miR-125a-5p调控BRMS1基因表达在胃癌侵袭转移机制中的作用研究

Gastric cancer (GC) is the main cause of cancer death in China, peritoneal metastasis indicates a poor prognosis in GC patients, but the mechanism responsible for metastatic dissemination has not been elucidated. Our previous work found that the levels of BRMS1 expression were significantly lower in GC tissue with peritoneal metastasis than in those without peritoneal metastasis. Additionally, we found that the upregulation of BRMS1 effectlively suppressed the gastric cancer cell lines invasion and migration. However, the molecular mechanisms by which BRMS1 is downregulated and promotes gastric cancer peritoneal metastasis remain to be clearly elucidated. The study on miRNAs has provides a new idea for the mechanisms of gene regulation. We found that upregulating miR-125a-5p expression increases BRMS1 protein and mRNA expression in GC cells, and miR-125a-5p likely targeting BRMS1. In this study, the effect of miR-125a-5p expression on GC cell invasion and peritoneal metastasis will be investigated in GC cell line and nude mice, also the molecular mechanism of miR-125a-5p on GC cell metastasis through targeting BRMS1 will be studied. This study will provide new strategies for prevention and treatment of GC peritoneal metastasis.

胃癌是我国发病率、死亡率较高的恶性肿瘤之一。腹膜转移是其预后不良的主要原因，当前关于胃癌腹膜转移的机制仍未阐明。BRMS1是一种肿瘤转移抑制基因，我们前期研究证实BRMS1 在有腹膜转移的胃癌组织中低表达，上调BRMS1 的表达能够明显降低SGC-7901细胞裸鼠胃癌模型的腹膜转移，但其调控机制尚不明确。我们通过生物信息学软件预测发现BRMS1 很可能是miR-125a-5p的靶基因，在上调胃癌细胞中miR-125a-5p的表达后，BRMS1 表达水平显著上调。因此，我们推测miR-125a-5p可以调控其靶基因BRMS1表达而影响胃癌细胞的侵袭转移。本研究拟从分子细胞及整体水平，通过观察miR-125a-5p过表达或低表达对胃癌细胞BRMS1蛋白变化及迁移侵袭能力和腹膜种植转能力的影响，探讨其具体调控机制，以求证实我们的推测。该研究的顺利完成将为胃癌腹膜转移防治提供新思路和新干预环节。

腹膜转移是导致胃癌患者预后不良的主要原因。乳腺癌转移抑制基因1（BRMS1）是一种肿瘤转移抑制基因，在前期的研究中我们发现BRMS1在有腹膜转移的胃癌组织中低表达，上调BRMS1的表达能够明显降低SGC-7901细胞裸鼠胃癌模型的腹膜转移。在本研究中，我们发现miR-125a-5p在胃癌细胞和胃癌组织中较正常胃粘膜细胞和正常胃粘膜组织表达下调，并且其表达与淋巴转移、腹膜转移、TNM分期及患者总生存时间相关；MiR-125a-5p可以与BRMS1的5’UTR靶向结合并促使其翻译，并影响胃癌细胞的侵袭迁移能力，参与胃癌转移进程。此后，生物信息学和分子生物学方法发现组蛋白甲基化修饰蛋白EZH2是导致miR-125a低表达的重要机制，拷贝数变异和启动子甲基化是影响BRMS1表达的主要机制，而miR-125a/BRMS1信号轴受到表观遗传的多重调控，影响着胃癌的侵袭转移。该研究为明确胃癌侵袭转移的机制及防治胃癌进展提供了新思路和新的干预措施。