mPGES-1抑制剂DMC通过LINC01933调控TGF-β信号通路在抑制肝癌进展中的机制研究

2,5-二甲基塞来昔布（DMC）靶向抑制mPGES-1，能规避COX抑制剂副作用，是更安全有效的抗炎小分子化合物。前期工作发现DMC还能促进PD-L1泛素降解改善肝癌免疫微环境，同时表达谱芯片分析发现DMC引发肝癌细胞多条lncRNAs表达变化。已知lncRNA可以通过多种方式参与肿瘤免疫逃逸，推测lncRNA在DMC抗肝癌免疫效应中发挥独特作用，但机制未明。预实验发现lncRNA LINC01933与免疫因素密切相关（参与调节TGF-β通路），可能是新的重要调控分子。本项目拟深入探究荷瘤小鼠模型中DMC对LINC01933的影响以及LINC01933对肝癌模型中肿瘤增殖和免疫微环境的影响，体外细胞验证DMC调控LINC01933参与肝癌免疫微环境改变，阐明DMC通过LINC01933调控TGF-β通路抑制肝癌的机制。本研究有助于更全面揭示DMC的多靶点效应，为肝癌免疫治疗提供新思路。

Targeted inhibition of mPGES-1, by 2,5-Dimethyl-celecoxib (DMC) can avoid the side effects of COX inhibitors and is a safer and more effective small molecular compound for anti-inflammatory. Previous work found that DMC can also promote the degradation of PD-L1 ubiquitin and improve the immune microenvironment of hepatocellular carcinoma. At the same time, expression microarray analysis showed that DMC induced multiple lncRNAs expression changes in hepatocellular carcinoma cells. It is known that lncRNA can participate in tumor immune escape in many ways. We speculated that lncRNA plays a unique role in the immune effect of DMC against hepatocellular carcinoma, but the mechanism is unknown. Pre-experiment found that lncRNA LINC01933 is closely related to immune factors (involved in the regulation of TGF-β pathway), and may be a new important regulatory molecule. The purpose of this project is to explore the effects of DMC on LINC01933 in tumor-bearing mice and the effects of LINC01933 on tumor proliferation and immune microenvironment in hepatoma model. In vitro cell verification that DMC participates in the changes of immune microenvironment of hepatocellular carcinoma by regulating LINC01933. To elucidate the mechanism that DMC inhibits hepatocellular carcinoma by regulating TGF-β pathway through LINC01933. This study is helpful to reveal the multi-target effect of DMC and provide a new idea for immunotherapy of hepatocellular carcinoma.