糖原合酶GYS1在卵巢癌增殖中的作用及机制研究

恶性肿瘤快速增殖常伴有糖原含量异常,但其调控机制尚未明了。我们前期观察到卵巢癌(OC)糖原含量增加，并且糖原合酶GYS1在卵巢癌组织中呈高表达。临床病例统计GYS1高表达与患者预后差相关；进一步体外实验显示：①敲降GYS1降低卵巢癌细胞糖原含量；②GYS1与RNF38相互结合，增加其蛋白稳定性和抑制其自身泛素化，并促进卵巢癌细胞增殖；③GYS1的表达受转录因子E2F1上调。因此，我们提出GYS1受E2F1调控，靶向RNF38促进卵巢癌细胞增殖的假说。本项目拟利用大样本人体标本、多株细胞和动物模型，在表达及细胞功能上，明确GYS1在卵巢组织中的表达及其临床意义，探究GYS1与RNF38调控的分子机制，揭示E2F1转录促进GYS1的作用机理，阐述E2F1/GYS1/RNF38信号轴在卵巢癌恶性进展中的作用，并解析其下游信号传导通路，为诠释卵巢癌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 ovarian cancer (OC) glycogen is dramatically increased and glycogen synthase GYS1 is up-regulated in OC. Our clinical data showed that increased GYS1 associated with poor prognosis. In vitro studies suggest that (a) GYS1 overexpression markedly increased the glycogen content; (b) GYS1 interacted with RNF38 to prevent its degradation and inhibit its autoubiquitination, which consequently resulted in the promotion of cell proliferation;(c) GYS1 expression was transcriptionally induced by E2F1. Based on these findings, we assume that GYS1 is modulated by E2F1 and increases OC cell proliferation via targeting RNF38. In this study, we aim to determine the expression and clinical significance of GYS1 in OC, to unveil how GYS1 is regulated by E2F1, to disclose the molecular mechanism of GYS1-mediated RNF38 modulation, and to reveal the role of E2F1/GYS1/RNF38 axis promotes OC cell proliferation, 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 GYS1 contributes to OC progression, but also a potential biomarker for OC clinical diagnosis and treatment.