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 administrafion of alcohol (8%, 15%, 35%, and 50%) promoted oral carcinogenesis in 4-nitroquinoline-1-oxide (4NQ0)-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 4NQ0-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. 4NQ0-treated mice will be fed with alcohol (35%), and sacriflced 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. 4NQ0-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 Keap 1-/- 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, oxidafive 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 chemoprevenfive 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 #
5U54AA019765-03
Application #
8381974
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
$167,998
Indirect Cost
$47,999
Name
North Carolina Central University
Department
Type
DUNS #
783691801
City
Durham
State
NC
Country
United States
Zip Code
27707
Fish, Eric W; Parnell, Scott E; Sulik, Kathleen K et al. (2017) Preaxial polydactyly following early gestational exposure to the smoothened agonist, SAG, in C57BL/6J mice. Birth Defects Res 109:49-54
Xu, Changqing; Hermes, Douglas J; Nwanguma, Blessing et al. (2017) Endocannabinoids exert CB1 receptor-mediated neuroprotective effects in models of neuronal damage induced by HIV-1 Tat protein. Mol Cell Neurosci 83:92-102
Zhang, Chengjin; Boa-Amponsem, Oswald; Cole, Gregory J (2017) Comparison of molecular marker expression in early zebrafish brain development following chronic ethanol or morpholino treatment. Exp Brain Res 235:2413-2423
Ma, Zhikun; Parris, Amanda B; Xiao, Zhengzheng et al. (2017) Short-term early exposure to lapatinib confers lifelong protection from mammary tumor development in MMTV-erbB-2 transgenic mice. J Exp Clin Cancer Res 36:6
Fan, Hong; Paiboonrungruan, Chorlada; Zhang, Xinyan et al. (2017) Nrf2 regulates cellular behaviors and Notch signaling in oral squamous cell carcinoma cells. Biochem Biophys Res Commun 493:833-839
Odera, Joab Otieno; Odera, Elizabeth; Githang'a, Jessie et al. (2017) Esophageal cancer in Kenya. Am J Dig Dis (Madison) 4:23-33
Lee, Harry; Saini, Nipun; Parris, Amanda B et al. (2017) Ganetespib induces G2/M cell cycle arrest and apoptosis in gastric cancer cells through targeting of receptor tyrosine kinase signaling. Int J Oncol 51:967-974
Zhao, Qingxia; Parris, Amanda B; Howard, Erin W et al. (2017) FGFR inhibitor, AZD4547, impedes the stemness of mammary epithelial cells in the premalignant tissues of MMTV-ErbB2 transgenic mice. Sci Rep 7:11306
Parris, Amanda B; Zhao, Qingxia; Howard, Erin W et al. (2017) Buformin inhibits the stemness of erbB-2-overexpressing breast cancer cells and premalignant mammary tissues of MMTV-erbB-2 transgenic mice. J Exp Clin Cancer Res 36:28
Burton, Derek F; Zhang, Chengjin; Boa-Amponsem, Oswald et al. (2017) Long-term behavioral change as a result of acute ethanol exposure in zebrafish: Evidence for a role for sonic hedgehog but not retinoic acid signaling. Neurotoxicol Teratol 61:66-73

Showing the most recent 10 out of 27 publications