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

背景先前的研究表明，铬酸盐肺癌中复制误差（RER）的频率非常高，并且DNA不匹配修复基因HMLH1表达的失活与微卫星高不稳定性表型密切相关。我们推测铬酸盐肺癌的致癌过程：HMLH1蛋白的表达→遗传不稳定性→癌症相关基因的异常。 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 bronchia of 3 dysplasia and 14 squamous metaplasia in the chromate workers and in the bronchio of 2 carcinoma in situ, 3 dysplasia and 7 squamous metaplasia in the heavy s … More moviers without chromate exposure.Immunohistochemical staining for hMLH1 in formalin-fixed, paraffin-embedded tissue sections was使用催化的信号扩增系统（Dako Co.，Carpinteria，CA）方法进行。对HMLH1的小鼠单克隆抗体（克隆G 168-728，BD Biosciences Pharmingen，San Diego，CA）使用，1：300稀释，将组织切片在48C下孵育2个过夜。在显微镜下，我们每个高功率场至少评估了至少200个肿瘤细胞，这些肿瘤细胞在所有场中都更染色。将核染色的频率评分为无（0％），很少（<35％），中度（> = 35％，70％<=）和弥漫性（> 70％）。结果，没有组的结果为2例，有8个病例，少数组中的5例，现代组中的5例和2例在Chromate工人中的分散组中的2例。另一方面，在浓烟中，中等组中有5例，弥漫组有7例。我们没有将其分类为HMLH蛋白的“抑制作用”。铬酸盐工人的表达率（88％）明显高于浓烟的浓烟（42％）。结论我们推测，DNA不匹配修复HMLH的功能障碍HMLH涉及铬酸盐癌癌癌的早期生成的早期阶段。较少的