Oral cancer is caused by multiple factors. Among these factors human papillomavirus (HPV) has received much attention, because certain HPV types are consistently associated with squamous cell carcinoma of human oral cavity. However, these viruses are also detected in histologically normal tissues and only a small portion of HPV-infected lesions progress to cancer which suggests that additional factors are involved in progression of this disease. In this proposal, we hypothesize that HPV and tobacco-related chemical carcinogens sequentially cooperate in a multistep process of oral cancer development. To test the hypothesis, we will establish immortalized, nontumorigenic oral keratinocyte cell lines by transfecting primary keratinocytes (from gingiva, tongue, and floor of mouth) with cloned HPV-16 or 18 DNA and investigate effects of tobacco-related chemical carcinogens on the biological properties of these cells: changes in cell morphology, growth rate, ability for soft agar colony formation, differentiation potential, karyotypes, and tumorigenicity in nude mice. Moreover, possible difference in the number of HPV DNA copies per cell, nature of integration site and possible deletion of viral genome, and viral gene expression will also be investigated in the nontumorigenic immortalized cells, chemically transformed tumorigenic cells, and cells from tumors induced by the tumorigenic cells in nude mice. Lastly, to determine the involvement of cellular proto-oncogenes (c-erbB-1/EGFR, c-Ha-ras, and c- myc) and tumor suppressor RB and p53 genes in multistep sequence of oral carcinogenesis, the activation state of proto-oncogenes and inactivation state of tumor suppressor RB and p53 genes in (1) normal oral keratinocytes, (2) HPV-immortalized cells, (3) chemically transformed tumorigenic cells, and (4) cells from tumors of nude mice will be investigated. These studies could provide an information for better understanding of the cellular response to sequential combined effect of HPV and tobacco-chemical carcinogens and help elucidate the sequential involvement of cellular proto-oncogenes and tumor suppressor genes in multistep oral carcinogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE010049-01A1
Application #
3223710
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1992-09-30
Project End
1996-09-29
Budget Start
1992-09-30
Budget End
1993-09-29
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Dentistry
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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