GP73在小鼠肝癌发生发展中的作用

Serum Golgi protein 73 (GP73) is gradually elevated during the course of hepatitis B virus (HBV) infection, liver fibrosis, cirrhosis to hepatocellular carcinoma(HCC) development. It is thus emerged as a serum marker for HCC and may promote the transformation from hepatitis to HCC. Our previous data showed that GP73 potentiated liver cancer cell proliferation and xenografted tumor development in nude mice. To investigate the role of GP73 in the development of hepatocellular carcinoma in situ, GP73 knockin and knockout mice have been generated. GP73 knockin mice will be crossed with HBV transgenic mice to examine the impact of GP73 on HBV-associated liver cancer. GP73 knockin and knockout mice will be then injected with diethylnitrosamine (DEN) to illustrate the significance GP73 in chemical induced HCC. Furthermore, DEN-induced mouse HCC will be treated with a monoclonal antibody against GP73 to test the efficacy of GP73 inhibition in the treatment of HCC.

从HBV感染、肝纤维化、肝硬化到肝癌发生的过程中，血清GP73进程性升高，提示GP73是肝癌血清标志物之一，并且可能参与肝炎向肝癌的转化。我们的前期工作显示GP73促进细胞增殖和裸鼠成瘤,为了探讨GP73在原位肝癌发生过程中的作用，我们已构建GP73基因敲入小鼠和敲除小鼠，将GP73基因敲入小鼠与乙肝病毒转基因小鼠杂交，观察GP73高表达对HBV致瘤的影响；用二乙基亚硝胺诱导GP73基因敲入和敲除小鼠发生肝癌，检查GP73在化学诱导肝癌中的作用；探讨GP73抗体治疗二乙基亚硝胺诱导小鼠肝癌的疗效。此项目将为肝癌研究提供新的动物模型，并为肝癌的靶向治疗提供新策略。

从HBV感染、肝纤维化、肝硬化到肝癌发生的过程中，血清GP73进程性升高，提示GP73是肝癌血清标志物之一，并且可能参与肝炎向肝癌的转化。我们的前期工作显示GP73促进细胞增殖和裸鼠成瘤,为了探讨GP73在原位肝癌发生过程中的作用，我们构建GP73基因过表达小鼠和敲除小鼠，将GP73基因过表达小鼠与乙肝病毒转基因小鼠杂交，观察到GP73高表达促进HBV小鼠肝脏肿瘤的发生；在DEN诱导下，过表达GP73可以加重肝损伤，促进肝癌的发生。GP73主要是通过促进炎性细胞因子CCL2的高表达，影响肿瘤浸润性巨噬细胞，加重肝损伤，促进肝脏肿瘤的发生。敲除GP73以后，肝损伤程度降低，肿瘤发生速度减慢，肿瘤体积减少。GP73可以作为肝癌治疗的一个新靶点。