BRMS1 transcriptional repression correlates with CpG island methylation and advanced pathological stage in non-small cell lung cancer.
BRMS1 transcriptional repression correlates with CpG island methylation and advanced pathological stage in non-small cell lung cancer.
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DOI：
10.1002/path.2707
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发表时间：
2010-06
影响因子：
7.3
通讯作者：
Jones, David R.
中科院分区：
文献类型：
--
作者：
Nagji, Alykhan S.;Liu, Yuan;Stelow, Edward B.;Stukenborg, George J.;Jones, David R.
关键词：
乳腺癌转移抑制基因-1（BRMS 1）mRNA和蛋白表达在非小细胞肺癌（NSCLC）中显著降低，这是一个预后不良的指标。鉴于BRMS 1启动子区包含一个包含转录起始位点的启动子相关CpG岛（CGI），我们假设NSCLC中BRMS 1 mRNA和蛋白水平的降低继发于BRMS 1启动子甲基化的增加。在NSCLC细胞中对BRMS 1基因组中的两个已知CGI（−3477至−2214和−531至+608）进行甲基化特异性PCR（MSP）。这表明启动子相关CGI的甲基化（-531至+608）显著增加，但上游CGI的甲基化（-3477至-2214）没有增加。为了实验验证甲基化有助于BRMS 1转录抑制，我们克隆了BRMS 1启动子区域，包括启动子相关的CGI，到荧光素酶报告基因，发现BRMS 1启动子活性显着抑制甲基化条件下。然后我们用MSP和亚硫酸氢盐测序PCR评估了人NSCLC腺癌（n = 20）和鳞状细胞癌（n = 20）相对于相邻非癌性支气管上皮的BRMS 1甲基化谱。所有NSCLC标本中BRMS 1启动子甲基化相对于非癌组织显著增加，鳞状细胞癌组织学差异最显著。随后的免疫染色表明，与正常支气管上皮细胞相比，肺癌标本中的核BRMS 1表达减少。BRMS 1启动子甲基化和特定的临床和组织病理学变量之间的关联使用一般线性模型进行了检查。病理肿瘤分期与鳞状细胞癌中BRMS 1甲基化增加相关。这些观察结果表明，BRMS 1中启动子相关CGI的甲基化导致其转录抑制，并突出了这种甲基化事件与NSCLC肿瘤组织学和病理学阶段的潜在临床相关性。
Breast cancer metastasis suppressor gene-1 (BRMS1) mRNA and protein expression are significantly decreased in non-small cell lung cancer (NSCLC) and this is a poor prognostic indicator. Given that the BRMS1 promoter region contains a promoter-associated CpG island (CGI) that encompasses the transcriptional start site, we hypothesized that decreased BRMS1 mRNA and protein levels in NSCLC was secondary to increased BRMS1 promoter methylation. Methylation-specific PCR (MSP) of the two known CGIs (−3477 to −2214 and −531 to +608) in the BRMS1 genome was performed in NSCLC cells. This demonstrated a robust increase in methylation of the promoter-associated CGI (−531 to +608) but not of the upstream CGI (−3477 to −2214). To experimentally verify that methylation contributes to BRMS1 transcriptional repression, we cloned the BRMS1 promoter region, including the promoter-associated CGI, into a luciferase reporter gene and found that BRMS1 promoter activity was dramatically inhibited under methylated conditions. We then assessed the BRMS1 methylation profile with MSP and bisulphite-sequencing PCR in human NSCLC adenocarcinoma (n = 20) and squamous cell carcinoma (n = 20) relative to adjacent non-cancerous bronchial epithelium. There was a significant increase in BRMS1 promoter methylation in all NSCLC specimens relative to non-cancerous tissues, with the most dramatic difference in squamous cell cancer histology. Subsequent immunostaining demonstrated that nuclear BRMS1 expression is reduced in lung cancer specimens compared to normal bronchial epithelium. The association between BRMS1 promoter methylation and specific clinical and histopathological variables was examined using a general linear model. Pathological tumour stage was associated with increased BRMS1 methylation in squamous cell cancers. These observations demonstrate that methylation of the promoter-associated CGI in BRMS1 results in its transcriptional repression, and highlight the potential clinical relevance of this methylation event with respect to NSCLC tumour histology and pathological stage.
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影响因子：
37.3
作者：
Samant RS;Clark DW;Fillmore RA;Cicek M;Metge BJ;Chandramouli KH;Chambers AF;Casey G;Welch DR;Shevde LA
通讯作者：
Shevde LA
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
DOI：
10.1073/pnas.0607521104
发表时间：
2007-01-02
影响因子：
11.1
作者：
Oakes, C. C.;La Salle, S.;Trasler, J. M.
通讯作者：
Trasler, J. M.
影响因子：
11.4
作者：
BOYES, J;BIRD, A
通讯作者：
BIRD, A
影响因子：
11.2
作者：
Cicek，M;Fukuyama，R;Casey，G
通讯作者：
Casey，G