LncRNA FARSA-AS1通过SRSF6蛋白调控Musashi2可变剪接促进结肠癌转移的机制研究

肿瘤转移是手术无法达到根治效果，造成患者生存时间降低的根本原因。我们前期研究证实LncRNA FARSA-AS1-SOX9/FARSA信号轴和Musashi2在结肠癌转移中发挥关键作用，预实验发现FARSA-AS1与剪接蛋白SRSF6的表达呈正相关，且与结肠癌的不良预后密切相关。通过序列比对在Musashi2基因第11号外显子上发现SRSF6的RNA结合基序的剪切位点，提示SRSF6蛋白能够增加其截短型异构体的生成。故提出科学假说：FARSA-AS1作用于剪接蛋白SRSF6，促进Musashi2第12和13号外显子的剪切跳跃，通过增加Musashi2截短型异构体进而促进结肠癌侵袭和转移。本课题拟从细胞实验、动物实验和临床研究三个层次重点探讨：(1)FARSA-AS1调控剪接蛋白SRSF6的机制；(2)SRSF6调控Musashi2可变剪接的机制，有望为精准防治结肠癌的转移提供新的治疗策略。

Tumor metastasis is the fundamental reason that surgery can not achieve the effect of radical treatment and reduce the survival time of patients. Our previous study confirmed that LncRNA FARSA-AS1-SOX9/FARSA signal axis and Musashi2 played a key role in the metastasis of colon cancer. Pre-experiment found that FARSA-AS1 was positively correlated with the expression of splicing protein SRSF6, and closely related to the poor prognosis of colon cancer. The splicing site of SRSF6 RNA binding motif in exon 11 of Musashi2 gene was found by sequence alignment, which suggested that SRSF6 protein could increase the production of truncated isomers. Therefore, we propose a scientific hypothesis: FARSA-AS1 acts on splicing protein SRSF6 to promote the splicing-jumping of exons 12 and 13 of Musashi2, thereby promoting the invasion and metastasis of colon cancer by increasing the truncated isomer of Musashi2. This project will focus on the following three levels (cell experiment, animal experiment and clinical research) to discuss: (1) the mechanism of FARSA-AS1 regulating splicing protein SRSF6; (2) the mechanism of SRSF6 regulating Musashi2 alternative splicing, which is expected to provide a new therapeutic strategy for the precise prevention and treatment of metastasis of colon cancer.