wnt/β-catenin pathway and a potential prognosis marker for Wnt-related tumorigenesis, and describes an intriguing link between gut microbiota and CRC via the IRF3-β-catenin axis. Colon and colon tumor tissue mRNA profiles of AOM/DSS day 90 wild type (WT) and IRF3-/- (KO) mice

结直肠癌（Colorectal cancer, CRC）的发生与肠道菌群密切相关。然而，作为固有免疫感知中的关键信号介导分子，干扰素调节因子3（Interferon Regulatory Factor 3, IRF3）在结直肠癌中的作用却鲜有研究。本研究意外发现，在氧化偶氮甲烷/葡聚糖硫酸钠（Azoxymethane/Dextran Sodium Sulfate, AOM/DSS）与ApcMin/+小鼠模型中，IRF3缺陷小鼠更易诱发肠道肿瘤。IRF3基因敲除可通过异常激活Wnt信号通路，显著促进肠上皮细胞增殖。机制上，静息状态下的IRF3可与细胞质内的活化β-连环蛋白紧密结合，从而阻止其核转位与细胞增殖；而微生物诱导的IRF3活化可解除这一抑制作用。临床数据显示，结直肠癌患者的生存率与IRF3的表达水平显著相关。综上，本研究证实IRF3是Wnt/β-连环蛋白通路的负调控因子，同时可作为Wnt相关肿瘤发生的潜在预后标志物，并揭示了肠道菌群通过IRF3-β-连环蛋白轴与结直肠癌之间的潜在关联。本数据集包含AOM/DSS造模90天后的野生型（Wild type, WT）与IRF3基因敲除（IRF3 knockout, KO）小鼠的结肠及结肠肿瘤组织的mRNA表达谱。