剪接因子YT521在子宫内膜癌中的临床意义及作用机制

The alternative splicing of pre-mRNA will generate protein isoforms with distinct structures, functions and expressing levels. Splicing factors are important regulators in this process. Abnormality of splicing events and splicing factors exert significant impacts on tumorigenesis and many of them are convinced as tumor biomarker or therapeutic targets. Endometrial cancer (EC) which is one of the most common female malignances and has a high recurrence rate is still in demand of effective prognostic factors to optimize its clinical interventions. The splicing factor YT521 might play a role as independent prognostic factor in EC according to previous regressive research. In this project the clinical implications, targets and mechanisms of YT521 in EC will be further studied. Moreover the specific splicing events in EC will be genome-wide identified through exon-arrays, so as to pick out the potential diagnostic marker and therapeutic targets of EC. Taken together this project will contribute to comprehensively understand the underlying molecular mechanisms of tumorigenesis and possess a profound significance in both clinical and theoretical levels.

前体mRNA 通过选择性剪接产生不同异构体进而影响其蛋白产物的结构、功能和表达水平，剪接因子在这个过程中发挥着重要调节作用。异常选择性剪接事件与剪接因子水平都与癌症的发生发展过程相关，许多基因的剪接异构体和剪接因子本身已被确定为肿瘤标记物和治疗靶向。内膜癌复发率高，目前尚缺乏有效预后因子来指导临床治疗。前期回顾性研究表明剪接因子YT521可能被确立为内膜癌独立的预后因子。本项目进一步研究YT521在内膜癌中的临床意义、作用目标和调节机制，并通过外显子芯片在基因组范围内筛查内膜癌中特异的选择性剪接事件，为内膜癌提供新的诊断标记物和治疗靶向，有助于进一步理解内膜癌发生发展过程中的分子机制，具有重要的临床实践和理论指导意义。

子宫内膜癌因其高度侵袭性的特征而具有较高的恶性程度。血管内皮生长因子A（VEGF-A）的mRNA的剪接与内膜癌的血管生成及侵袭有关。近期以来，我们发现预后差的子宫内膜癌组织中YT521水平较高。YT521是一种新发现的剪接蛋白，其在VEGF-A的剪接中的机制尚未明确。内膜癌组织中的YT521水平与其相邻的正常内膜组织有显著差异，呈高表达。同样的，内膜癌转移灶中的YT521也呈高表达。同时我们发现，YT521的高表达与预后不良有关。为了检测YT521在内膜癌组织中是否与VEGF-A的mRNA的剪接有关，我们在HEC-1A细胞系中转染不同水平的YT521，并且发现被转染细胞中VEGF-165相较于VEGF-121的mRNA转录和蛋白表达水平都有提高，且与YT521的转染量相关。该结果表明YT521能使VEGF-A的mRNA剪接倾向于VEGF-165。更重要的是，细胞迁移实验的结果表明，YT521通过增高VEGF-165的表达强化了子宫内膜癌细胞的侵袭性。VEGF-165过表达但VEGF-121低表达时，内膜癌细胞的侵袭性得到增强。综上，子宫内膜癌组织中VEGF-165与VEGF-121的表达与YT521有关，YT521调节了VEGF-A的mRNA的剪接，从而促进子宫内膜癌的生长。