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Carcinogenesis mechanism of lung cancer of the chromate industrial workers with chromate exposure -Relationship between DNA mismatch repair hMLH gene and gene instability-

铬酸盐作业工人肺癌的致癌机制-DNA错配修复hMLH基因与基因不稳定性的关系-

基本信息

批准号：
18591551
负责人：
KONDO Kazuya
金额：
$ 2.43万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

BackgroundOur previous studies have revealed that the frequency of replication error (RER) in chromate lung cancer is very high and that the inactivation of DNA mismatch repair gene hMLH1 expression strongly correlated with the microsatellite high instability phenotype. We speculate the carcinogenesis process of chromate lung cancer: the repression of hMLH1 protein→the genetic instability→the abnormality of cancer-related genes. In this study, we examined the expression of hMLH protein in pre-malignant lesions of the bronchial biopsy specimens from chromate workers and heavy smokers without chromate exposure.Material and methodsTo detect lung carcinoma at an early stage, we performed biopsies of the bronchus for 83 chromate industry workers in Tokushima, Japan, in 1982. We examined the expression of hMLH protein in the bronchi of 3 dysplasia and 14 squamous metaplasia in the chromate workers and in the bronchi of 2 carcinoma in situ, 3 dysplasia and 7 squamous metaplasia in the heavy s … More mokers without chromate exposure.Immunohistochemical staining for hMLH1 in formalin-fixed, paraffin-embedded tissue sections was performed using the Catalyzed Signal Amplification system (DAKO Co., Carpinteria, CA) method. Mouse monoclonal antibodies to hMLH1 (clone G 168-728, BD Biosciences Pharmingen, San Diego, CA) were applied, diluted 1: 300, and tissue sections were incubated 2 overnight at 48C. Under microscopy, we evaluated at least 200 tumor cells per high power field, which were more stained in all fields. The frequency of nuclear staining was scored as none (0%), scant (<35%), moderate (>=35%,70%<=), and diffuse (>70%).ResultsThere were 2 cases in none group, 8 cases in scant group, 5 cases in moderate group and 2 cases in diffuse group in the chromate workers. On the other hand, there were 5 cases in moderate group and 7 cases in diffuse group in the heavy smokers. We classified none, scant and moderate groups as "repression" of hMLH protein.The repression rate of the chromate workers (88%) was significantly higher than that of the heavy smokers (42%).ConclusionWe speculate that dysfunction of DNA mismatch repair hMLH involve early stage of carcinogenesis of chromate lung cancer. Less

我们前期的研究表明，铬酸盐肺癌的复制错误（RER）频率非常高，DNA错配修复基因hMLH1表达失活与微卫星高不稳定性表型密切相关。我们推测了铬酸盐肺癌的癌变过程：hMLH1蛋白的抑制→遗传不稳定→癌相关基因的异常。在这项研究中，我们检测了hMLH蛋白在没有铬酸盐暴露的铬酸盐工人和重度吸烟者的支气管活检标本的恶性病变前的表达。材料与方法为了早期发现肺癌，我们于1982年在日本德岛对83名铬酸盐工业工人进行了支气管活检。我们检测了hMLH蛋白在铬酸盐工人3例非典型增生和14例鳞状化生的支气管中的表达，以及在重度铬酸盐工人2例原位癌、3例非典型增生和7例鳞状化生的支气管中的表达。使用Catalyzed Signal Amplification system （DAKO Co., Carpinteria， CA）方法对福尔马林固定石蜡包埋的组织切片进行hMLH1免疫组化染色。应用小鼠hMLH1单克隆抗体（克隆G 168-728， BD Biosciences Pharmingen, San Diego， CA），稀释1:300，组织切片在48℃孵育2晚。在显微镜下，我们在每个高倍视野下评估了至少200个肿瘤细胞，在所有视野中都有更多的染色。核染色频率分为无（0%）、少（<35%）、中度（>=35%,70%<=）和弥漫性（>70%）。结果铬酸盐工人无氧组2例，缺氧组8例，中度组5例，弥漫组2例。重度吸烟者中，中度组5例，弥漫组7例。我们将hMLH蛋白的“抑制”分为无、少和中度组。铬酸盐工人的抑制率（88%）明显高于重度吸烟者（42%）。结论我们推测DNA错配修复功能紊乱参与了铬酸盐肺癌的早期癌变。少