Hepatocellular carcinoma (HCC) is a major malignancy worldwide. Epidemiological studies have suggested that hepatitis B virus infection and dietary aflatoxin B1 (AFB1) are the two major etiological agents for human HCC. However, the underlying mechanisms of how these two agents induce hepatocarcinogenesis remain unclear. In rats HCC can be induced by a choline-deficient diet (CDD). The pathogenesis of CDD-induced HCC in rats mimics the pathogenesis of human HCC: hepatitis at an early stage, followed by steatosis, cirrhosis and finally HCC. Rats on CDD therefore provide an excellent model for studying HCC. It has been found that the lipid peroxidation (LPO) level and LPO product-induced DNA damage are significantly increased in liver cells of rats on CDD; LPO has thus been suspected of playing an important role in hepatocarcinogenesis. LPO is a cellular process that commonly takes place under normal physiological conditions, and this process becomes significant when cells are under oxidative stress. LPO generates a variety of aldehydes, such as acrolein (Acr), crotonaldehyde, malondialdehyde (MDA), and trans-4-hydroxy- 2-nonenal (4-HNE), that are able to interact with DNA; these adducts induce mainly G to T transversion. Aldehydes are also able to interact with proteins with a thiol group. We have recently found that 4-HNE and MDA are able to significantly inhibit cellular nucleotide excision repair (NER). Based on these results we hypothesize that these aldehydes may play important roles in carcinogenesis through two effects: induction of mutations by their interactions with DNA and inhibition of DNA repair by their interactions with repair proteins. By mapping the 4-HNE-DNA adduct distribution at the sequence level in human p53 gene fragments and genomic DNA we have found that 4-HNE preferentially binds to -GAGGC/A- sequences, including codon 249 of the p53 gene, the sole mutational hotspot in liver cancer. Our results raise the strong possibility that 4-HNE may play a particularly important role in hepatocarcinogenesis in both rats and humans. We propose to test these hypotheses using both the rat and cultured human hepatocyte model. We will determine how 4-HNE-DNA adducts in the p53 gene are processed, and the role of the p53 gene in aldehyde-mediated inhibition of DNA repair in human cells. We will also determine the effect of CDD on the repair capacity in rat liver cells, the formation of 4-HNE- and other aldehyde-induced DNA adducts formed in the p53 gene and the p53 mutational spectrum in CDD-induced HCC in rats. In addition, we will determine the effect of stereostructure of 4-HNE-dG at GAGGC sites on repair and mutagenicity. Results from these studies should greatly enhance our understanding of the role of LPO in hepatocarcinogenesis. ? ? ?

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Cancer Etiology Study Section (CE)
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Shreffler, Carol K
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New York University
Public Health & Prev Medicine
Schools of Medicine
New York
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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