基于Mal依赖的IFNγR1/p38 MAPK/STAT1通路诱导巨噬细胞极化探讨杨梅素抑制结肠癌的作用机制

结肠癌为常见消化道恶性肿瘤，现有药物疗效欠佳。诱导巨噬细胞向M1表型极化可以增加抗肿瘤疗效，但巨噬细胞极化在结肠癌发病中的机制尚不明确。我们发现，杨梅素可促使MyD88与IFNγR1通过Mal连接形成异二聚体，引发p38MAPK及STAT1磷酸化，进而诱导M2型巨噬细胞向M1转化。基于p38MAPK活化可引起STAT1磷酸化，而STAT1磷酸化引发巨噬细胞M1极化，藉此提出“Mal依赖的IFNγR1/p38MAPK/STAT1信号诱导巨噬细胞M1极化抑制结肠癌”假说。由于结肠癌患者体内低IFN-γ水平阻碍IFN-γ/STAT1信号活化及由此引发的巨噬细胞M1极化，而杨梅素可重启巨噬细胞极化功能，抑制结肠癌进展。拟采用CRISPR、p38MAPK抑制剂、siRNA及过表达质粒转染等方法，抑制异二聚体形成及相关信号通路，从细胞和动物水平探讨诱导巨噬细胞M1极化的新通路及杨梅素抗结肠癌作用机制。

Colon cancer is a common malignant tumor in the digestive tracts. The current drugs are not very effective against colon cancer. Drugs of inducing phenotypic polarization of macrophages contributes to improve the anti-tumor effects, but mechanism of macrophage polarization in the pathogenesis of colon cancer is still unknown. Our preliminary study found that myricetin induced macrophage polarization from M2 to M1 phenotype. MyD88 was associated with IFNγR1 induced by myricetin to form the heterodimer, which was mediated by Mal. Besides, the phosphorylation of p38 MAPK and STAT1 was improved by myricetin. It is reported that activated p38 MAPK induces phosphorylation of STAT1 and the phosphorylation of STAT1 induces M1 macrophage polarization. We thus put forward the hypothesis of “Activating IFNγR1/p38 MAPK/STAT1 signaling pathway mediated by Mal induces M1 macrophage polarization and inhibits colon cancer progression.” Because of the low level of IFN-γ in colon cancer patients, M1 macrophage polarization induced by IFN-γ/STAT1 signaling is limited. Myricetin might induce macrophage polarization and inhibit colon cancer progression thought this pathway mediated by Mal. We intend to utilize CRISPR, p38 MAPK inhibitor, siRNA and plasmid transfection to inhibit the heterodimer formation and related signaling pathway. We try to explore a new signaling pathway of M1 macrophage polarization and study the effects of myricetin against colon cancer at the cellular and animal levels.