SPIN1激活IL-10诱导M2巨噬细胞极化促进胃癌浸润转移的机制研究

浸润转移是胃癌患者死亡的主要原因。申请人前期研究发现癌基因SPIN1与胃癌浸润转移密切相关，但作用机制尚不清楚。预实验结果初步表明SPIN1能激活IL-10/JAK2/STAT3通路，临床样本及生物信息学分析显示SPIN1可能与M2巨噬细胞极化有关。已知IL-10是M2巨噬细胞极化的关键因子，且分泌主要来源于巨噬细胞，我们推测:SPIN1激活IL-10后诱导M2巨噬细胞极化促使IL-10分泌增加，进而激活JAK2/STAT3信号通路，促进胃癌浸润转移。本项目将进一步完善体内外功能实验，明确SPIN1在胃癌浸润转移中的作用，通过细胞学、动物模型及临床样本三个方面阐明SPIN1通过IL-10对M2巨噬细胞及JAK2/STAT3通路的调控作用，进一步通过CO-IP、免疫荧光、ChIP、双荧光素酶等试验从转录水平探究SPIN1激活IL-10的分子机制，为胃癌浸润转移的监测和治疗提供新思路和靶点。

Invasive and metastasis is the main cause of death in patients with gastric cancer. The applicant’s previous study found that the oncogene SPIN1 is closely related to the invasion and metastasis of gastric cancer, but the mechanism of action is still unclear. Preliminary experimental results indicate that SPIN1 can activate the IL-10/JAK2/STAT3 pathway. Clinical samples and bioinformatics analysis show that SPIN1 may be related to the polarization of M2 macrophages. It is known that IL-10 is a key factor in the polarization of M2 macrophages, and the secretion is mainly derived from macrophages. We speculate that the activation of IL-10 by SPIN1 induces the polarization of M2 macrophages, which leads to the increase of IL-10 secretion, and then activates the JAK2/STAT3 signaling pathway to promote the infiltration and metastasis of gastric cancer. This project will further improve the in vivo and in vitro functional experiments to clarify the role of SPIN1 in gastric cancer invasion and metastasis, and elucidate the regulation of SPIN1 on M2 macrophage polarization and IL-10/JAK2/STAT3 pathway through three aspects: cytology, animal models and clinical samples. Furthermore, CO-IP, immunofluorescence, ChIP, dual luciferase and other tests are used to explore the molecular mechanism of SPIN1 activating IL-10 at the transcription level. Completion of this project will provide new ideas and targets for the monitoring and treatment of gastric cancer infiltration and metastasis.