胃癌中Synbindin调节肿瘤相关巨噬细胞极化及功能的研究

Tumor-associated macrophage (TAM) is an important component of tumor microenvironment, which participants in development and progression in gastric cancer (GC) and closely correlates with the prognosis and survival of GC patients. Previous studies indicated that Synbindin functioned as scaffold protein which regulates the activation of ERK/MAPK so as to affect development and progression of GC. Furthermore there is significant co-localization and positive correlation both in Synbindin and p50 expression in human GC tissues via dual-immunofluorescence staining. Synbindin and CD11b also showed partly co-localization in the stroma of GC. All these clues indicate that Synbindin might play a role in tumor microenvironment of GC. What’s the relationship between Synbindin and TAMs? Whether Synbindin regulates the polarization of TAMs? How does Synbindin regulate TAMs to induce malignant phenotype of GC cells and what’s the exact mechanisms? We attempt at explaining these questions by means of immunofluorescence staining, flow cytometry analysis in peripheral blood mononuclear cells, immunity induction by chemicals and cytokines, co-culture of immune cells and gastric cancer cells, and gene interference in GC xenograft model, for the purpose of discovering and establishing molecular targets of prevention and therapy in gastric cancer.

肿瘤相关巨噬细胞（TAMs）是肿瘤微环境的重要组成部分，它在胃癌的发生发展中发挥了重要作用，且数量与胃癌患者的预后生存密切相关。前期研究发现Synbindin作为ERK/MAPK通路的脚手架蛋白调节其活性从而影响胃癌的发生发展，此外通过免疫荧光染色发现Synbindin与p50表达在胃癌组织中存在明显的共定位和正相关性，且间质中Synbindin与CD11b亦存在部分共定位，提示胃癌的肿瘤微环境中Synbindin可能发挥某种作用。那Synbindin与TAMs是否存在正相关性？Synbindin是否调节了TAMs极化的过程？ Synbindin调节TAMs诱导胃癌细胞恶性表型的具体机制是什么？本研究将通过免疫荧光、PBMC流式分析、免疫化学诱导、免疫细胞与胃癌细胞共培养及裸鼠胃癌移植瘤模型中基因干预等方法解答上述问题，为进一步发现和确立胃癌分子预防与治疗的新靶点提供实验依据。

肿瘤相关巨噬细胞(TAMs)是肿瘤微环境的重要组成部分，它在胃癌的发生发展中发挥了重要作用，且数量与胃癌患者的预后生存密切相关。前期研究发现Synbindin作为ERK/MAPK通路的脚手架蛋白调节其活性从而影响胃癌的发生发展，此外通过免疫荧光染色发现Synbindin与p50表达在胃癌组织中存在明显的共定位和正相关性，且间质中Synbindin与CD11b亦存在部分共定位，提示胃癌的肿瘤微环境中Synbindin可能发挥某种作用。本研究中，胃癌组织中synbindin与巨噬细胞表面分子有共定位，两者存在正相关关系。在THP-1细胞中敲除Synbindin后，加IL-4分化成M2型细胞数明显减少；M2型标志物(Arg1，Mrc2，IL-10， CCL22)的mRNA水平降低, 细胞上清中炎症因子 IL-10、 CCL22 明显降低。THP-1 细胞诱导 TAMs 后，敲低 Synbindin，将其与胃癌细胞共培养后，胃癌细胞增殖减慢，侵袭功能降低。进一步的机制研究显示分化后的THP-1敲低Synbindin，MAPK 通路(p-ERK/p-P38/p-JNK)表达水平明显减少。THP-1中Synbindin的水平降低会减少THP-1向M2型巨噬细胞的分化，抑制代表M2型巨噬细胞的炎症因子分泌，并能抑制共培养中胃癌细胞的恶性表型。Synbindin可能是胃癌防治的新靶点。