乙型肝炎病毒相关肝细胞癌患者外周血miR-155、miR-181a表达意义探究

doi:10.19871/j.cnki.xfcrbzz.2024.06.009

摘要/Abstract

摘要： 目的探究外周血微小核糖核酸-155（microribonucleic acid-155,miR-155）、微小核糖核酸-181a（microribonucleic acid-181a,miR-181a）在乙型肝炎病毒（hepatitis B virus,HBV）相关肝细胞癌（hepatocellular carcinoma,HCC）患者中的表达水平,分析两者对HBV HCC的诊断价值及与临床病理特征和生存预后的关系。方法选取2017年1月至2021年1月在重庆市中医院接受治疗的HBV HCC患者117例作为肝细胞癌组、HBV相关良性肝病117例作为慢性肝病组,包括慢性乙型肝炎患者71例、乙型肝炎肝硬化患者46例,采集外周血,比较两组miR-155、miR-181a表达差异,分析miR-155、miR-181a表达与HBV相关HCC患者发病及临床病理特征的关系。绘制受试者操作特征（receiver operating characteristic,ROC）曲线评价外周血miR-155、miR-181a表达对HBV相关HCC的诊断价值。随访3年,Kaplan-Meier法分析miR-155、miR-181a对HBV相关HCC患者生存率的影响。结果肝细胞癌组外周血miR-155、miR-181a表达均较慢性肝病组高（P<0.05）。外周血miR-155、miR-181a表达与HBV相关HCC发病、HBV-DNA载量、门静脉侵袭、临床分期、淋巴结转移呈正相关,与分化程度呈负相关（P<0.05）。外周血miR-155、miR-181a诊断HBV相关HCC的曲线下面积（area under the curve,AUC）值分别为0.768、0.818,二者联合诊断AUC值0.923,明显高于各指标单独诊断,此时最佳敏感度、特异度分别为83.76%、88.03%。miR-155高表达亚组3年生存率为82.14%,明显低于低表达亚组的94.74%（P<0.05）;miR-181a高表达亚组3年生存率为80.36%,明显低于低表达亚组的96.49%（P<0.05）。结论 HBV相关HCC患者外周血miR-155、miR-181a表达异常升高,二者共同参与HBV相关HCC发病及恶性进展,检测其水平对于疾病诊断及预后预测具有一定价值。

关键词: 乙型肝炎病毒, 肝细胞癌, 微小核糖核酸-155, 微小核糖核酸-181a

Abstract: Objective To explore the expression levels of microribonucleic acid-155 (miR-155) and microribonucleic acid-181a (miR-181a) in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), analyze their diagnostic value for HBV-related HCC, as well as their relationship with clinical pathological characteristics and survival prognosis. Method A total of 117 HBV-related HCC patients who received treatment in Chongqing Hospital of Traditional Chinese Medicine from January 2017 to January 2021 were selected as the hepatocellular carcinoma group, and 117 cases of HBV-related benign liver disease were selected as the benign liver disease group. The peripheral blood was collected for comparison between the two groups on miR-155 and miR-181a expression differences, and analysis of the relationship between miR-155 and miR-181a expression and the pathogenesis and clinical pathological characteristics of HBV-related HCC patients. Receiver operating characteristic (ROC) curve was drawn to evaluate the diagnostic value of peripheral blood miR-155 and miR-181a expression for HBV-related HCC. After a 3-year follow-up, the impact of miR-155 and miR-181a on the survival rate of HBV-related HCC patients was analyzed using Kaplan-Meier method. Result The expressions of miR-155 and miR-181a in peripheral blood of hepatocellular carcinoma group were higher than those of benign liver disease group (P<0.05). The expression of miR-155 and miR-181a in peripheral blood was positively correlated with the onset of HBV-related HCC, HBV-DNA load, portal vein invasion, clinical stage and lymph node metastasis, and negatively correlated with the differentiation degree (P＜0.05). The area under the curve (AUC) values of miR-155 and miR-181a in peripheral blood for diagnosing HBV-related HCC were 0.768 and 0.818, respectively, and the AUC value of combined diagnosis was 0.923, which was significantly higher than that of individual diagnosis. At this time, the optimal sensitivity and specificity were 83.76% and 88.03%, respectively. The 3-year survival rate of miR-155 high expression subgroup was 82.14%, significantly lower than that of low expression subgroup (94.74%) (P＜0.05). The 3-year survival rate of miR-181a in the high-expression subgroup was 80.36%, which was significantly lower than that in the low-expression subgroup (96.49%) (P＜0.05). Conclusion The expression of miR-155 and miR-181a in peripheral blood of HBV-related HCC patients is abnormally elevated, and both of them are involved in the pathogenesis and malignant progression of HBV-related HCC. The detection of their levels is of certain value for disease diagnosis and prognosis prediction.

Key words: Hepatitis B virus, Hepatocellular carcinoma, Microribonucleic acid-155, Microribonucleic acid-181a

中图分类号:

R735.7

王凌, 刘志东, 周丹丹. 乙型肝炎病毒相关肝细胞癌患者外周血miR-155、miR-181a表达意义探究[J]. 新发传染病电子杂志, 2024, 9(6): 48-53.

Wang Ling, Liu Zhidong, Zhou Dandan. Expression significance of miR-155 and miR-181a in peripheral blood of patients with HBV-associated hepatocellular carcinoma[J]. Electronic Journal of Emerging Infectious Diseases, 2024, 9(6): 48-53.

参考文献

[1] 陈倩倩, 芮法娟, 倪文婧, 等. 原发性肝癌的流行病学及其危险因素研究进展[J].中国全科医学, 2024, 27(6):637-642.
[2] SANGRO B, SAROBE P, HERVÁS-STUBBS S, et al.Advances in immunotherapy for hepatocellular carcinoma[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(8):525-543.
[3] JIANG Y, HAN QJ, ZHAO HJ, et al.The Mechanisms of HBV-Induced Hepatocellular Carcinoma[J].J Hepatocell Carcinoma, 2021, 8(12):435-450.
[4] REN ZG, XU JM, BAI YX, et al.Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32):a randomised, open-label,phase 2-3 study[J].Lancet Oncol, 2021, 22(7):977-990.
[5] 王苏华, 罗滢, 陆静尔. B3型柯萨奇病毒感染的胰岛β细胞中microRNAs表达的变化及生物学意义[J].病毒学报, 2022, 38(2):298-304.
[6] 刘若琪, 杨永裕, 肖旺, 等. 恩替卡韦通过微小RNA-199a-5p抑制乙型肝炎病毒复制的机制研究[J].中国临床药理学杂志, 2022, 38(24):2969-2973.
[7] HUANG WT, KUO SH, KUO YC, et al.miR-155-regulated mTOR and Toll-like receptor 5 in gastric diffuse large B-cell lymphoma[J].Cancer Med, 2022, 11(3):555-570.
[8] 王伟, 陈文青, 陈建丽, 等. 慢性乙型肝炎患者血清miR-375和miR-155与miR-629的表达及临床意义[J].中华医院感染学杂志, 2023, 33(4):481-484.
[9] JIN H, LI CX, DONG PH, et al.Circular RNA cMTO1 Promotes PTEN Expression Through Sponging miR-181b-5p in Liver Fibrosis[J]. Front Cell Dev Biol, 2020 ,8(11):714-721.
[10] 中华医学会肝病学分会, 中华医学会感染病分会. 慢性乙型肝炎防治指南[J]. 中国临床医生, 2012, 40(4):66-78.
[11] 中华医学会传染病与寄生虫病学分会, 中华医学会肝病学分会. 病毒性肝炎防治方案[J].中华传染病杂志, 2001, 19(1):56-62
[12] 中华人民共和国卫生和计划生育委员会医政医管局.原发性肝癌诊疗规范(2017年版)[J].中华肝脏病杂志, 2017, 25(12):886-895.
[13] CHENG Y, GUNASEGARAN B, SINGH HD, et al.Non-terminally exhausted tumor-resident memory HBV-specific T cell responses correlate with relapse-free survival in hepatocellular carcinoma[J].Immunity, 2021, 54(8):1825-1840.
[14] 李晓月, 李述捷, 易永祥. 乙型肝炎病毒和丙型肝炎病毒相关性肝癌的研究进展[J/CD]. 新发传染病电子杂志, 2022, 7(1):92-99.
[15] 李渊, 何开明, 王超. 肺癌患者血清中miRNA-144-3p表达及临床意义[J].临床肿瘤学杂志, 2022,27(10):891-895.
[16] 周传亚, 陈东英, 满晓丽. HR-HPV阳性宫颈癌血浆中miRNA-10b、miRNA-664、FEZF1-AS1的表达及其对预后的评估价值[J].实用癌症杂志, 2023, 38(11):1817-1822.
[17] 唐炜, 张丰林, 胡楠, 等. miR-155、CD1d在胃腺癌患者外周血中的表达及其与预后的相关性研究[J].临床和实验医学杂志, 2022, 21(17):1840-1845.
[18] MOHAMED MA, MOHAMED EI, EL-KAREAM SAA, et al.Underexpression of miR-486-5p but not Overexpression of miR-155 is Associated with Lung Cancer Stages[J].Microrna, 2018, 7(2):120-127.
[19] SONG XJ, TAN SY, WU ZC, et al.HBV suppresses ZHX2 expression to promote proliferation of HCC through miR-155 activation[J].Int J Cancer, 2018, 143(12):3120-3130.
[20] 罗艳香, 程含, 吴波, 等. 慢性HBV感染血清miR-122和miR-155与miR-375表达及意义[J].中华医院感染学杂志, 2021, 31(21):3230-3234.
[21] EL TAYEBI HM, WALY AA, ASSAL RA, et al.Transcriptional activation of the IGF-Ⅱ/IGF-1R axis and inhibition of IGFBP-3 by miR-155 in hepatocellular carcinoma[J]. Oncol Lett, 2015, 10(5):3206-3212.
[22] ZHANG L, WANG W, LI XB, et al.MicroRNA-155 promotes tumor growth of human hepatocellular carcinoma by targeting ARID2[J].Int J Oncol,2016,48(6):2425-2434.
[23] SUN CF, SHEN C, ZHANG YP, et al.LncRNA ANRIL negatively regulated chitooligosaccharide-induced radiosensitivity in colon cancer cells by sponging miR-181a-5p[J]. Adv Clin Exp Med, 2021, 30(1):55-65.
[24] WANG Y, FANG YX, DONG B, et al.Discovery of extracellular vesicles derived miR-181a-5p in patient's serum as an indicator for bone-metastatic prostate cancer[J].Theranostics, 2021, 11(2):878-892.
[25] 何畔, 汪志军, 曾旭凯. miR-181a通过靶向PTEN促进软骨肉瘤细胞的生长[J].中国医师杂志, 2023, 25(4):541-545.
[26] 余蕙君, 刘青, 崔胜金, 等. 结直肠癌组织lncRNA CRNDE、miR-181 a表达变化及其与患者临床病理特征的关系[J].山东医药, 2019, 59(19):57-59,81.