MT1G 在中晚期肝细胞癌组织中的甲基化状态 及对索拉非尼治疗预后的预测价值

Expression and methylation of MT1G and its predictive value for sorafenib effect of advanced HCC patients

摘要:

目的 探讨MT1G 在中晚期肝细胞癌组织中的表达和甲基化状态，以及对索拉非尼治疗预后的 预测价值。方法 调取西安交通大学第一附属医院病理室保存的2016 年11 月—2018 年5 月行肝切除术的 86 例中晚期肝细胞癌患者的病理组织蜡块。分别采用免疫组织化学法和甲基化特异性聚合酶链反应（MSP） 检测肝细胞癌组织中MT1G 蛋白的表达和甲基化状态，并分析其与患者临床病理特征的关系。所有患者术 后接受索拉非尼治疗，随访患者停药时间和总生存期。结果 肝细胞癌组织样本MT1G 蛋白阳性表达率低 于癌旁组织[34.88% VS 66.28%]，且MT1G 基因启动子甲基化率高于癌旁组织[60.46% VS 37.21%]（P <0.05）。 MT1G 蛋白阳性表达率与MT1G 基因启动子甲基化率呈负相关（r =-0.787，P =0.000）。肝细胞癌组织 MT1G 蛋白表达与肿瘤Child-Pugh 分级、BCLC 分期、术前血清甲胎蛋白水平有关（P <0.05）。MT1G 蛋白 阳性表达患者中位停药时间为15.0 个月，短于MT1G 蛋白阴性表达患者20.0 个月（P <0.05）。MT1G 蛋白阳 性表达患者与阴性表达患者中位生存时间[20.0 个月 VS 25.0 个月] 和总生存率[43.33% VS 60.71%] 比较，差 异无统计学意义（P >0.05）。结论 MT1G 蛋白在中晚期肝细胞癌组织中表达降低，可能与MT1G 基因启动 子过度甲基化有关。而且MT1G 阳性表达预示中晚期肝细胞癌患者接受索拉非尼治疗预后不良。

Abstract:

Objective To detect the expression and methylation of metallothionein 1G (MT1G) and its predictive value for sorafenib prognosis of advanced hepatocellular carcinoma (HCC) patients. Methods The colon cancer and adjacent tissue specimens were taken from 86 advanced HCC patients treated with sorafenib from 2016.11 to 2018.05. Immunohistochemistry method and methylation-specific PCR (MSP) were respectively performed to detect the expressions of MT1G protein and MT1G DNA promoter methylation. The relationships between MT1G protein and the clinical features was analyzed. Sorafenib treatment duration and overall survival were recorded. Results The positive expression rate of MT1G protein in HCC tissues was lower than that in peritumoral tissues [34.88% (30/86) VS 66.28% (57/86)], while MT1G DNA promoter methylation rate in HCC tissues was higher than that in peritumoral tissues [60.46% (52/86) VS 37.21% (32/86)] (all P < 0.05). MT1G protein expressions were negatively related with MT1G DNA promoter methylation status (r = -0.787, P = 0.000). MT1G protein levels would be related with Chil-Pugh classification, BCLC stage and serum AFP levels (P < 0.05). The median sorafenib treatment duration of patients with MT1G positive expressions was 15.0 months (4.0 to 27.0 months), shorter than that of patients 20.0 months (1.0 to 33.0 months) with MT1G negative expressions (P < 0.05). Besides, there were no statistical differences of the median survival [20.0 months (11.0 to 38.0 months) VS 25.0 months (4.0 to 40.0 months)] or overall survival [43.33% (13/30) VS 60.71% (34/56)] of patients with MT1G positive expressions and MT1G negative expression (P > 0.05). Conclusions There is significant evidence proofs that MT1G protein in HCC tissues may be low and related with DNA promoter methylation. And the positive MT1G protein expression may indicate the poor prognosis of advanced HCC patients with sorafenib.