TNF-α通过抑制circLIFR表达参与调控NEMO蛋白的类泛素化修饰促进肝癌进展的机制研究

炎症在肝癌的发生发展过程中具有重要的调控作用。我们前期研究证实，炎症因子TNF-α可促进肝癌的恶性进展，但TNF-α参与调控肝癌的具体机制并未阐明。本项目预实验结果显示TNF-α可抑制circLIFR表达，从而增强肝癌细胞增殖和侵袭迁移能力；更深入的探索提示circLIFR可通过结合SENP2蛋白，降低NEMO蛋白（IKK-γ）的SUMO1修饰水平，从而发挥调控NF-κB信号通路活性的作用。由此，我们提出TNF-α通过抑制circLIFR的表达，进而抑制circLIFR与SENP2蛋白的结合，提高NEMO蛋白（IKK-γ）的SUMO1修饰水平，最终激活NF-κB信号通路并促进肝癌进展这一科学假说。基于此，本项目将采用RIP、RNA-pulldown、Co-IP等技术证实上述科学假说，项目的实施将为从非编码RNA角度阐明炎症因子TNF-α参与调控肝癌进展的具体机制提供新的研究依据。

Chronic inflammation was considered to be one of the main triggers of hepatocellular carcinoma (HCC). Our previous study found that TNF-α could promote the progression of HCC, but its molecular mechanism remains largely unclear. Recently, our preliminary study found that TNF-α could promote the progression of HCC by inhibiting the expression of circLIFR. We further explored that circLIFR could bind to SENP2, a deSUMOylation enzyme which could remove SUMO molecules from substrates. Then, we found that SENP2 could regulate NF-κB signal pathway through modification the deSUMOylation of NEMO. Therefore, we speculate that TNF-α prompts the progression of HCC via regulating circLIFR/SENP2 to activate NEMO/NF-κB signal pathway. On the basis of our previous studies, we will further elucidate the exact mechanism of circLIFR/SENP2/NEMO complex in regulating TNF-α/NF-κB signal pathway and HCC progression via RNA-pulldown, RIP, Co-IP and other technologies. This study will help to clarify the molecular mechanism of TNF-α and circRNA involving in HCC progression and explore the potential therapeutic targets for HCC patients.