乙型肝炎病毒C蛋白促进Src/PI3K/Akt通路介导的肝细胞周期进程及机制

The Src protein is one of the most important regulatory factors in tumor development. Phosphorylation of Tyr527 inactivates Src, while Tyr416 can be auto-phosphorylated to activate itself. Src/PI3K/Akt-mediated G1-S cell cycle progression in hepatocytes is accelerated by active Src. However, the fine balance between activation and inactivation of Src by disruption will result in cell cycle disorder and tumor development. In our previous studies, we found that Hepatitis B virus C protein (HBc) could promote cell proliferation by acceleration of G1-S cell cycle progression in hepatocytes, and enhance the transcription of Src gene and its Tyr416 phosphorylation level with downregulated Tyr527 phosphorylation level. In this study, we aim to elucidate the role of HBc in hepatocarcinogenesis from the perspective of Src/PI3K/Akt-mediated G1-S cell cycle progression, the main contents include: 1. Mechanisms involved in the enhancement effects of HBc on Src gene transcription, and how HBc oppositely regulates Tyr416 and Tyr527 phosphorylation level in Src itself; 2. Mechanisms involved in the acceleration of G1-S cell cycle progression in hepatocytes after Src/PI3K/Akt signal activation by HBc. The results obtained in this study will contribute to a better understanding of the HBV-related hepatocarcinogenesis.

Src蛋白是肿瘤发生发展的重要调控因子，Tyr527位点磷酸化使其失去活性，而Tyr416位点被磷酸化后使其活化，Src被激活后通过Src/PI3K/Akt通路促进G1-S转换以加速细胞周期进程。Src失活与活化的失衡是导致细胞周期紊乱及肿瘤发生发展的关键因素。我们先前的研究发现乙型肝炎病毒C蛋白（HBc）促进肝细胞增殖并加速细胞周期G1-S转换进程，HBc上调Src基因转录，并促进Tyr416位点磷酸化水平而抑制Tyr527位点磷酸化。本研究从Src/PI3K/Akt通路调控细胞周期G1-S转换的角度出发，探讨HBc在肝癌发生发展中的作用。主要研究内容包括：1.HBc促进Src基因转录的机制以及HBc如何差异性调控Src蛋白Tyr416及Tyr527位点磷酸化水平；2.HBc激活Src/PI3K/Akt通路后加速细胞周期G1-S转换的机制。所获得的结果将有助于更深入了解HBV致肝癌机制。

细胞周期的动态平衡促进肝细胞分裂与增殖，维持肝细胞新陈代谢和肝脏再生。细胞周期紊乱会促进肝细胞恶性增殖，最终导致肝癌的发生发展。乙型肝炎病毒C蛋白（HBc）可导致肝癌，确切机制尚未完全阐明。研究表明，Src激酶Tyr527位点的磷酸化使其失去活性，而Tyr416位点被磷酸化后则使其活化。Src被激活后通过Src/PI3K/Akt通路促进G1-S转换以加速细胞周期进程。本研究旨在通过研究HBc蛋白对Src基因转录及蛋白活化的调控，深入探讨HBc蛋白致细胞周期紊乱及肝癌发生的机制。本研究显示，HBc蛋白以Sp1依赖的方式激活Src 1A启动子，促进Src转录与表达；HBc蛋白以CSK依赖的方式促进Src活化，继而激活Src/PI3K/Akt信号通路。HBc激活Src导致细胞周期G1-S转换加速，细胞增殖和裸鼠成瘤能力增强，而表达HBc的肝癌细胞增殖和裸鼠成瘤能力被Src抑制剂塞卡替尼（Saracatinib）抑制。本课题研究证实在HBc诱导的肝细胞恶性增殖过程中，Src是关键的调控因子。因此，在HBV相关的肝癌治疗中，Src可能作为潜在的靶点。