RNA结合蛋白PABPC4在c-MYC诱导肝细胞癌发生中的作用及机制

肝细胞癌是全球发病率第五、死亡率第二的恶性肿瘤。原癌基因MYC异常激活是肝细胞癌变的重要原因。RNA结合蛋白（RBPs）介导的转录后调控在许多生理和病理进程中发挥重要作用。然而，RBPs是否参与MYC诱导的肝癌发生尚不清楚。我们前期研究表明，小鼠肝癌模型中的MYC激活导致RBPs表达谱改变；功能筛选发现，RNA结合蛋白PABPC4对MYC高表达的肝癌细胞增殖和周期运转至关重要。由此我们推测，MYC上调PABPC4表达，PABPC4通过转录后调控细胞周期相关的基因表达，进而促进肝癌进展。本课题拟在MYC诱导的小鼠原发肝癌模型上研究敲除PABPC4对肝癌发生的影响；明确PABPC4对细胞周期、增殖、克隆形成的影响；阐明PABPC4上游调控机制及下游参与MYC促癌作用的潜在靶基因。本课题将揭示PABPC4通过转录后调控在MYC诱导的肝癌中的促肿瘤机制，为肝癌的临床治疗提供新的靶标。

Hepatocellular carcinoma (HCC) is the fifth and the second most common malignant tumor in morbidity and mortality respectively. Abnormal activation of protooncogene MYC is an important cause of HCC. Post-transcriptional regulation mediated by RNA-binding proteins (RBPs) plays an important role in many physiological and pathological processes. However, whether RBPs are involved in MYC-induced HCC remains unclear. Our previous studies have shown that MYC activation in mouse liver leads to changes in the expression profile of RBPs. Further functional screening revealed that the RNA-binding protein PABPC4 was essential for the proliferation and cell cycle of MYC-activated HCC cells. Thus, we hypothesize that MYC up-regulates the expression of PABPC4, which promotes the initiation and progression of liver cancer through post-transcriptional regulation of cell cycle-related genes. This project intends to investigate the effect of PABPC4 knockout on HCC development in mouse HCC models induced by MYC, and the effects of PABPC4 on cell cycle, proliferation and clone formation in a panel of human HCC cell lines. The upstream regulation mechanism of PABPC4 and the downstream target genes of PABPC4 will be investigated. The present project will uncover the tumor-promoting effect of PABPC4 in MYC-induced HCC progression through post-transcriptional regulation, and provide potential therapeutic targets for HCC treatment.