课题组前期实验证实Sulfatase2和GLI1在肝细胞癌（HCC）中过表达，均被证实促进HCC术后复发和转移，但是两者过表达机制仍不明。本项目通过免疫共沉淀、基因沉默、spheroid 3D细胞培养、转基因小鼠等生物实验，力图证实如下学术假说：HCC肿瘤微环境中Sulfatase2通过释放更多细胞膜表面基质中Shh配体与受体相结合或激活TGFβ1通路，上调GLI1表达。过表达GLI1促使HCC细胞分泌TGFβ1和IL-6，激活周围肝星状细胞分泌Sulfatase2，形成Sulfatase2-GLI1-TGFβ1-Sulfatase2的正反馈通路，维持HCC肿瘤微环境中Sulfatase2过表达，进而导致HCC细胞GLI1高表达，从而维持HCC细胞EMT表型。同时，本项目试图研究Sulfatase2抑制物OKN007在动物体内的抗HCC作用。本项目预期研究结果具有较高的科研意义和临床价值。

Our preliminary data showed that both Sulfatase2 and GLI1 were overexpressed in hepatocellular carcinoma (HCC) and promoted tumor recurrence and metastasis after radical resection. However, the underlying mechanism remains unclear. This project seeks to verify the following hypothesis via a research strategy including immunoprecipitation, gene silencing, spheroid 3D cell culture and transgenic mouse. In the tumor mircoenvironment of HCC, Sulfatase2 upregulates GLI1 expression by 2 distinct pathway, the first one is that more Shh is released by Sulfatase2 from the matrix of cell membrance, binded with Patchened and activate Hedgehog signaling; the second one is that Sulfatase2 increases GLI1 expression via activating TGFβ1 signaling directly. Consequently, overexpression of GLI1 promotes HCC cells to express and secrete more TGFβ1 and IL-6, and activates hepatic stellate cells in tumor microenviroment to express and secrete more Sulfatase2. Due to the Sulfatase2-positive feedback mentioned above, both Sulfatase2 and GLI1 remain overexpressed in HCC mircoenvironment, by which EMT phenotype of HCC cells is maintained. Another aim of this project is to figure out the anti-HCC effect of OKN007, a Sulfatase2 inhibitor, in vivo in the mouse HCC model. The expected results of this project can contribute to understand the regulatory mechanism and function of Sulfatase2 and GLI1 in HCC microenviroment, and develop a novel targeted reagent for HCC. Therefore, proposed studies here are highly significant in improving understanding of the mechanism of HCC development and laying the groundwork for future testing of much-needed rational strategies for the treatment of HCC.