M1型巨噬细胞旁分泌的SEMA3A与肿瘤细胞上新受体MST1R结合抑制结直肠癌进展的机制研究

M1型肿瘤相关巨噬细胞（TAMs）在杀伤肿瘤过程中发挥关键作用，但具体机制尚未完全阐明。我们前期发现M1型TAMs分泌SEMA3A；重组SEMA3A能抑制结直肠癌（CRC）细胞增殖和侵袭；SEMA3A能结合癌细胞上新受体MST1R，抑制PI3K/AKT信号。由此我们提出“M1型TAMs分泌的SEMA3A与CRC细胞上新受体MST1R结合，通过PI3K/AKT信号抑制细胞生长和上皮间质转化；肿瘤细胞又可诱导TAMs向M1型逆向极化，形成正反馈环路，最终抑制CRC进展”的假说。本项目将进一步利用体内外功能实验探究M1型TAMs来源的SEMA3A对CRC增殖及转移的影响；通过Co-IP等鉴定SEMA3A通过肿瘤细胞上新受体MST1R抑制CRC进程的分子机制；并初步探讨外源性SEMA3A与MST1R靶向药的联合抗肿瘤作用。本课题的顺利完成可以为CRC的防治提供重要的理论依据，具重要的临床指导意义。

M1-type tumor-associated macrophages (TAMs) plays a vital role in the regulation of anti-tumor. However, the underlying mechanisms are still elusive. Our preliminary experiments indicate that SEMA3A was mainly secreted by the M1-type macrophages, and exogenous SEMA3A could inhibit the proliferation, invasion and migration of CRC cells in vitro. SEMA3A can bind to a new receptor MST1R on CRC cells and inhibit PI3K/ Akt pathway in a dose-dependent manner.Thus, we hypothesized that "SEMA3A secreted by M1-type TAMs binds to the new tumor transmembrane receptor MST1R, and inhibits tumor cells growth and epithelial-mesenchymal transformation through PI3K/ Akt pathway. On the other hand, tumor cells can also induce the reverse polarization of TAMs to M1-type, forming a positive feedback loop, and ultimately inhibit the progression of CRC" In this study, we will further clarify the effects of SEMA3A derived from M1-type TAMs on CRC proliferation and metastasis by in vivo and in vitro functional experiments. Moreover, Co-IP, GST-pulldown and other experimental methods were adopted to further reveal the competitive mechanisms of SEMA3A in the CRC progression inhibiton through binding to the novel tumor transmembrane receptor MST1R. In addition, we will preliminarily investigate the combined anti-tumor effect of exogenous SEMA3A and MST1R targeting drugs. This research will provide an important theoretical basis for the prevention and treatment of CRC，which has an important clinical significance.