染色质重塑相关基因APC在子宫内膜癌免疫应答中的作用及分子机制

子宫内膜癌发病率在我国乃至全球呈上升态势,严重威胁女性生殖健康。当前迅猛发展的免疫治疗并未在子宫内膜癌的治疗中取得显著成果。申请人前期研究利用二代测序技术对相关癌组织进行520个肿瘤相关基因的检测，发现肿瘤免疫微环境的变化（肿瘤突变负荷，PD-L1 表达以及微卫星不稳定）与染色质重塑相关基因APC的突变密切相关。但APC与子宫内膜癌免疫微环境相互作用及其调控的分子机制仍不清楚。在前期研究基础上将模拟临床发现的APC突变形式，构建APC突变型内膜癌细胞系，通过体外细胞和体内动物实验分析APC突变在表观遗传学层次上调控靶基因信号的网络途径，以及APC蛋白与染色质及相关转录因子互作机制，深入探讨APC突变对内膜癌免疫微环境动态变化及免疫应答的影响，评估其作为免疫治疗标志物的可行性和准确性。本研究有望阐明APC突变在内膜癌的发生发展过程中的作用机制，为子宫内膜癌的免疫治疗提供新的治疗靶点和理论依据

Endometrial cancer seriously threatens female reproductive health, whose incidence is on the rise in both China and the world. The rapid development of immunotherapy has not achieved significant results in the treatment of endometrial cancer. In our previous research, we used next-generation sequencing technology to detect 520 tumor-related genes in endometrial cancer tissues, and we found the tumor immune microenvironment, including tumor mutation load, PDL-1 expression and microsatellite instability, strong linked to the mutation of the chromatin remodeling related gene APC. However, the molecular mechanism of the interaction between APC and the immune microenvironment in the endometrial cancer is still unclear. In this project, we will first generate APC mutation endometrial cancer cell lines by expressing the plasmids that carrying APC mutations in human EC, then analyze the APC mutation epigenetically regulate the global chromatin occupancy and RNA transcription as well as the molecular interaction between APC mutations, chromatin and transcription factors. Furthermore, we will explore the effect of APC mutation on the immune microenvironment and immune response of endometrial cancer to evaluate the feasibility and accuracy of APC as a marker of immunotherapy. This study is expected to clarify the three-dimensional molecular mechanism of APC mutation in endometrial cancer, and provide new therapeutic targets and solid theoretical basis for immunotherapy of endometrial cancer.