雌激素调控MTA1介导的上皮-间质转化与肝癌转移及复发关系的研究

Invasion and metastasis is one of main reasons of the affecting efficacy and long-term survival of hepatocellular carcinoma which is a cancer of gender differences in incidence. MTA1 has been a recently discovered metastasis-related gene, enhancing tumor infiltration into the surrounding and remote tissues by promoting cell migration. In this study, human HCC tissue samples will be involved to determine gender disparity of incidence and to analyze the correlation among MTA1 expression and carcinogenesis, recurrence and metastasis. Wide type and ERα binding site mutation MTA1 promoter will be cloned into luciferase reporter gene system to determine the transcription regulation of MTA1 by estrogen. MTA1 overexpression and gene silencing cell model will be further established by the molecular biology techniques, combining with orthotopic liver implantation model to observe the effect of MTA1 on EMT and related cell invasion and metastasis. At last, the possible mechanism of MTA1 on EMT will be explored by transcriptomic screen, and will be verified through the relevant cells and animal models. Clarification of the mechanism of the impact of MTA1 on metastasis and recurrence of HCC via EMT will be benefit for lying theoretical basis for developing novel therapeutic targets.

肝癌的高侵袭转移是影响其疗效和长期生存的主要原因之一，其发病具有明显的性别差异。MTA1是近年发现的肿瘤转移相关基因，能够促进肿瘤细胞迁移并向周围及远端组织浸润。本研究拟利用人肝癌组织标本研究MTA1与肝癌发生、转移和复发之间的关系及其表达的性别差异，并构建MTA1启动子相关的荧光虫素酶报告基因系统，通过对ERα可能结合的序列作突变处理，研究雌激素对MTA1转录的调控。进一步利用分子生物学技术构建MTA1过表达及基因沉默的细胞模型，利用裸鼠原位肝种植瘤模型观察MTA1对EMT和肝癌侵袭转移的影响，通过组学的方法探讨MTA1对EMT的可能作用机制，并通过相关细胞及动物模型加以验证，以便进一步阐明MTA1通过调节EMT影响肝癌转移和复发的分子机制，在为解释肝癌的转移和复发提供新的机制的同时，也为寻找新的治疗靶点提供依据。