CpG岛甲基化表型及OPCML基因甲基化与肝细胞癌发生的关系

Correlations of CpG Island Methylator Phenotype and OPCML Gene Methylation to Carcinogenesis of Hepatocellular Carcinoma

背景与目的:CpG岛甲基化表型(CpGislandmethylatorphenotype,CIMP)涉及到多个基因启动子同时甲基化,具有肿瘤特异性,与多种肿瘤的发生或预后相关,但有关肝癌CPG岛甲基化表型的研究罕见报道。OPCML(opioid-bindingprotein/celladhesionmolecule-like)基因目前多为针对上皮性卵巢癌的研究,被认为是卵巢癌的候选抑癌基因。本研究旨在探讨CIMP及OPCML基因与肝癌的发生是否有关。方法:运用甲基化特异性PCR方法检测50例肝细胞癌组织及48例癌旁组织中OPCML、p15、SOCS-1、GST-p、RAR-b、p16、p73、p14、MGMT和hMLH1基因的甲基化状况。结果:肝癌组织甲基化率普遍比相应癌旁组织甲基化率高:OPCML(70.0%vs.64.6%)、p15(58.0%vs.50.0%)、SOCS-1(78.0%vs.50.0%)、GST-p(56.0%vs.27.1%)、RAR-b(30.0%vs.6.3%)、p16(26.0%vs.14.6%)、p73(16.0%vs.0%)、p14(36.0%vs.27.1%)、MGMT(16.0%vs.10.4%)和hMLH1(18.0%vs.4.2%)。SOCS-1,GST-p,RAR-b,p16和p73基因甲基化率在肝癌组与癌旁组差异有显著性(P<0.05),其它基因两组之间的甲基化率差异无显著性。CIMP阳性组(同时具有≥3个位点甲基化)复发时间较早,1年无瘤生存率为18.2%,而CIMP阴性组(具有<3个位点甲基化)复发时间较晚,1年无瘤生存率为75.0%(P<0.05)。结论:肝癌中存在着CpG岛甲基化表型(CIMP),CIMP可作为肝癌患者预后判断的指标之一;OPCML基因甲基化可能在肝癌的发生中发挥重要的作用。

BACKGROUND ＆ OBJECTIVE.. CpG island methylator phenotype （CIMP） is cancer-specific and involves in the promoter hypermethylation of multiple genes. It is correlated to the genesis or prognosis of various tumors, but it has rarely been reported in hepatocellular carcinoma （HCC）. OPCML （opioid-binding protein/cell adhesion molecule-like） gene has been studied mainly in epithelial ovarian cancer, and is thought to be a candidate tumor suppressor gene in epithelial ovarian cancer. This study was to explore the correlations of CIMP and OPCML gene expression to the carcinogenesis of HCC. METHODS. The methylation status of OPCML, p15, SOCS-1, GST-p, RAR-b, p16, p73, p14, MGMT, hMLH1 in 50 specimens of HCC and pericancer tissues was detected using methylation-specific polymerase chain reaction （MSP）. RESULTS： The hypermethylation rates of genes were higher in HCC than in pericancer tissues [OPCML （70.0% vs. 64.6%）, p15 （58.0% vs. 50.0%）, SOCS-1 （78.0% vs. 50.0%）, GST-p （56.0% vs. 27.1%）, RAR-b （30.0% vs. 6.3%）, p16 （26.0% vs. 14.6%）, p73 （16.0% vs. 0%）, p14 （36.0 vs. 27.1%）, MGMT （16.0% vs. 10.4%）, and hMLH1 （18.0% vs. 4.2%）]. The methylation rates of SOCS-1, GST-p, RAR-b, p16 and p73 were significantly higher in HCC than in adjacent non- neoplastic tissues （P〈0.05）. The recurrence occurred earlier in CIMP-positive group （≥3 methylated genes） than in CIMP-negative group （〈3 methylated genes） （P〈0.05）. The 1-year disease-freely survival rate was significantly lower in CIMP-positive group than in CIMP-negative group （18.2% vs. 75.0%, P〈0.05）. CONCLUSIONS： CiMP exists in HCC, and may be a prognostic factor of HCC. Promoter methylation of OPCML gene may play an important role in hepatocarcinogenesis.