抑癌基因FOXO1相关microRNA与肝细胞癌发生发展的关系及机制研究

Hepatocellular carcinoma (HCC) is a most malignant tumor with high incidence in Guangxi province, which is characterized by a high invasive and recurrent rate that restricts the overall curative effect. FOXO1, a tumor-suppressor, is a vital downstream molecule of PI3K/AKT signaling pathway and play an important role in physiological regulation, metabolism, cell proliferation and apoptosis by transcriptional regulation and signal transduction. On the basis of last NSFC, we discovered polymorphism of rs17592236 in FOXO1 was associated with HCC risk and the mechanism may lie on targeted adjustment of miR-137. Base on our previous studies of FOXO1 and the current state of FOXO1-related miRNA, we hypothesized FOXO1-related miRNA may affect PI3K/AKT-FOXO1 axis by targeted FOXO1 and were associated with the development of HCC. In this study, we will conduct a massive clinical samples association study and survival analysis to find out the HCC related miRNA that targets FOXO1 and then detect their molecular mechanism in vitro, of which the result may provide new advice for early diagnosis and prognosis prediction of HCC.

肝癌是广西高发的恶性肿瘤，其高侵袭性、高转移复发性，往往是制约整体疗效的关键。抑癌基因FOXO1是PI3K/AKT信号通路中一个重要的下游分子，可通过转录调控及信号转导途径对机体的生理调节、代谢、细胞增殖和细胞凋亡等诸多方面起重要作用。在国家自然基金基础上，我们前期发现FOXO1的rs17592236位点多态性与肝癌发生有关，其机制可能通过与miRNA-137靶向调节有关。本项目基于前期对FOXO1基因研究及其相关miRNA研究的最新现状，提出FOXO1基因相关miRNA可能通过靶向调节FOXO1影响PI3K/AKT-FOXO1信号轴与肝癌发生发展发生关联，拟采用大规模临床肝癌样本的关联研究和预后生存分析筛选肝癌相关并可靶向结合FOXO1的miRNA,再通过体外细胞实验探索其相关机制，为肝癌早期诊断和预后预测提供新的依据。

肝癌高居我国肿瘤死因顺位的第二位，其发生发展的分子机制仍未阐明。肝细胞癌是肝癌中最常见的类型。本研究按计划首先在肝癌与癌旁组织检测FOXO1及8个相关miRNAs表达情况，发现FOXO1在肝癌中低表达，选取在肝癌中表达增高miR-18a进行进一步的研究，结果发现该miRNA虽然在肝癌中高表达，但是仅影响了肝癌细胞系的增殖能力，而对FOXO1基因表达及蛋白表达均无影响。在此项目资助，对肿瘤研究领域的热点问题进行了探索，利用lncRNA芯片筛选出多个肝癌相关的lncRNAs，对验证明确的9个差异表达的lncRNAs和10个mRNAs综合分析结果提示细胞周期在HCC起始阶段起着至关重要的作用；发现LINC00598作为抑癌因子影响肝癌的发生发展，可能通过顺式调控FOXO1表达，并抑制Wnt信号通路来实现；利用原有SNP数据库，发现细胞周期通路基因SMAD3基因rs11556090位点、RBL2基因rs3929位点与肝癌预后有关；通过与上海同济医学院同行合作，发现miRNA-338-3p / CDK4信号通路抑制肝星状细胞活化和增殖。上述的研究结果，对于深入阐述肝癌发生发展的分子机制具有重要的学术价值，有望用于肝癌的精准治疗与预后预测。