The alteration of nucleotide excision repair gene expressions may associate with non-small cell lung cancer development

• Main Authors: Yi-Hui Wu, 吳怡慧
• Other Authors: Huei Lee
• Format: Others
• Language: zh-TW
• Published: 2001
• Online Access: http://ndltd.ncl.edu.tw/handle/73614186982744187649

碩士 === 中山醫學院 === 毒理學研究所 === 89 === Lung cancer is the leading cause of cancer death in Taiwanese women and men. Cigarette smoking is well known to be the major cause of lung cancer. However, less than 50% of lung cancer in Taiwan cannot be explained by cigarette smoking. Therefore, we suspect that different tumorigenic mechanisms may be involved in Taiwanese lung cancer development, especially for women because of only 4% of female lung cancer patients were smokers. One major DNA repair pathway capable of removing a variety of structurally unrelated DNA lesions, including those induced by tobacco carcinogen, is nucleotide excision repair (NER). Knockout mice defective XPC gene have been developed and used for chemical carcinogenesis experiment showing that a significantly higher incidence of chemically induced liver and lung tumors in XPC-/- mice compared with normal and heterozygous. Thus, we hypothesized that the genetically determined baseline expression level of genes involved in NER is associated with risk of lung cancer. In order to verify the role of DNA repair gene expressions in lung tumor progression, 100 lung cancer and 50 non-cancer patients were collected to determine DNA repair mRNA expressions in non-tumor and tumor tissues from lung cancer patients and normal lung tissues from non-cancer controls using by RT-PCR. Our results indicated that ERCC1、ERCC5 and XPC mRNA expression frequencies were significantly lower in lung tumor tissues than those of non-cancer controls. We also observed that XPC mRNA expression in non-tumor (19/33, 58%) and tumor tissues (18/33, 55%) in non-smoking male lung cancer patients were significantly lower than in smoking male lung cancer patients (30/34, 89%; 28/34, 82%) respectively (P = 0.005 for non-tumor tissues, P = 0.014 for tumor tissues). We hypothesized that genetic polymorphism may be associated with differences in the repair efficiency of DNA damage and may influence the risk of lung cancer. Our result indicated that XPC —A/A genotype might be associated with the increase of XPC mRNA expression frequency, but not associated with lung cancer risk. In addition, inactivation of gene may medicate through promoter hypermethylation. PCR-based methylation analysis data indicated that significantly higher frequencies of XPC promoter hypermethylation of lung cancer patients (34/100, 34%) were observed in comparison with those of non-cancer controls (3/50, 6%; P = 0.000001). This result suggests that XPC hypermethylation to cause its gene inactivation may be as a tumor suppressor gene to associate with development of lung cancer especially for non-smoking patients. Our previous reports indicated that DNA adduct levels of lung cancer patients were significantly higher than those of non-cancer controls. Moreover, individual difference in DNA adduct levels of the lung cancer patients (61.3 folds) was extremely higher than those of non-cancer controls (26.1 folds). This reflects that certain gene alteration may be linked the individual difference in DNA adduct levels of lung cancer patients. In this study, 52 lung cancer patients were collected to determine ERCC1、ERCC5、ERCC6 and XPC mRNA expressions in non-tumor lung tissues by RT-PCR. Among these four NRE genes, only ERCC1 mRNA expression levels were significantly associated with DNA adduct levels. In conclusion, the decrease of ERCC1, ERCC5 and XPC mRNA expressions in lung tumor compared to normal lung tissues seem to reveal that the reduction of NER gene expressions may be associated the lung tumorigenesis. In addition, inactivation of XPC gene expression by promoter hypermethylation may be involved in non-smoking lung cancer development, especially in non-smoking male lung cancer patients.