目前肝癌分子治疗效果不佳，尚需深入了解肝癌进展分子机制以获得新的治疗靶点。我们发现肝刺激因子（HSS）在肝癌转移患者肿瘤组织内异常低表达，且HSS低表达的细胞迁移能力增强，提示HSS表达下调与肝癌转移相关，但其中的分子机制尚不明了。前期发现HSS表达下调后ERK异常活化，而ERK的特异性抑制剂，双特异性磷酸酶2（DUSP2）表达下降，肝癌组织内DUSP2表达与HSS表达密切相关。据此提出假设，HSS表达下调使DUSP2表达下降，ERK异常活化，诱导上皮-间质转化，促进肝癌转移。本课题拟在细胞及动物水平，利用Western blot、siRNA、细胞迁移实验、高内涵细胞成像分析技术及裸鼠体内注射等方法阐明此假说，并通过报告基因分析及染色质免疫沉淀等实验确定DUSP2表达下降的调控机制；最后应用人肝癌组织芯片加以证实。此研究将建立新的与肝癌转移相关的分子通路，为肝癌分子治疗提供新的潜在靶点。

Currently the effect of hepatocellular carcinoma (HCC) treatment remains to be improved. And there are needs to search for more detailed molecular mechanism for HCC pathogenesis and to find new therapeutic targets. We found that the expression levels of hepatic stimulator substance (HSS) were low in tumors among patients with HCC metastasis. And the cells with low expression levels of HSS had increased ability of migration, indicating that the down regulation of HSS is correlated to HCC metastasis. However, its molecular mechanism remains to be understood. Our previous studies revealed HSS down-regulation resulted in ERK activation. The expression levels of a specific ERK inhibitor, dual-specificity phosphatase (DUSP) 2 decreased in the cells with low expression levels of HSS. And the expression of HSS and DUSP2 are closely correlated in HCC. We hypothesize that the down regulation of HSS causes a decrease in DUSP2, which resulted in sequential alterations including ERK activation, epithelial-mesenchymal transition, and HCC metastasis. In our current study, research is going to be conducted with cell model as well as animal model, using techniques including Western blot, siRNA, cell migration assay, high content analysis, reporter gene analysis, and chromatin immunoprecipitation, and injection into nude mice to investigate the mechanism of the DUSP2 down-regulation. Human HCC tissue chip would also be used to confirm this finding. We hope this project would help us to find a new pathway related to HSS metastasis and to provide new potential therapeutic targets for HCC treatment.