Carcinogens generated in tobacco smoke (TS) are able to cause DNA damage and mutations that may initiate lung carcinogenesis. Intriguingly, despite the presence of substantial amounts of DNA damaging agents in TS, only 10-15% lifetime tobacco smokers develop lung cancer. Although TS has been found to cause mutations in many genes related to lung cancer, a definable cause-effect relationship has not been established. The p53 and K-ras genes are two frequently mutated genes in TS-related lung cancers. Mutational features in these two genes in the lung cancers of smokers and non-smokers are different. Using a cultured human lung cell system as a model, we have made three discoveries: TS carcinogens preferentially form DNA adducts at p53 mutational hotspots and at codon 12 of the K-ras gene, adducts formed at these sequences are poorly repaired, and most of p53 mutational hotspots occur at sites that contain a CpG sequence and C5 cytosine methylation causes preferential adduct formation at these sites. These findings led us to hypothesize that TS-induced DNA damage plays a central role in lung carcinogenesis. In lung cells, both the cytosine methylation status in the p53 gene and an unknown epigenetic factor in the K-ras gene may determine an individual's susceptibility to TS-induced DNA damage. We recently found that nickel, chromium, and lipid peroxidation metabolites can greatly reduce cellular DNA repair capacity. Since TS contains significant amounts of these heavy metals and also induces excessive oxidative stress, it is possible that TS may cause inhibition of DNA repair. We propose that variations in every individual's response contribute to the differences in susceptibility to TS-induced lung cancer. TS may induce different levels of one, DNA damage at genes crucial for developing lung cancer, such as p53and K-ras genes, and two, inhibition of DNA repair capacity among different individuals. To test these hypotheses we proposed to determine three factors in the lung cells of tobacco smokers with and without lung cancer: one, DNA damage distribution in the p53 and K-ras genes, two, C5 cytosine methylation status in the p53 gene, and three, the repair capacity. We will also determine the mutations in genes related to lung cancer in both tumor and """"""""normal"""""""" cells in these lung tissue samples. Finally, we will determine the epigenetic modification in the K-ras gene that causes preferential carcinogen binding and poor repair at codon12 of this gene. Results from these studies will enhance our understanding of lung cancer susceptibility and DNA damage-induced carcinogenesis in humans, and enable us to develop biomarkers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA114541-02
Application #
7055300
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Poland, Alan P
Project Start
2005-05-01
Project End
2010-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
2
Fiscal Year
2006
Total Cost
$355,932
Indirect Cost
Name
New York University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Lee, Hyun-Wook; Wang, Hsiang-Tsui; Weng, Mao-wen et al. (2014) Acrolein- and 4-Aminobiphenyl-DNA adducts in human bladder mucosa and tumor tissue and their mutagenicity in human urothelial cells. Oncotarget 5:3526-40
Wang, Hsiang-Tsui; Weng, Mao-wen; Chen, Wen-chi et al. (2013) Effect of CpG methylation at different sequence context on acrolein- and BPDE-DNA binding and mutagenesis. Carcinogenesis 34:220-7
Wang, Hsiang-Tsui; Hu, Yu; Tong, Dan et al. (2012) Effect of carcinogenic acrolein on DNA repair and mutagenic susceptibility. J Biol Chem 287:12379-86
Arakawa, Hirohumi; Weng, Mao-Wen; Chen, Wen-Chi et al. (2012) Chromium (VI) induces both bulky DNA adducts and oxidative DNA damage at adenines and guanines in the p53 gene of human lung cells. Carcinogenesis 33:1993-2000
Tang, Moon-shong; Wang, Hsiang-tsui; Hu, Yu et al. (2011) Acrolein induced DNA damage, mutagenicity and effect on DNA repair. Mol Nutr Food Res 55:1291-300
Weng, Mao-wen; Zheng, Yi; Jasti, Vijay P et al. (2010) Repair of mitomycin C mono- and interstrand cross-linked DNA adducts by UvrABC: a new model. Nucleic Acids Res 38:6976-84
Wang, Hsiang-Tsui; Choi, Bongkun; Tang, Moon-shong (2010) Melanocytes are deficient in repair of oxidative DNA damage and UV-induced photoproducts. Proc Natl Acad Sci U S A 107:12180-5
Wang, Hsiang-Tsui; Zhang, Siyi; Hu, Yu et al. (2009) Mutagenicity and sequence specificity of acrolein-DNA adducts. Chem Res Toxicol 22:511-7
Arakawa, Hirohumi; Tang, Moon-Shong (2008) Recognition and incision of Cr(III) ligand-conjugated DNA adducts by the nucleotide excision repair proteins UvrABC: importance of the Cr(III)-purine moiety in the enzymatic reaction. Chem Res Toxicol 21:1284-9
Mehta, Manju; Chen, Lung-Chi; Gordon, Terry et al. (2008) Particulate matter inhibits DNA repair and enhances mutagenesis. Mutat Res 657:116-21

Showing the most recent 10 out of 13 publications