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人类原发性肝细胞癌中p53基因表达的降低与启动子区域甲基化相关,而与编码区突变无关。

Reduction of p53 gene expression in human primary hepatocellular carcinoma is associated with promoter region methylation without coding region mutation.

作者信息

Pogribny I P, James S Jill

机构信息

Division of Biochemical Toxicology, National Center for Toxicological Research, Food & Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA.

出版信息

Cancer Lett. 2002 Feb 25;176(2):169-74. doi: 10.1016/s0304-3835(01)00748-0.

Abstract

Functional inactivation of tumor suppressor genes during tumor progression has been shown to occur by either coding region mutation or promoter region methylation. Because of the functional equivalence of these two mechanisms, loss of tumor suppressor function generally occurs by one or the other mechanism, but rarely by both. Aberrant de novo methylation in most tumor suppressor promoter regions is found within CpG islands that occur near the transcription start site. The p53 promoter region is unique in that it does not contain a CpG island and therefore it is possible that methylation at critical CpG sites may be more important in gene silencing than total CpG methylation density. Other than site-specific aflatoxin B(1)-induced mutations, p53 coding region mutations are not frequently observed in most human primary hepatocellular carcinomas. In the present study, paired samples of human primary liver carcinoma and uninvolved tissue obtained from the same individual were evaluated for site-specific p53 promoter methylation status by methylation sensitive single nucleotide primer extension (Ms-SNuPE) and also for coding region mutations using polymerase chain reaction (PCR)- single strand conformation polymorphism (SSCP). The methylation pattern in the uninvolved tissue was variable at specific CpG sites, whereas the same sites had become highly methylated in tumor tissue from the same individual. Associated with de novo methylation, the level of p53 mRNA was significantly reduced in the tumor DNA relative to the uninvolved tissue DNA. None of the samples exhibited coding region mutations. Given that p53 mutations are rare in primary human liver tumors, these data suggest that transcriptional repression by p53 promoter methylation may contribute to tumor progression.

摘要

肿瘤进展过程中肿瘤抑制基因的功能失活已被证明是通过编码区突变或启动子区甲基化发生的。由于这两种机制在功能上等效,肿瘤抑制功能的丧失通常通过其中一种机制发生,但很少同时通过两种机制。大多数肿瘤抑制基因启动子区域的异常从头甲基化发生在转录起始位点附近的CpG岛中。p53启动子区域的独特之处在于它不包含CpG岛,因此关键CpG位点的甲基化在基因沉默中可能比总CpG甲基化密度更重要。除了位点特异性黄曲霉毒素B(1)诱导的突变外,在大多数人类原发性肝细胞癌中很少观察到p53编码区突变。在本研究中,通过甲基化敏感单核苷酸引物延伸(Ms-SNuPE)评估了从同一个体获得的人类原发性肝癌和未受累组织的配对样本的位点特异性p53启动子甲基化状态,并使用聚合酶链反应(PCR)-单链构象多态性(SSCP)评估了编码区突变。未受累组织中特定CpG位点的甲基化模式是可变的,而来自同一个体的肿瘤组织中相同位点已高度甲基化。与从头甲基化相关,相对于未受累组织DNA,肿瘤DNA中p53 mRNA的水平显著降低。所有样本均未表现出编码区突变。鉴于p53突变在原发性人类肝肿瘤中很少见,这些数据表明p53启动子甲基化导致的转录抑制可能促进肿瘤进展。

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