Abstract
A better understanding of key molecular changes during transformation of lung epithelial cells could affect strategies to reduce mortality from lung cancer. This study uses an in vitro model to identify key molecular changes that drive cell transformation and the likely clonal outgrowth of preneoplastic lung epithelial cells that occurs in the chronic smoker. Here, we show differences in transformation efficiency associated with DNA repair capacity for two hTERT/cyclin-dependent kinase 4, immortalized bronchial epithelial cell lines after low-dose treatment with the carcinogens methylnitrosourea, benzo(a)pyrene-diolepoxide 1, or both for 12 weeks. Levels of cytosine-DNA methyltransferase 1 (DNMT1) protein increased significantly during carcinogen exposure and were associated with the detection of promoter hypermethylation of 5 to 10 genes in each transformed cell line. Multiple members of the cadherin gene family were commonly methylated during transformation. Stable knockdown of DNMT1 reversed transformation and gene silencing. Moreover, stable knockdown of DNMT1 protein before carcinogen treatment prevented transformation and methylation of cadherin genes. These studies provide a mechanistic link between increased DNMT1 protein, de novo methylation of tumor suppressor genes, and reduced DNA repair capacity that together seem causal for transformation of lung epithelial cells. This finding supports the development of demethylation strategies for primary prevention of lung cancer in smokers.
Highlights
Lung cancer accounts for 30% of all cancer deaths in both men and women in the United States, and 1.5 million deaths are expected worldwide by 2010 [1]
The in vitro model developed in these studies mimics the clonal outgrowth of preneoplastic cells that occurs in the chronic smoker and has provided new insight into factors involved in the earliest stages of cell transformation
Our studies show an association between DNA repair capacity (DRC) and transformation and identify genes in the cell adhesion pathway as one common target for gene silencing through promoter methylation that culminate in complete loss of transcription and the establishment of heterochromatin
Summary
Lung cancer accounts for 30% of all cancer deaths in both men and women in the United States, and 1.5 million deaths are expected worldwide by 2010 [1]. The high mortality from this disease stems from the lack of an effective screening approach for early diagnosis and the refractiveness of advanced cancers to conventional chemotherapy, substantiating the need to develop more effective targeted therapies and chemoprevention Both these strategies to reduce mortality would benefit from a better understanding of the key molecular changes that are driving cell transformation and the clonal outgrowth of preneoplastic cells. Malignant transformation occurs after years of chronic DNA damage to the pulmonary epithelial cells by the carcinogens in tobacco Both genetic and epigenetic changes in oncogenes and tumor suppressor genes are clearly important in the development of lung cancer. Gene silencing through methylation can occur at the earliest stages of lung cancer development, both in histologic precursors to adenocarcinoma and squamous cell carcinoma and in the bronchial epithelium of smokers. Inactivation of genes by promoter methylation is likely one of the major factors contributing to the development of premalignant cells throughout the respiratory epithelium
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
