Kanai Y, Hui A M, Sun L, Ushijima S, Sakamoto M, Tsuda H, Hirohashi S
Pathology Division, National Cancer Center Research Institute, Tokyo, Japan.
Hepatology. 1999 Mar;29(3):703-9. doi: 10.1002/hep.510290338.
To examine the significance of aberrant DNA methylation in hepatocarcinogenesis, the DNA methylation status at the D17S5 locus and mRNA expression of a candidate tumor suppressor gene, HIC-1 (hypermethylated-in-cancer), which was identified at the D17S5 locus, in primary hepatocellular carcinomas (HCCs) and their corresponding noncancerous liver tissues were assessed. DNA hypermethylation at the D17S5 locus was detected in 44% of the noncancerous liver tissues showing chronic hepatitis or cirrhosis, which are widely considered to be precancerous conditions, but was not observed in noncancerous liver tissues showing no remarkable histological findings. The incidence of DNA hypermethylation at this locus was significantly higher in HCCs (90%) than noncancerous liver tissues (P <.001). Loss of heterozygosity at the D17S5 locus, which was preceded by DNA hypermethylation at the same locus, was detected in 54% of HCCs. The HIC-1 mRNA expression level of noncancerous liver tissues showing chronic hepatitis or cirrhosis was significantly lower than that of noncancerous liver tissues showing no remarkable histological findings (P <.01), and that of HCCs was even lower than that of noncancerous liver tissues (P <.05). Poorly differentiated HCCs showed lower expression levels than well- to moderately differentiated HCCs. Mutation of the p53 gene may be involved in HIC-1 inactivation. Moreover, wild-type p53 did not overcome DNA hypermethylation at the D17S5 locus to activate HIC-1 in HCCs. These data suggest that aberrant DNA methylation at this locus and reduced HIC-1 mRNA expression participate in hepatocarcinogenesis during both early developmental stages and malignant progression of HCCs.
为了研究异常DNA甲基化在肝癌发生中的意义，我们评估了原发性肝细胞癌（HCC）及其相应的非癌性肝组织中D17S5位点的DNA甲基化状态以及在该位点鉴定出的候选肿瘤抑制基因HIC-1（癌症中高甲基化）的mRNA表达。在44%显示慢性肝炎或肝硬化的非癌性肝组织中检测到D17S5位点的DNA高甲基化，慢性肝炎或肝硬化被广泛认为是癌前病变，但在无明显组织学改变的非癌性肝组织中未观察到这种情况。该位点DNA高甲基化的发生率在HCC中（90%）显著高于非癌性肝组织（P<.001）。在54%的HCC中检测到D17S5位点的杂合性缺失，其发生在同一位点的DNA高甲基化之后。显示慢性肝炎或肝硬化的非癌性肝组织的HIC-1 mRNA表达水平显著低于无明显组织学改变的非癌性肝组织（P<.01），而HCC的HIC-1 mRNA表达水平甚至低于非癌性肝组织（P<.05）。低分化HCC的表达水平低于高分化至中分化HCC。p53基因的突变可能参与了HIC-1的失活。此外，野生型p53不能克服HCC中D17S5位点的DNA高甲基化来激活HIC-1。这些数据表明，该位点的异常DNA甲基化和HIC-1 mRNA表达降低在HCC的早期发育阶段和恶性进展过程中均参与了肝癌发生。
