Re: Promoter methylation and silencing of the retinoic acid receptor-beta gene in lung carcinomas.
Re: Promoter methylation and silencing of the retinoic acid receptor-beta gene in lung carcinomas.
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回复：肺癌中视黄酸受体-β基因的启动子甲基化和沉默。
DOI：
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
R. Sesboüé
中科院分区：
文献类型：
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作者：
A. Lamy;J. Métayer;L. Thiberville;T. Frebourg;R. Sesboüé
Virmani等人。(1)最近报道，维甲酸受体(RAR)基因启动子P2的甲基化在肺癌中是一种常见的事件，并提示去甲基化在肺癌中可能具有治疗意义。因此，确定正常支气管细胞向侵袭性癌细胞转化的表观遗传学改变的时间是很重要的。虽然许多研究人员认为RAR表达的改变是肺癌发生的早期现象，但由于大多数上皮内肿瘤性病变在传统的白光支气管镜下是无法发现的，因此很难研究癌前阶段的这种变化。最近引入的光诱导荧光内窥镜(LIFE)系统(2)极大地提高了检测癌前病变的能力，使我们能够从肺癌高危患者(因石棉和/或烟草暴露或头颈癌病史)收集大量支气管活检标本。在给予书面知情同意后，患者接受荧光支气管镜检查(LIFE-肺部成像系统；Xillix公司，加拿大里士满，BC)。这项研究已得到地区伦理委员会(CCPPRB-HN：ComitéConsulatif de Personnes Dans la Recherche Biomédicale de HauteNormandie)的批准。活检标本取自异常区域和尽可能正常的区域。从每个部位取两个样本：一个用于病理检查，另一个按前面所述进行培养(3)以获得纯的支气管细胞群。取自38例患者的活检标本，取自71例不同的活检标本。组织病理学检查显示，这71例活检标本包括正常上皮9例，炎症13例，增生19例，轻度不典型增生16例，中重度不典型增生11例，原位癌3例，按国际标准分类(4)。用亚硫酸氢钠处理第2代培养细胞提取的基因组DNA后，按照Côtéet al的方法，用甲基化特异性聚合酶链式反应分析RAR基因启动子P2的甲基化状态。(5)。与用作阳性对照的DLD-1结肠癌细胞系相比(5)，71个样本中没有一个显示出甲基化的RAR启动子P2。为了排除体外培养对甲基化过程可能造成的干扰而导致的假阴性结果，我们分析了同一样本中CDKN2A/p16基因(6)内的CpG岛的甲基化状态，发现71个样本中有13个确实存在该基因的甲基化。在这一系列中，RAR基因启动子P2缺乏甲基化，这表明甲基化可能不是肺癌发生的早期事件，至少在非小细胞肺癌(NSCLC)中是这样。尽管显然需要进一步研究肺癌发生过程中遗传或表观遗传改变的动力学，但这些结果表明，对于非小细胞肺癌的化学预防，类维甲酸可能比去甲基化药物更合适。
Virmani et al. (1) recently reported that methylation of the retinoic acid receptor(RAR ) gene promoter P2 was a frequent event in lung carcinomas and suggested that demethylation could be of therapeutic interest in these tumors. The timing of this epigenetic alteration in the transformation of normal bronchial cells to invasive cancer cells is, therefore, important to determine. Although many investigators have suggested that alteration of RAR expression is an early phenomenon in lung carcinogenesis, it is difficult to study such alterations in precancerous stages because most intraepithelial neoplastic lesions are not detectable under conventional white-light bronchoscopy. The recent introduction of the light-induced fluorescence endoscopy (LIFE) system (2) greatly enhances the ability to detect preneoplastic lesions and allowed us to collect a large series of bronchial biopsy specimens from patients at high risk (because of asbestos and/or tobacco exposure or a history of head and neck cancer) for the development of lung cancer. After giving written informed consent, patients were examined under fluorescence bronchoscopy (LIFE-Lung Imaging System; Xillix Co., Richmond, BC, Canada). This study has been approved by the regional Ethics Committee (CCPPRB-HN: Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale de HauteNormandie). Biopsy specimens were taken from abnormal and, whenever possible, normal areas. Two samples were taken from each site: one was used for pathologic examination, and the other was cultured as described previously (3) to obtain pure bronchial cell populations. Biopsy specimens were collected from 38 patients, and bronchial cells were derived from 71 different biopsy specimens. Histopathologic examination subsequently revealed that these 71 biopsy specimens included normal epithelium (nine cases), inflammation (13 cases), hyperplasia (19 cases), mild dysplasia (16 cases), moderate to severe dysplasia (11 cases), and carcinoma in situ (three cases), classified according to the international nomenclature (4). After sodium bisulfite treatment of genomic DNA extracted from cultured cells at the second passage, the methylation status of the RAR gene promoter P2 was analyzed by the methylation-specific polymerase chain reaction according to the procedure of Côté et al. (5). In contrast to the DLD-1 colon carcinoma cell line used as a positive control (5), none of the 71 samples displayed a methylated RAR promoter P2. To exclude false-negative results caused by possible interference of in vitro culture with the methylation process, we analyzed the same samples for the methylation status of CpG islands within the CDKN2A/p16 gene (6) and found that this gene was indeed methylated in 13 of 71 samples. The lack of methylation of the RAR gene promoter P2 in this series, which included 30 dysplastic lesions, indicates that methylation is probably not an early event in lung carcinogenesis, at least in non-small-cell lung carcinoma (NSCLC). Although further investigations exploring the kinetics of genetic or epigenetic alterations in the development of lung cancer are clearly needed, these results suggest that retinoids may be more appropriate than demethylating agents for chemoprevention of NSCLC.
DOI：
10.1073/pnas.93.18.9821
发表时间：
1996-09-03
影响因子：
11.1
作者：
Herman, JG;Graff, JR;Baylin, SB
通讯作者：
Baylin, SB
化学预防之前和期间吸烟者支气管上皮中的核视黄酸受体β。
DOI：
10.1093/jnci/91.15.1317
发表时间：
1999
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Xu,XC;Lee,JS;Lee,JJ;Morice,RC;Liu,X;Lippman,SM;Hong,WK;Lotan,R
通讯作者：
Lotan,R