TNF-a通过调控lncRNA-SNHG1/G3BP1/USP10蛋白复合体促进IL-6自分泌参与肝癌进展的机制研究

炎症因子在肝癌进展中具有重要的调控作用。我们前期研究证实，TNF-a可增强肝癌细胞增殖和侵袭能力，但其机制并未阐明。预实验研究显示，TNF-a通过上调肝癌细胞lncRNA-SNHG1（SNHG1）表达，促进肝癌进展。结合生信分析和蛋白芯片检测，我们进一步发现SNHG1可能与G3BP1/USP10蛋白结合形成复合体，解除去泛素化酶USP10对NF-κB通路的抑制作用，进而刺激IL-6自分泌并促进肝癌进展。由此，我们提出TNF-a通过上调SNHG1表达促进IL-6自分泌，形成炎症因子“级联效应”调控肝癌进展这一科学问题。基于以上研究发现，本项目将在组织、细胞和动物实验层面，采用RNA-pull down、RIP、EMSA等方法阐明SNHG1/G3BP1/USP10复合体介导TNF-a促进IL-6分泌参与肝癌进展的具体机制。本项目将为明确炎症因子调控肝癌的分子机制及治疗靶点选择提供新的科学依据。

Relative studies have showed that inflammatory cytokines play important role during the progression of hepatocellular carcinoma. Our previous report also demonstrated that TNF-a could enhance the proliferation and invasion ability of hepatocellular carcinoma cells. However, the involved mechanism remains unclear. Recently, our pre-experimental study suggested that TNF-α prompts the progression of hepatocellular carcinoma through up-regulating the expression level of lncRNA-SNHG1. By bioinformatics analysis and protein chip assay, we further found that TNF-a could combine with RNA-binding protein, G3BP1/USP10, and thus activate NF-κB signal pathway through releasing the inhibiting ability of deubiquitinating enzymes USP10, which prompted the autocrine of IL-6 and subsequently caused the progression of hepatocellular carcinoma. Therefore, we speculate that TNF-α up-regulates the expression level of lncRNA-SNHG1, and then enhances the autocrine of IL-6, which finally prompts the progression of hepatocellular carcinoma. On the basis of the above experiments, the current study will further explore and elucilate the exact mechanisms of SNHG1/G3BP1/USP10 complex in TNF-α regulating hepatocellular carcinoma progression via enhancing IL-6 autocrine. This study will help to clarify the molecular mechanism of hepatocellular carcinoma progression caused by inflammatory cytokines and explore the potential therapeutic targets for patients with hepatocellular carcinoma.