我国肝癌患者就诊时多为晚期且伴肝纤维化，以奥沙利铂为主的化疗是可选方案之一，但存在原发和获得性耐药。前期基因芯片筛查：奥沙利铂耐药肝癌的结缔组织生长因子（CCN2）表达上调。CCN2作为微环境母细胞蛋白通过与多种功能蛋白结合调控肿瘤进展。活化星状细胞（aHSC）作为肝癌纤维微环境数量最多的间质细胞，能分泌大量CCN2。预实验：癌旁肝CCN2与肝纤维化程度及肝癌恶性表型正相关，CCN2与肝癌p-Met及奥沙利铂耐药亦正相关。我们推测：aHSC旁分泌CCN2通过增加肝癌p-Met水平，激活奥沙利铂耐药相关信号促进肝癌奥沙利铂耐药。本课题将探索CCN2促奥沙利铂耐药机制，并验证抑制CCN2在合并纤维化背景肝癌奥沙利铂耐药中的作用，进而阐明CCN2在肝纤维化背景促癌的机制，并为晚期肝癌靶向CCN2联合奥沙利铂综合治疗方案提供理论依据。

Many patients suffered from hepatocarcinoma are complicated with cirrhosis, and most of them have lost the opportunity of radical treatments. Oxaliplatin is applied for advanced hepatocarcinoma treatment, but its therapeutic effect is restricted by primary or acquired drug resistance. It is important to explore the mechanisms of oxaliplatin resistance for improving its treatment effects. Previously, we have found the higher expression of CCN2 in oxaliplatin resistant hepatocarcinoma tissues by Gene microarray. As one of the matricellular protein in the CCN family, CCN2 played important roles in many biological processes including tumor malignant progression. Actived hepatic stellate cell (aHSC) as the most stromal cells in HCC microenvironment could secrete high level of CCN2. In our pre-experiment, we have found that CCN2 has been involved in the malignant phenotype. And we have also proved CCN2 was positively correlated with p-met expression and oxaliplatin resistance. Thus, we hypothesized that HCC high expression of CCN2 from aHSC could enhanced oxaliplatin resistance through Met signaling pathway. In the further study, we will analyze the relationship among the expression of CCN2, the degree of liver fibrosis, and Oxaliplatin resistance in HCC. Then, the mechanism of CCN2 in Oxaliplatin resistance will be verified. Finally, the role of inhibition CCN2 secreted by aHSC in the remission oxaliplatin resistance will be explored. This project will firstly elucidate the mechanism of CCN2 in the malignant progression in HCC, and provide for the treatment options of targeted inhibition of CCN2 combined with oxaliplatin programs in HCC complicated with cirrhosis.