Ding Sheng, Gong Bang-Dong, Yu Jian, Gu Jun, Zhang Hong-Yu, Shang Zu-Bin, Fei Qi, Wang Peng, Zhu Jing-De
The State-key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, LN 2200/25, Xie-Tu Road, Shanghai 200032, China.
World J Gastroenterol. 2004 Dec 1;10(23):3433-40. doi: 10.3748/wjg.v10.i23.3433.
To establish the DNA methylation patterns of the promoter CpG islands of 14 "drug-resistance" genes in hepatocellular carcinoma (HCC).
The methylation specific polymerase chain reaction in conjunction with sequencing verification was used to establish the methylation patterns of the 14 genes in the liver tissues of four healthy liver donors, as well as tumor and the paired non-cancerous tissues of 30 HCC patients.
While 11 genes (ATP-binding cassette, sub-family G (WHITE), member 2(ABCG2), activating transcription factor (ATF2), beta-2-microglobulin (B2M), deoxycytidine kinase (DCK), occludin (OCLN), v-raf-1 murine leukemia viral oncogene homolog (RAF1), ralA binding protein 1 (RALBP1), splicing factor (45 kD) (SPF45), S-phase kinase-associated protein 2 (p45) (SKP2), tumor protein p53 (Li-Fraumeni syndrome) (TP53) and topoisomerase (DNA) II beta (TOP2B)) maintained the unmethylated patterns, three genes displayed to various extents the hypermethylation state in tumor tissues in comparison with the normal counterparts. The catalase (CAT) was hypermethylated in tumor and the neighboring non-cancerous tissue of one case (3.3%). Both glutathione S-transferase pi (GSTpi) (80%, 24/30 in tumor and 56.7%, 17/30 in the paired non-cancerous tissues) and cystic fibrosis transmembrane conductance regulator, ATP-binding cassette (sub-family C, member 7) (CFTR) (77%, 23/30 in tumor and 50%, 15/30 in the paired non-cancerous tissues) genes were prevalently hypermethylated in HCC as well as their neighboring non-cancerous tissues. No significant difference in the hypermethylation occurrence was observed between the HCC and its neighboring non-cancerous tissues.
Hypermethylation of promoter CpG islands of both CFTR and GSTpi genes occurs prevalently in HCC, which may correlate with the low expression of these two genes at the mRNA level and has the profound etiological and clinical implications. It is likely to be specific to the early phase of HCC carcinogenesis.
建立肝细胞癌（HCC）中14个“耐药”基因启动子CpG岛的DNA甲基化模式。
采用甲基化特异性聚合酶链反应结合测序验证，以建立4名健康肝脏供体肝组织以及30例HCC患者肿瘤组织和配对癌旁组织中14个基因的甲基化模式。
11个基因（ATP结合盒亚家族G（白色）成员2（ABCG2）、激活转录因子（ATF2）、β2微球蛋白（B2M）、脱氧胞苷激酶（DCK）、闭合蛋白（OCLN）、v-raf-1鼠白血病病毒癌基因同源物（RAF1）、ralA结合蛋白1（RALBP1）、剪接因子（45kD）（SPF45）、S期激酶相关蛋白2（p45）（SKP2）、肿瘤蛋白p53（李-弗劳梅尼综合征）（TP53）和拓扑异构酶（DNA）Ⅱβ（TOP2B））保持未甲基化模式，与正常组织相比，3个基因在肿瘤组织中不同程度地呈现高甲基化状态。1例患者（3.3%）的肿瘤组织及其相邻癌旁组织中的过氧化氢酶（CAT）呈高甲基化。谷胱甘肽S-转移酶π（GSTpi）（肿瘤组织中80%，24/30；配对癌旁组织中56.7%，17/30）和囊性纤维化跨膜传导调节因子、ATP结合盒（亚家族C，成员7）（CFTR）（肿瘤组织中77%，23/30；配对癌旁组织中50%，15/30）基因在HCC及其相邻癌旁组织中均普遍呈高甲基化。HCC与其相邻癌旁组织在高甲基化发生率上无显著差异。
CFTR和GSTpi基因启动子CpG岛的高甲基化在HCC中普遍存在，这可能与这两个基因在mRNA水平的低表达相关，并具有深远的病因学和临床意义。它可能是HCC致癌早期阶段所特有的。
