Oral cancer is a major health problem in the United States; it is a disease of high mortality and severe morbidity. While risk factors include alcohol and tobacco usage, some oro-pharyngeal tumors develop without a defined pattern of alcohol or tobacco abuse. In fact, the increased use of alcohol based mouth washes in the United States may be a risk factor. Although it has been reported that consumption of fresh fruits and vegetables is associated with protective effects on the development of oro-pharyngeal tumors in high risk groups, identification of specific nutritional components such as one specific antioxidant that protects against the development of this type of tumor has not been successful. The inability to isolate a protective effect of a specific vitamin (e.g., beta-carotene) might be secondary to synergistic protective effects of multiple dietary components or to inadequate previous study of methyl supplying components such as folate or vitamin B-12. Localized folate and vitamin B-12 deficiencies may be especially relevant to the development of these tumors since levels of active folate and vitamin B-12 in tissues may be decreased by exposure to components of tobacco or alcohol usage. We hypothesize that the normal proliferative homeostasis of basal cells of the oral epithelium is dysregulated by localized deficiencies of folate and vitamin B-12 and that the resulting abnormality in basal cell proliferation is exacerbated by exposure to alcohol and tobacco products. Ultimately, increased cellular proliferation increases immature cells at intermediate and higher layers (i.e., above the basal cell layer) in the oral epithelium and leads to the development of histologically recognizable pre-malignant characteristics in the epithelium (e.g., dysplasia). These changes can be identified by decreased regional vitamin levels and by changes in the expression of intermediate endpoint biomarkers (IEBs) in the proliferating or dysplastic epithelium. We will select tissues for evaluation based on standard epidemiological methods in order to validate our hypothesis. We will evaluate the relation of folate and vitamin B-12 levels geographically within the epithelium and their correlation with the development of neoplastic changes and with expression of the following IEBs: TGFalpha, EGF-R, EGF, p185/crbB-2, TGF-beta, fatty acid synthetase, markers of proliferation and p53. This proposal is strengthened by nesting state-of- the-art biochemical, molecular, and pathological assessments of normal, pre-malignant and squamous cell cancers within a sound epidemiological investigation of well characterized patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Specialized Center (P50)
Project #
3P50DE011910-03S1
Application #
6104926
Study Section
Project Start
1998-08-01
Project End
1999-07-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Deng, Wentao; Jin, Ge; Lin, Biing-Yuan et al. (2003) mRNA splicing regulates human papillomavirus type 11 E1 protein production and DNA replication. J Virol 77:10213-26
Broker, T R; Jin, G; Croom-Rivers, A et al. (2001) Viral latency--the papillomavirus model. Dev Biol (Basel) 106:443-51; discussion 452-3, 465-7
Lee, J H; Engler, J A; Collawn, J F et al. (2001) Receptor mediated uptake of peptides that bind the human transferrin receptor. Eur J Biochem 268:2004-12
Balague, C; Noya, F; Alemany, R et al. (2001) Human papillomavirus E6E7-mediated adenovirus cell killing: selectivity of mutant adenovirus replication in organotypic cultures of human keratinocytes. J Virol 75:7602-11
Noya, F; Chien, W M; Broker, T R et al. (2001) p21cip1 Degradation in differentiated keratinocytes is abrogated by costabilization with cyclin E induced by human papillomavirus E7. J Virol 75:6121-34
Aznavoorian, S; Moore, B A; Alexander-Lister, L D et al. (2001) Membrane type I-matrix metalloproteinase-mediated degradation of type I collagen by oral squamous cell carcinoma cells. Cancer Res 61:6264-75
Windsor, L J; Steele, D L (2001) Expression of recombinant matrix metalloproteinases in Escherichia coli. Methods Mol Biol 151:191-205
Foster, K W; Frost, A R; McKie-Bell, P et al. (2000) Increase of GKLF messenger RNA and protein expression during progression of breast cancer. Cancer Res 60:6488-95
Ma, T; Van Tine, B A; Wei, Y et al. (2000) Cell cycle-regulated phosphorylation of p220(NPAT) by cyclin E/Cdk2 in Cajal bodies promotes histone gene transcription. Genes Dev 14:2298-313
Steele, D L; El-Kabbani, O; Dunten, P et al. (2000) Expression, characterization and structure determination of an active site mutant (Glu202-Gln) of mini-stromelysin-1. Protein Eng 13:397-405

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