Oncotarget

Research Papers:

AFB1 hepatocarcinogenesis is via lipid peroxidation that inhibits DNA repair, sensitizes mutation susceptibility and induces aldehyde-DNA adducts at p53 mutational hotspot codon 249

Mao-Wen Weng, Hyun-Wook Lee, Bongkun Choi, Hsiang-Tsui Wang, Yu Hu, Manju Mehta, Dhimant Desai, Shantu Amin, Yi Zheng and Moon-Shong Tang _

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Oncotarget. 2017; 8:18213-18226. https://doi.org/10.18632/oncotarget.15313

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Abstract

Mao-Wen Weng1,*, Hyun-Wook Lee1,*, Bongkun Choi1,*, Hsiang-Tsui Wang1,*, Yu Hu1, Manju Mehta1, Dhimant Desai2, Shantu Amin2, Yi Zheng1, Moon-Shong Tang1

1Departments of Environmental Medicine, Pathology and Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA

2Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA

*These authors have contributed equally to this work

Correspondence to:

Moon-Shong Tang, email: moon-shong.tang@nyumc.org

Keywords: aflatoxin B1, hepatocellular carcinoma, p53 codon 249 mutations, AFB1-8,9-epoxide-deoxyguanosine, cyclic α-methyl-γ-hydroxy-1,N2-propano-dG

Received: September 22, 2016    Accepted: December 01, 2016    Published: February 14, 2017

ABSTRACT

Aflatoxin B1 (AFB1) contamination in the food chain is a major cause of hepatocellular carcinoma (HCC). More than 60% of AFB1 related HCC carry p53 codon 249 mutations but the causal mechanism remains unclear. We found that 1) AFB1 induces two types of DNA adducts in human hepatocytes, AFB1-8,9-epoxide-deoxyguanosine (AFB1-E-dG) induced by AFB1-E and cyclic α-methyl-γ-hydroxy-1,N2-propano-dG (meth-OH-PdG) induced by lipid peroxidation generated acetaldehyde (Acet) and crotonaldehyde (Cro); 2) the level of meth-OH-PdG is >30 fold higher than the level of AFB1-E-dG; 3) AFB1, Acet, and Cro, but not AFB1-E, preferentially induce DNA damage at codon 249; 4) methylation at –CpG- sites enhances meth-OH-PdG formation at codon 249; and 5) repair of meth-OH-PdG at codon 249 is poor. AFB1, Acet, and Cro can also inhibit DNA repair and enhance hepatocyte mutational sensitivity. We propose that AFB1-induced lipid peroxidation generated aldehydes contribute greatly to hepatocarcinogenesis and that sequence specificity of meth-OH-PdG formation and repair shape the codon 249 mutational hotspot.


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