Kim Dong-Sun, Kim Min-Jin, Lee Ji-Yun, Lee Su-Man, Choi Jun-Young, Yoon Ghil-Suk, Na Yeon-Kyung, Hong Hae-Sook, Kim Sang-Geol, Choi Jin-Eun, Lee Shin-Yeop, Park Jae-Yong
Department of Anatomy, Kyungpook National University, Daegu 702-422, Republic of Korea.
Mol Carcinog. 2009 Dec;48(12):1109-15. doi: 10.1002/mc.20561.
Promoter methylation is an important mechanism in gene silencing and is a key epigenetic event in cancer development. Homeobox A5 (HOXA5) is a master regulator of the morphogenesis and cell differentiation to be implicated as a tumor suppressor gene in breast cancer, but its role in lung cancer is still unknown. In this study, we have investigated the methylation status of the promoter region of the HOXA5 gene in nonsmall cell lung cancers (NSCLCs) using nested and standard methylation-specific PCR (MSP) and correlated the methylation status with clinicopathological features. With standard MSP analysis, HOXA5 methylation were found in 113 (81.3%) of 139 NSCLCs and 72 (51.8%) in their corresponding nonmalignant lung tissues. RT-PCR and immunohistochemical analysis showed that HOXA5 methylation correlates with gene expression. Moreover, in the patients with stage I disease, HOXA5 methylation was more frequent in smokers than in never-smokes (P = 0.01). There was no influence of HOXA5 methylation on survival in all NSCLCs or at stages II-IV. However, in the patients with stage I disease, HOXA5 methylation was associated with a borderline significantly worse survival (P = 0.09). These findings suggest that downregulation of the HOXA5 gene by aberrant promoter methylation occurs in the vast majority of NSCLCs and that it may play a role in the pathogenesis of NSCLC. Additional studies with larger sample sizes are required to evaluate the prognostic value of HOXA5 methylation in patients with stage I NSCLC.
启动子甲基化是基因沉默的重要机制，也是癌症发展过程中的关键表观遗传事件。同源框A5（HOXA5）是形态发生和细胞分化的主要调节因子，被认为是乳腺癌中的肿瘤抑制基因，但其在肺癌中的作用尚不清楚。在本研究中，我们使用巢式和标准甲基化特异性PCR（MSP）研究了非小细胞肺癌（NSCLC）中HOXA5基因启动子区域的甲基化状态，并将甲基化状态与临床病理特征相关联。通过标准MSP分析，在139例NSCLC中有113例（81.3%）发现HOXA5甲基化，在其相应的非恶性肺组织中有72例（51.8%）发现甲基化。RT-PCR和免疫组化分析表明，HOXA5甲基化与基因表达相关。此外，在I期疾病患者中，吸烟者中HOXA5甲基化比从不吸烟者更常见（P = 0.01）。HOXA5甲基化对所有NSCLC患者或II-IV期患者的生存没有影响。然而，在I期疾病患者中，HOXA5甲基化与生存率略差相关（P = 0.09）。这些发现表明，绝大多数NSCLC中存在异常启动子甲基化导致的HOXA5基因下调，并且它可能在NSCLC的发病机制中起作用。需要更多大样本量的研究来评估HOXA5甲基化在I期NSCLC患者中的预后价值。
