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首页> 外文期刊>Cell biology international. >Promoter hypermethylation of DNA damage response genes in hepatocellular carcinoma.
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Promoter hypermethylation of DNA damage response genes in hepatocellular carcinoma.

机译：肝细胞癌中DNA损伤反应基因的启动子高甲基化。

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摘要

Aberrant methylation of promoter CpG islands is a major inactivation mechanism of tumour-related genes that play a crucial role in the progression of silencing in human cancers, including HCC (hepatocellular carcinoma). We have examined the promoter methylation status of five important DNA damage response genes in fresh-frozen HCC tissues and cell lines, as well as the possible correlation between methylation patterns and clinical features of the carcinoma. Promoter methylation status of RASSF1A (Ras association domain family 1), CHFR (checkpoint with forkhead and ring finger domains), GSTP1 (glutathione-S-transferase-pi gene), MGMT [O(6)-methylguanine-DNA methyltransferase] and hMLH1 (human mutL homologue 1) were examined by the MSP (methylation-specific PCR) in 70 HCC tissues and five HCC cell lines. The mRNA expression levels of these genes were measured by RT-PCR (reverse transcription-PCR). Methylation frequencies of these genes tested in HCC were 54 (78%) for RASSF1A, 30 (43%) for CHFR, 26 (38%) for GSTP1 and 22 (32%) for MGMT. No hypermethylation was detected for hMLH1 in any case of HCC or HCC cell lines. Moreover, promoter hypermethylation of RASSF1A, CHFR and GSTP1 in both HepG2 and SNU398 cells, and hypermethylation of MGMT in Huh7 cells, were detected. Treatment of three cell lines with 5Aza-dC (5-aza-20-deoxycytidine) restored or increased the expression of these genes, implicating aberrant DNA methylation in transcriptional silencing. Hypermethylation of RASSF1A and patient age were significantly associated. CHFR methylation status showed a statistically significant correlation with HCC progression. Methylation of the RASSF1A, CHFR, GSTP1 and MGMT genes seem therefore to play an important role in the pathogenesis of HCC. These epigenetic changes may have prognostic importance for patients with HCC.
机译：启动子CpG岛的异常甲基化是肿瘤相关基因的主要失活机制，这些基因在人类癌症（包括HCC（肝细胞癌））的沉默进程中起着至关重要的作用。我们已经检查了新鲜冷冻的HCC组织和细胞系中五个重要的DNA损伤反应基因的启动子甲基化状态，以及甲基化模式与癌症临床特征之间的可能相关性。 RASSF1A（Ras关联结构域家族1），CHFR（带有叉头和无名指结构域的检查点），GSTP1（谷胱甘肽-S-转移酶-pi基因），MGMT [O（6）-甲基鸟嘌呤-DNA甲基转移酶]和hMLH1的启动子甲基化状态通过MSP（甲基化特异性PCR）检查了70个HCC组织和5个HCC细胞系中的人（人mutL同源物1）。通过RT-PCR（逆转录-PCR）测量这些基因的mRNA表达水平。在HCC中测试的这些基因的甲基化频率对于RASSF1A是54（78％），对于CHFR是30（43％），对于GSTP1是26（38％），对于MGMT是22（32％）。在任何HCC或HCC细胞系中，均未检测到hMLH1的甲基化过高。此外，检测到HepG2和SNU398细胞中RASSF1A，CHFR和GSTP1的启动子超甲基化，以及Huh7细胞中MGMT的超甲基化。用5Aza-dC（5-aza-20-脱氧胞苷）处理三种细胞系可恢复或增加这些基因的表达，暗示转录沉默中DNA甲基化异常。 RASSF1A的超甲基化与患者年龄显着相关。 CHFR甲基化状态显示与HCC进展有统计学显着相关性。因此，RASSF1A，CHFR，GSTP1和MGMT基因的甲基化似乎在HCC的发病机理中起重要作用。这些表观遗传学改变对于肝癌患者可能具有预后意义。

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