As a cancer of significant racial disparity, oral cancer has the strongest association with alcohol consumption among all types of cancer. Such an association depends on both the dose and the concentration of alcohol. Our preliminary data have clearly shown that oral administration of alcohol (8%, 15%, 35%, and 50%) promoted oral carcinogenesis in 4-nitroquinoline-1-oxide (4NQO)-treated mice. Treatment with alcohol of these concentrations mimicked drinking beer, wine, diluted liquor, or straight liquor in humans, respectively. Gene knockout of Nrf2, which regulates expression of multiple anti-oxidative phase 11 enzymes, dramatically enhanced carcinogenesis in the same animal model. Therefore we hypothesize that alcohol promotes oral carcinogenesis by generating oxidative stress in the oral epithelium, and Nrf2-mediated antioxidative response may play a critical role in preventing oral cancer. We plan to test our hypothesis in this grant proposal with the following specific aims: 1. To determine whether alcohol promotes 4NQO-induced oral carcinogenesis in mice through oxidative stress on the oral epithelium, and whether Cyp2E1 is a major enzyme leading to alcohol-generated oxidative stress. 4NQO-treated mice will be fed with alcohol (35%), and sacrificed at several time points during the experiment (Week 8, 9, 12, 16, 24). Mouse tongue will be analyzed for histopathology, oxidative damage and Nrf2-mediated antioxidative response. Using wild-type and Cyp2E1[-/-] mice, we will also determine whether alcohol-generated oxidative stress in the oral epithelium is dependent on Cyp2E1. 2. To examine the role of Nrf2 in alcohol-promoted oxidative stress and oral carcinogenesis using Nrf2[-/-] and Keap1[-/-] mice. 4NQO-treated wild-type and Nrf2[-/-] mice will be fed with alcohol, and histopathology, oxidative damage, and anti-oxidative response in the oral epithelium will be analyzed to determine the impact of Nrf2[-/-] on alcohol-promoted oxidative stress and oral carcinogenesis. A short-term experiment on Keap1[-/-] mice will determine if genetic activation of Nrf2 may inhibit alcohol-promoted oxidative stress. 3. To investigate whether chemical activators of Nrf2 have chemopreventive effects on alcohol-promoted oral carcinogenesis. 4NQ0-treated wild-type and Nrf2[-/-] mice will be fed with alcohol, and treated with two chemically distinct Nrf2 activators from dietary sources, sulforaphane and 3H-1,2-dithiole-3-thione. Histopathology, oxidative damage and antioxidative response in the oral epithelium will be analyzed.

Public Health Relevance

These studies are expected to contribute to mechanistic understanding of alcohol-associated oral carcinogenesis, and develop chemopreventive agents for alcohol-associated oral cancer, especially African Americans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AA019767-03
Application #
8381569
Study Section
Special Emphasis Panel (ZAA1-DD)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$36,200
Indirect Cost
$11,741
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Crews, Fulton T; Lawrimore, Colleen J; Walter, T Jordan et al. (2017) The role of neuroimmune signaling in alcoholism. Neuropharmacology 122:56-73
Vetreno, Ryan P; Patel, Yesha; Patel, Urvi et al. (2017) Adolescent intermittent ethanol reduces serotonin expression in the adult raphe nucleus and upregulates innate immune expression that is prevented by exercise. Brain Behav Immun 60:333-345
Coleman Jr, Leon G; Zou, Jian; Qin, Liya et al. (2017) HMGB1/IL-1? complexes regulate neuroimmune responses in alcoholism. Brain Behav Immun :
Coleman Jr, Leon G; Zou, Jian; Crews, Fulton T (2017) Microglial-derived miRNA let-7 and HMGB1 contribute to ethanol-induced neurotoxicity via TLR7. J Neuroinflammation 14:22
Crews, Fulton T; Walter, T Jordan; Coleman Jr, Leon G et al. (2017) Toll-like receptor signaling and stages of addiction. Psychopharmacology (Berl) 234:1483-1498
Fish, Eric W; Murdaugh, Laura B; Sulik, Kathleen K et al. (2017) Genetic vulnerabilities to prenatal alcohol exposure: Limb defects in sonic hedgehog and GLI2 heterozygous mice. Birth Defects Res 109:860-865
Lawrimore, Colleen J; Crews, Fulton T (2017) Ethanol, TLR3, and TLR4 Agonists Have Unique Innate Immune Responses in Neuron-Like SH-SY5Y and Microglia-Like BV2. Alcohol Clin Exp Res 41:939-954
Vetreno, Ryan P; Yaxley, Richard; Paniagua, Beatriz et al. (2016) Diffusion tensor imaging reveals adolescent binge ethanol-induced brain structural integrity alterations in adult rats that correlate with behavioral dysfunction. Addict Biol 21:939-53
Crews, Fulton T; Vetreno, Ryan P; Broadwater, Margaret A et al. (2016) Adolescent Alcohol Exposure Persistently Impacts Adult Neurobiology and Behavior. Pharmacol Rev 68:1074-1109
Crews, Fulton T; Vetreno, Ryan P (2016) Mechanisms of neuroimmune gene induction in alcoholism. Psychopharmacology (Berl) 233:1543-57

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