去甲基化酶FTO介导的circ_0089551 m6A修饰调控肝癌转移的机制研究

肝癌转移是影响患者预后的主要因素。我们预实验发现：与无转移的肝癌组织相比，circ_0089551（CIRC）在有转移的肝癌组织中高表达；过表达CIRC促进了肝癌细胞的侵袭迁移。此外，有转移的肝癌组织总RNA的m6A修饰水平较无转移的肝癌组织低；去甲基化酶FTO在肝癌组织中高表达，而过表达FTO降低了CIRC的m6A修饰水平，同时上调了CIRC的表达，并促进了肝癌细胞的侵袭迁移。基于此我们推测：FTO通过降低CIRC的m6A修饰水平，上调CIRC的表达，从而促进肝癌的转移。本项目拟从细胞、动物和临床标本水平：①进一步明确CIRC促进肝癌转移的具体机制；②评价及证实FTO介导的m6A修饰调控CIRC的表达及其在肝癌转移中的作用；③动物实验探讨FTO/CIRC通路对肝癌转移的影响。本研究有助于揭示circRNA参与调控肿瘤转移的新机制，为预测肝癌转移和临床实施个体化治疗提供新的靶点及理论基础。

The metastasis of hepatocellular carcinoma (HCC) is one of the most factors associating with the prognosis. In previous studies, we examined the differential expression profile of circRNAs between HCC tissues with metastasis and that without metastasis by microarray, and found that circ_0089551 was markedly up-regulated in HCC tissues with metastasis, whereas overexpression of circ_0089551 significantly promoted invasion and migration of HCC cells. Preliminary results suggest that m6A methylation levels were decreased in HCC tissues with metastasis compared with that without metastasis. And the expression of demethylase FTO was up-regulated in HCC tissue, whereas overexpression of FTO resulted in decreased m6A methylation levels of circ_0089551, significantly upregulated the expression of circ_0089551 and promoted invasion and migration of HCC cells. Given the above, we speculated that the demethylase FTO could promote HCC metastasis through reducing the m6A methylation levels of circ_0089551 and upregulating the level of circ_0089551. Based upon these results, the applicant is planning to carry out a series of experiments on clinical sample analysis, experimental studies and mouse model, which will obtain the key evidence that circ_0089551 involved the pathogenesis of HCC metastasis further, evaluate the role of FTO mediated m6A methylation in regulating the level of circ_0089551, explore the influence of selective blocking FTO/circ_0089551 signaling pathways on HCC metastasis in vivo. The findings of this project will be of significance for prevention and target therapy of HCC.