| Budget Amount *help |
¥3,790,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Research Abstract |
Background
Our 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 methods
To 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
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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%).
Results
There 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%).
Conclusion
We speculate that dysfunction of DNA mismatch repair hMLH involve early stage of carcinogenesis of chromate lung cancer. Less
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