MiR-151a-3p在酒精相关性肝癌中作用机制的研究

Study on the mechanism of action of MiR-151a-3p in alcohol-related liver cancer

目的本研究旨在通过寻找酒精性肝炎向肝癌进展过程中的肿瘤标志物,为其早期诊断提供参考。方法查阅酒精相关肝癌患者的病历并进行分析。选择酒精性肝炎/肝癌患者和酒精性肝炎/肝硬化患者以筛选目标微小RNA(MicroRNA miRNA)。在肝癌细胞系中检测miR-151a-3p在癌细胞中的作用,并研究了它们的机制。结果酒精性肝炎未经历肝硬化阶段而直接进展为肝癌的患者较经历肝硬化阶段的患者年轻(P<0.05);酒精性肝炎/肝癌患者中miR-151a-3p的表达水平显著高于酒精性肝炎/肝硬化患者;肝癌细胞系中miR-151a-3p的表达水平显著高于正常肝细胞系,其中HepG2表达最高。在HepG2和Bel-7402中,下调miR-151a-3p的表达水平,显示G0/G1期增加而G2/M期减少。在Si-miR-151a-3p(HepG2)和Si-miR-151a-3p(Bel-7402)细胞中,ATM的mRNA和蛋白表达水平增加,P53的mRNA表达水平增加,P-P53蛋白的表达水平增加,而Cyclin D1的mRNA和蛋白的表达水平下降。结论部分酒精性肝炎患者可以不经过肝硬化阶段而直接进展为肝癌。miR-151a-3p在其中扮演重要角色,通过直接靶向ATM抑制P53,从而促进Cyclin D1的表达,导致肝癌发生、发展。

Objective To provide reference for early diagnosis by searching for tumor markers in the progression of alcoholic hepatitis to liver cancer.Methods The medical records of patients with alcohol-related liver cancer were retrieved and analyzed.Alcoholic hepatitis/liver cancer patients and alcoholic hepatitis/cirrhosis patients were selected to screen target MicroRNA(miRNA).The role of miR-151a-3p in cancer cells was tested in liver cancer cell lines,and their mechanism was studied.Results Patients with alcoholic hepatitis who did not undergo the stage of liver cirrhosis and directly progressed to liver cancer were younger than those who experienced the stage of liver cirrhosis(P<0.05);the expression level of miR-151a-3p in patients with alcoholic hepatitis/liver cancer was significantly higher than that in patients with alcoholic hepatitis/liver cirrhosis.The expression level of miR-151a-3p in liver cancer cell lines was significantly higher than that in normal liver cell lines,and HepG2 had the highest expression.In HepG2 and Bel-7402,the expression level of miR-151a-3p was down-regulated,showing an increase in the G0/G1 phase and a decrease in the G2/M phase.In Si-miR-151a-3p(HepG2)and Si-miR-151a-3p(Bel-7402)cells,mRNA and protein expression levels of ATM increased,mRNA expression levels of P53 increased,and protein expression levels of P-P53 increased,while mRNA and protein expression levels of Cyclin D1 decreased.Conclusion Some patients with alcoholic hepatitis can directly progress to liver cancer without going through the stage of cirrhosis,in which miR-151a-3p plays an important role,by directly targeting ATM to inhibit P53,thereby promoting the expression of cyclin D1,and leading to the occurrence and development of liver cancer.