METTL1下调PTEN促进肝细胞癌侵袭转移的机制研究

肿瘤侵袭转移是肝细胞癌（HCC）患者死亡的主要原因，但机制尚未明了。研究表明甲基转移酶（例如EZH2和METTL3）在肿瘤恶性进展中发挥重要作用。我们前期观察到METTL1在HCC组织中高表达，与患者预后差相关；体外实验结果显示沉默METTL1上调PTEN而失活PI3K/AKT通路，抑制HCC细胞增殖迁移；此外，沉默转录因子c-Myc显著下调METTL1。因此，我们提出METTL1受c-Myc转录调控，靶向PTEN/AKT通路并促进HCC侵袭转移的科学假设。本项目拟开展一系列体内外实验，在基因表达调控和细胞功能上，明确METTL1在HCC组织中的表达及临床意义，探明c-Myc调控METTL1的分子机制，阐述METTL1下调PTEN的确切机理并解析其下游信号通路，揭示c-Myc/METTL1/PTEN信号轴在HCC恶性进展中的作用，为诠释HCC发生发展机制和寻找抗癌治疗新靶点提供实验依据。

Tumor invasion and metastasis are responsible for the poor prognosis of hepatocellular carcinoma (HCC). However, the underling mechanism of HCC progression remains unclear. Current literatures indicate that methyltransferases, such as EZH2 and METTL3, play important roles in tumor progression. Our preliminary data showed that methyltransferase like 1 (METTL1) was up-regulated in HCC. High expression of METTL1 was correlated with poor survival in HCC. In vitro studies demonstrated that knockdown of METTL1 resulted in an increase of PTEN expression, inactivation of PI3K/AKT signaling and subsequent suppression of cell proliferation and migration in HCC. Furthermore, the expression of METTL1 was inhibited by the treatment of c-Myc siRNA. Collectively, we assume that METTL1 is modulated by c-Myc and enhances tumor growth and metastasis via suppression of PTEN in HCC. In this study, we aim to determine the expression of METTL1 and its clinical significance in HCC, to unveil how c-Myc transcriptioanlly regulates METTL1, to disclose the mechanism via which METTL1 represses the expression of PTEN, and to illustrate the role of c-Myc/METTL1/PTEN axis in the progression of HCC, using a series of in vitro and in vivo experiments. Our study is likely to provide not only the new insight of the mechanism of HCC progression, but also a promising biomarker for clinical management of HCC.