ARRB2通过Rac1诱导结直肠癌细胞伪足形成逃离NK细胞免疫杀伤的机制研究

结直肠癌是全球高发的恶性肿瘤，其发病率和死亡率逐年升高，NK细胞的免疫治疗为晚期结直肠癌患者带来了长期生存的希望。本项目发现当NK细胞靠近结直肠癌细胞时，癌细胞会以形成伪足的方式逃离NK细胞的免疫杀伤，我们发现主要是由于NK细胞分泌的细胞因子促进肿瘤细胞内ARRB2的表达及聚集，ARRB2通过与Rac1结合，激活Rho/ROCK信号通路，从而促进细胞骨架重组，诱导伪足形成，最终发生免疫逃逸。这部分内容国内外未见报道，本课题将通过分子病理学及分子生物学方法，结合体内外实验及临床组织标本，从细胞、分子、动物及临床四个层面，全方位阐明ARRB2在结直肠癌细胞发生发展、侵袭转移及细胞伪足形成中的功能，明确ARRB2与Rac1调控细胞骨架重组及伪足形成的机制，提供肿瘤细胞通过ARRB2诱导细胞伪足形成逃离NK细胞免疫杀伤的直接证据，以期为结直肠癌患者的治疗和药物筛选提供理想的靶点。

The incidence rate and mortality rate of colorectal cancer are increasing year by year. The immunotherapy of NK cells has brought long-term survival hope for patients with advanced colorectal cancer. In this project, we found that when NK cells are close to colorectal cancer cells, the cytokines secreted by NK cells can promote the expression and aggregation of arrb2 in tumor cells. By combining with Rac1, arrb2 can activate Rho / rock signal pathway, thus promoting the reorganization of cytoskeleton, inducing the formation of cell pseudopods, and finally generating immune escape. This part of content has not been reported. In our study, we will use molecular pathology and molecular biology methods, in combination with in vivo and in vitro experiments and clinical tissue samples, study the function of ARRB2 in the proliferation, metastasis and pseudopodia formation of colorectal cancer cells from four aspects of cell, molecule, animal and clinic, clarify the mechanism of ARRB2 and Rac1 regulating cytoskeleton recombination, and clarify the role of ARRB2 in escaping from NK cell immunokilling by inducing pseudopodia formation, so as to provide theoretical basis for the treatment and drug screening of colorectal cancer patients.