白细胞介素-6启动子低甲基化作为乙型肝炎病毒相关肝细胞癌的诊断生物标志物。
IL-6 Promoter Hypomethylation Acts As a Diagnostic Biomarker in Hepatitis B Virus-Associated Hepatocellular Carcinoma.
作者信息
Yang Jie-Ru, Wang Ju, Li Hai-Ming, Gao Shuai, Fan Yu-Chen, Wang Kai
机构信息
Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China.
Institute of Hepatology, Shandong University, Jinan, China.
出版信息
Front Oncol. 2022 Mar 11;12:746643. doi: 10.3389/fonc.2022.746643. eCollection 2022.
BACKGROUND
New biomarkers are needed to detect hepatocellular carcinoma at an earlier stage and to individualize treatment strategies. IL-6 has been proven to be associated with liver cancer in numerous studies.
AIM
To evaluate the value of the IL-6 promoter methylation level as a noninvasive biomarker for the diagnosis of liver cancer.
METHODS
A retrospective analysis of 165 patients with HBV-associated hepatocellular carcinoma (HCC), 198 patients with chronic hepatitis B (CHB) and 31 healthy controls were involved. The methylight was detected the methylation level of the IL-6 promoter in peripheral blood mononuclear cells (PBMCs), clinical and laboratory parameters were obtained.
RESULTS
IL-6 promoter methylation levels were significantly lower in patients with HCC (median 53.59%, interquartile range 52.01-54.75%) than in those with CHB (median 56.05%, interquartile range 54.65-57.67%; P<0.001). The level of IL-6 mRNA in patients with HCC (median 0.371, interquartile range 0.173-0.671) was significantly higher than that in patients with CHB (median 0.203, interquartile range 0.108-0.354; P<0.001) and HCs (median 0.189, interquartile range 0.140-0.262; P=0.001). Meanwhile, the PMR value of IL-6 was notably negatively correlated with the mRNA expression level (Spearman's R=-0.201, P<0.001). The IL-6 PMR value of HCC patients in age (Spearman's R=0.193, P=0.026) and TBIL (Spearman's R=0.186, P=0.032) were very weak correlated. At the same time, the level of IL-6 promoter methylation was also an independent factor in the development of liver cancer. When the IL-6 promoter methylation level was used to diagnose HCC, its detective value was superior to AFP [area under the receiver operating characteristic curve (AUC) 0.773 . 0.686, P=0.027], And the combined use of AFP and IL-6 methylation level can improve the area under the receiver operating characteristic curve (p=0.011).
CONCLUSION
IL-6 promoter hypomethylation is present in hepatocellular carcinoma, and it may be used as a noninvasive biomarker to detect early liver cancer.
背景
需要新的生物标志物来更早地检测肝细胞癌并使治疗策略个体化。众多研究已证实白细胞介素-6（IL-6）与肝癌有关。
目的
评估IL-6启动子甲基化水平作为肝癌诊断的非侵入性生物标志物的价值。
方法
对165例乙型肝炎病毒相关肝细胞癌（HCC）患者、198例慢性乙型肝炎（CHB）患者和31例健康对照进行回顾性分析。采用甲基化特异性PCR检测外周血单个核细胞（PBMCs）中IL-6启动子的甲基化水平，并获取临床和实验室参数。
结果
HCC患者的IL-6启动子甲基化水平（中位数53.59%，四分位间距52.01 - 54.75%）显著低于CHB患者（中位数56.05%，四分位间距54.65 - 57.67%；P<0.001）。HCC患者的IL-6 mRNA水平（中位数0.371，四分位间距0.173 - 0.671）显著高于CHB患者（中位数0.203，四分位间距0.108 - 0.354；P<0.001）和健康对照（中位数0.189，四分位间距0.140 - 0.262；P = 0.001）。同时，IL-6的启动子甲基化率（PMR）值与mRNA表达水平显著负相关（Spearman相关系数R = -0.201，P<0.001）。HCC患者的IL-6 PMR值与年龄（Spearman相关系数R = 0.193，P = 0.026）和总胆红素（TBIL）（Spearman相关系数R = 0.186，P = 0.032）的相关性非常弱。同时，IL-6启动子甲基化水平也是肝癌发生的独立因素。当用IL-6启动子甲基化水平诊断HCC时，其诊断价值优于甲胎蛋白[受试者操作特征曲线下面积（AUC）0.773对0.686，P = 0.027]，并且联合使用甲胎蛋白和IL-6甲基化水平可提高受试者操作特征曲线下面积（P = 0.011）。
结论
肝细胞癌中存在IL-6启动子低甲基化，它可能作为检测早期肝癌的非侵入性生物标志物。
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