Nam Jeong-Seok, Ino Yoshinori, Kanai Yae, Sakamoto Michiie, Hirohashi Setsuo
Pathology Division, National Cancer Center Research Institute, Tokyo, Japan.
Clin Exp Metastasis. 2004;21(1):49-56. doi: 10.1023/b:clin.0000017180.19881.c1.
Down-regulation of the E-cadherin-mediated cell adhesion system is strongly related to cancer invasion and metastasis. Aberrant CpG hypermethylation in the promoter region of the E-cadherin gene has been shown to be responsible for reduction of E-cadherin expression. The present study was designed to test the hypothesis that the demethylating agent 5-aza-2'-deoxycytidine (AZA) can restore the E-cadherin system and reduce the potential for metastasis. AZA treatment modified the methylation status of the 5' CpG island in the E-cadherin promoter, and induced re-expression of E-cadherin in human cancer cells whose E-cadherin expression had been silenced. The re-expressed E-cadherin was correlated with increased in vitro aggregation and reduced motility. After inoculation of cancer cells (MDA-MB-435S) into the mammary fat pads of mice with severe combined immunodeficiency, the mice were treated for nine consecutive weeks with AZA three times per week i.p. The AZA treatment suppressed both growth of the primary tumor and lung metastasis in comparison with untreated controls, suggesting that the suppression of metastasis may be, at least partly, attributable to restoration of E-cadherin expression. Therefore, inhibition of DNA methylation may be useful for preventing cancer metastasis.
E-钙黏蛋白介导的细胞黏附系统下调与癌症侵袭和转移密切相关。E-钙黏蛋白基因启动子区域异常的CpG高甲基化已被证明是E-钙黏蛋白表达降低的原因。本研究旨在验证脱甲基剂5-氮杂-2'-脱氧胞苷（AZA）能否恢复E-钙黏蛋白系统并降低转移潜能这一假说。AZA处理改变了E-钙黏蛋白启动子中5'CpG岛的甲基化状态，并在E-钙黏蛋白表达已沉默的人类癌细胞中诱导E-钙黏蛋白重新表达。重新表达的E-钙黏蛋白与体外聚集增加和运动性降低相关。将癌细胞（MDA-MB-435S）接种到严重联合免疫缺陷小鼠的乳腺脂肪垫中后，每周给小鼠腹腔注射三次AZA，连续治疗九周。与未处理的对照组相比，AZA处理抑制了原发性肿瘤的生长和肺转移，这表明转移的抑制可能至少部分归因于E-钙黏蛋白表达的恢复。因此，抑制DNA甲基化可能对预防癌症转移有用。
