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or many years the human papillomavirus (HPV) has been
suspected as a possible culprit in the etiology of oral cancer. Two types
of the virus, HPV-16 and HPV-18, are found in oral cancer tissues more frequently
than in normal tissues. Scientists are still not sure, though, how HPV might
contribute to the development of oral cancer.
Recently, a team of NIDCR-funded investigators at the State University of New York Health Sciences Center in Syracuse discovered mutations in the long control region (LCR) of HPV-16 and HPV-18 taken from oral cancer cell lines. This region of the virus plays an important role in regulating the expression of two viral genes called E6 and E7. Earlier research implicated overexpression of these two genes in the development of cervical cancer, and the oral cancer researchers suspect the same phenomenon might be at play producing oral neoplasms. They speculate that the LCR mutations disturb the normal balance between up- and down-regulation of E6 and E7, leading to their overexpression and thus to oral cancer. Future research by these scientists and others will focus on trying to locate concrete molecular evidence of E6 and E7 overexpression in oral cancer cells. Taken together, these studies will eventually help confirm, or rule against, HPV's involvement in oral cancer development.
Animal and cell line studies have led two other groups of NIDCR grantees to make discoveries about genetic variations that might play a part in oral cancer development. At the Harvard School of Dental Medicine one group has identified, isolated, and partially characterized an oral tumor suppressor gene. Discovered in the hamster oral cancer model, the gene is dubbed 'doc-1' for 'deleted in oral cancer.' The mutation of this gene in malignant hamster oral keratinocytes leads to a reduction of its expression and protein production, while re-expression of the gene results in the reversion of malignant phenotypes to normal.
Importantly, the scientists now have data to support the existence
of a human version of doc-1. They also have evidence that the gene seems
to work by regulating cell cycle progression, as do other tumor suppressor
genes such as Rb and p53. Studies are currently under way to determine whether
doc-1 is a tissue-specific tumor suppressor or whether it might be involved
in the development of other cancers as well.
A team of NIDCR-supported scientists at the University of Pittsburgh has shown that genetic variations occurring in head and neck cancers have been extended to include the FHIT gene, which was not previously associated with these malignancies. The finding that 22 of 26 squamous cell carcinoma lines showed aberrations in this gene strongly indicates that its function may be important in the development and progression of these neoplasias. Studies on the FHIT gene are continuing, and the scientists hope their findings will add to the knowledge of underlying genetic variations related to oral cancer.
A country halfway around the world and a U.S. island territory are the sites of two NIDCR studies correlating environmental and biological factors with oral cancer. In Taiwan, researchers are studying families with multiple members affected by nasopharyngeal cancer (NPC). The study capitalizes on recent investigations of NPC in Taiwan that found strong evidence of a genetic susceptibility to the disease and identified dietary factors that might contribute to its development. The current project is providing scientists with an ideal opportunity to investigate the association of NPC with environmental factors such as diet and to identify and characterize susceptibility genes for the disease. The molecular genetic work resulting from this study will almost certainly have implications for research into other subtypes of oral and pharyngeal cancer.
Closer to home, a case-control study of oral cancer is continuing in
Puerto Rico, chosen as a study site because of its high oral cancer mortality
rate for males. One of the study's strengths is that it is population-based,
with cases derived from the island's central cancer registry. Biological
specimens and information on diet and the use of tobacco and alcohol have
already been collected from the 800-plus participants, and data analysis
has begun. The idea is to discover how behavioral factors and genetic variations
influence the development of oral cancer.