Honda T, Tamura G, Waki T, Kawata S, Terashima M, Nishizuka S, Motoyama T
Department of Pathology, Yamagata University School of Medicine, Yamagata, Japan.
Br J Cancer. 2004 Feb 23;90(4):838-43. doi: 10.1038/sj.bjc.6601600.
Melanoma antigen (MAGE)-encoding genes are expressed in various tumour types via demethylation of their promoter CpG islands, which are silent in all non-neoplastic tissues except for the testis and placenta. The clinicopathological significance of demethylation of MAGE genes in gastric carcinoma is not known. We investigated the promoter methylation status of MAGE-A1 and -A3 in 10 gastric cancer cell lines and in surgical specimens from 84 gastric cancer patients by methylation-specific PCR (MSP). Expression of MAGE-A1 and -A3 in the 10 gastric cancer cell lines was also investigated by RT-PCR. Any correlation between the methylation status of the MAGE promoters and clinicopathological characteristics of the gastric cancer patients was then assessed. Eight of the 10 gastric cancer cell lines showed demethylation of both MAGE-A1 and -A3, and the remaining two cell lines did either of MAGE-A1 or -A3. Expression of MAGE-A1 and -A3 was confirmed in seven and nine of the 10 gastric cancer cell lines, respectively. The MAGE-A1 and -A3 promoters were demethylated in 29% (25 out of 84) and 66% (56 out of 84) of the gastric tumour specimens, respectively. Demethylation of both MAGE-A1 and -A3 promoters (n=22) was found more frequently in gastric cancer patients in advanced clinical stages (P=0.0035), and these patients also exhibited a higher incidence of lymph node metastasis (P=0.0007) compared to those patients without demethylation (n=25). Furthermore, demethylation patients tended to have a worse prognosis, although this difference was not statistically significant (P=0.183). Demethylation of MAGE-A1 and -A3 occurs during progressive stages of gastric cancer, and may be associated with aggressive biological behaviour of gastric cancer.
黑色素瘤抗原（MAGE）编码基因通过其启动子CpG岛的去甲基化在多种肿瘤类型中表达，这些启动子在除睾丸和胎盘外的所有非肿瘤组织中均保持沉默。MAGE基因去甲基化在胃癌中的临床病理意义尚不清楚。我们通过甲基化特异性PCR（MSP）研究了10种胃癌细胞系以及84例胃癌患者手术标本中MAGE-A1和-A3的启动子甲基化状态。还通过RT-PCR研究了10种胃癌细胞系中MAGE-A1和-A3的表达。然后评估MAGE启动子的甲基化状态与胃癌患者临床病理特征之间的相关性。10种胃癌细胞系中有8种显示MAGE-A1和-A3均去甲基化，其余两种细胞系仅MAGE-A1或-A3其中之一去甲基化。分别在10种胃癌细胞系中的7种和9种中证实了MAGE-A1和-A3的表达。胃癌标本中MAGE-A1和-A3启动子去甲基化的比例分别为29%（84例中的25例）和66%（84例中的56例）。在临床晚期胃癌患者中，MAGE-A1和-A3启动子均去甲基化（n=22）的情况更为常见（P=0.0035），与未去甲基化的患者（n=25）相比，这些患者的淋巴结转移发生率也更高（P=0.0007）。此外，去甲基化患者的预后往往较差，尽管这种差异无统计学意义（P=0.183）。MAGE-A1和-A3的去甲基化发生在胃癌进展阶段，可能与胃癌的侵袭性生物学行为有关。
