Methylation status of p14ARF, p15INK4b, and p16INK4a genes in human hepatocellular carcinoma
Methylation status of p14ARF, p15INK4b, and p16INK4a genes in human hepatocellular carcinoma
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DOI：
10.1111/j.1478-3231.2005.01162.x
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发表时间：
2005-12-01
影响因子：
6.7
通讯作者：
Saisho, H
中科院分区：
文献类型：
--
作者：
Fukai, K;Yokosuka, O;Saisho, H
背景资料：INK 4基因座由参与细胞周期调控的三个基因p16 INK 4a、p15 INK 4 b和p14 ARF组成，在人类肿瘤中经常被破坏。方法：应用甲基化特异性PCR技术检测肝细胞癌（HCC）中各基因启动子区甲基化。结果如下：p16 INK 4a、p15 INK 4 b和p14 ARF的甲基化分别在39例HCC肿瘤中的27例（69.2%）、7例（17.9%）和0例中发生。对于相应的非肿瘤性肝组织，p16 INK 4a，p15 INK 4 b和p14 ARF的启动子区域分别在17个样品中的3个（17.6%），3个（17.6%）和0个中甲基化。mRNA表达分析显示p16 INK 4a表达缺失在HCC中常见。p14 ARF和p15 INK 4 b的表达分别为88.9%（16/18）和88.9%（16/18）。结论：p16 INK 4a基因启动子甲基化在肝癌早期和晚期均存在，提示p16 INK 4a基因启动子的表观遗传学改变可能参与了肝癌的发生。结合RT-PCR分析结果，认为p14 ARF或p15 INK 4a启动子异常甲基化在肝癌发生中的作用是有限的。
Background: The INK4 locus consisting of three genes involved in the regulation of cell cycle, p16INK4a, p15INK4b, and p14ARF is often disrupted in human neoplasms. Methods: We analyzed the promoter methylation of each gene by methylation-specific PCR in hepatocellular carcinoma (HCC). Results: The methylation of p16INK4a, p15INK4b, and p14ARF was found to occur in 27 (69.2%), seven (17.9%), and none out of 39 HCC tumors, respectively. Regarding corresponding nontumorous liver tissues, the promoter regions of p16INK4a, p15INK4b, and p14ARF were methylated in three (17.6%), three (17.6%), and none out of 17 samples, respectively. Analysis of mRNA expression revealed that loss of p16INK4a expression was frequently observed in HCC. In contrast, transcripts of p14ARF and p15INK4b were detected in 16 (88.9%) and 16 (88.9%) of 18 tumors, respectively. Conclusions: The frequent loss of transcription of p16INK4a with promoter methylation not only in the advanced but also in the early stages of HCC suggests that the epigenetic alteration of p16INK4a promoter is likely to be involved in hepatocarcinogenesis. Together with the result of RT-PCR analysis, the role of aberrant methylation of p14ARF or p15INK4a promoter in hepatocarcinogenesis is thought to be limited.