GYS2上调p53抑制肝癌细胞增殖的分子机制

快速增殖的恶性肿瘤细胞常伴有糖原含量异常,但其调控机制尚未明了。我们前期观察到肝细胞癌(HCC)糖原含量减少，并且糖原合成关键酶GYS2在HCC组织中呈低表达。大样本病例统计GYS2低表达与患者预后差相关；进一步体外实验显示：①过表达GYS2增加HCC细胞糖原含量；②GYS2与p53相互结合，促进p53乙酰化和蛋白稳定性，并抑制HCC细胞增殖；③GYS2的表达受HBx抑制。因此，我们提出GYS2受HBx调控，靶向p53抑制HCC细胞增殖的假说。本项目拟利用大样本人体标本、多种细胞和动物模型，在表达及细胞功能上，明确GYS2在HCC组织中的表达及其临床意义，探究GYS2与p53调控的分子机制，揭示HBx转录抑制GYS2的作用机理，阐述HBx/GYS2/p53信号轴在HCC恶性进展中的作用，并解析其下游信号传导通路，为诠释HCC发生发展的分子机制和寻找诊治新靶点提供科学依据。

The glycogen content in malignant tumors is aberrant. However, the underlying mechanism remains elusive. Our preliminary data show that Hepatocellular carcinoma (HCC) glycogen is dramatically decreased and glycogen synthase GYS2 is down-regulated in HCC. Our clinical data showed that decreased GYS2 associated with poor prognosis. In vitro studies suggest that (a) GYS2 overexpression markedly increased the glycogen content; (b) GYS2 interacted with p53 to prevent its degradation and enhance its acetylation, which consequently resulted in the suppression of cell proliferation;(c) GYS2 expression was transcriptionally inhibited by HBx. Based on these findings, we assume that GYS2 is modulated by HBx and inhibits HCC invasion and metastasis via targeting p53. In this study, we aim to determine the expression and clinical significance of GYS2 in HCC, to unveil how p53 was regulated by HBx, to disclose the molecular mechanism of GYS2-mediated p53 modulation, and to reveal the role of HBx/GYS2/p53 axis suppresses HCC cell proliferation, using using a series of biological and immunological experiments in cell and animal models. Our study is likely to provide not only solid evidence that dysregulation of GYS2 contributes to HCC progression, but also a potential biomarker for HCC clinical diagnosis and treatment.