HCV激活自噬促进肝癌细胞增殖与转移的机制研究

项目名称： HCV激活自噬促进肝癌细胞增殖与转移的机制研究

项目编号： No.81472285

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 章意亮

作者单位： 中国人民解放军第二军医大学

项目金额： 81万元

中文摘要： 自噬是真核细胞生长、分化与死亡的重要调控机制，其活性异常与肿瘤的发生发展密切相关。诱导肿瘤发生的遗传因素与表观遗传因素异常均参与自噬活化。因此，HCV激活自噬可能是其诱导肝癌发生的中心环节。在前期研究中，我们发现HCV感染激活了细胞自噬，自噬活化有助于细胞的增殖与迁移，HCV感染的肝癌细胞中自噬关键基因ATG10,ATG12的甲基化水平降低，这提示HCV通过表观遗传学调控激活自噬从而促进细胞增殖与迁移。本课题拟进一步鉴定HCV导致ATG10/12异常的甲基化位点；鉴定HCV参与甲基化调控与自噬活化的结构蛋白；证实自噬通过调控缺氧与营养缺乏等微环境而促进细胞增殖与迁移；确证ATG10/12在HCV诱导肝癌形成过程中的重要介导作用，进而分析自噬在HCV相关肝癌生长与转移中的促进作用及其机制。最终，探讨ATG10/12或其他自噬相关基因作为HCV-HCC早期诊断或预后判断标志物的可行性。

中文关键词： C09_肝和肝内胆管肿瘤；细胞自噬；肿瘤微环境；增殖与转移；丙型肝炎病毒

英文摘要： Autophagy describes several metabolic pathways, by which cytoplasmic constituents are imported into lysosomes for degradation. These pathways and inparticular macroautophagy play an important role during oncogenesis by apparently inhibiting cellular transformation initially, but then ensuring tumor cell survival in established cancers. Furthermore, the conditioning of the tumor microenvironment, including the cross-talk with the immune system, isinfluenced by autophagy. Recent studies showed that autophagy is activated by the epigenetic regulation. Autophagy maintains cellular viability in the setting of various stressors. Mediated via the lysosomal degradation pathway, autophagy recycles cellular proteins and organelles to ensure cell survival.Autophagy plays a important role in the liver tumorigenesis and cancer progression. In the our previous studies, we demonstrated that HCV infection induces the activation of autophagy, and that autophagy activation is helpful to cell proliferation and cell migration. Furthermore, we showed that the methylation level is abnormal in the promoter region of autophagy-related gene 10 (ATG10) and ATG12. Therefore, we speculated that HCV may promote HCC by regulating autophagy. In the study, we will investigate whether and how HCV activates autophagy by the epigenetic regulation, and whether HCV infection decreases the methylation level of ATG10 and ATG12, and promotes its expression level and results in the activation of autophagy. Then we will identify whether ATG10 and ATG12 play a crucial role in the liver tumorigenesis, how autophagy promotes cell proliferation and migration by regulating tumor microenviroment. Finally, we will identify the role of autophagy in the growth and metastasis of HCV-HCC and its underlying mechanisms. New data from this proposal will provide a better understanding of the mechanisms of hepatocarcinogenesis, and provide new targets for early diagnosis, treatment and prognosis analysis of HCV-HCC.

英文关键词： liver cancer;Autophagy;Tumor microenviroment;proliferation and metastasis;HCV