Oral squamous cell carcinoma is a condition that will kill approximately half of patients afflicted within five years of diagnosis and may leave surviving patients with severe esthetic and/or functional compromise. Oral cancer progresses through a series of morphologic changes, which if treated early, vastly improve prognosis. though cancer is widely believed to e the result of chromosomal alterations leading to the activation of oncogenes and suppression of antioncogenes, the actual biochemical and molecular changes preceding the morphologic progression of oral lesions are poorly understood. This is a two-year application to support investigations for the isolation and re-expression of genetic sequences that are involved in the suppression of malignant phenotypes during oral carcinogenesis. We hypothesize that chromosomal rearrangements and deletions during oral cancer development result in the loss of genetic suppressors of malignant transformation. The well-established chemically-induced hamster oral cancer model has been demonstrated to involve suppressor gene loss during malignant progression. A subtraction library of 130 molecular clones has been created using normal and malignant hamster oral keratinocytes by the method of subtractive hybridization. this library of normal-specific genes theoretically contains oral tumor suppressor genes. Three of the 130 clones were shown to be expressed only by the normal hamster oral keratinocytes. More importantly, all three clones demonstrated evidence of loss of heterozygosity, a common mechanism for the loss of tumor suppressor activity. We hypothesize that these three are putative oral tumor suppressor genes (TSGs). This application proposes to generate the necessary molecular reagents in order to test the functional and biological significance of these three putative oral TSGs.
The first Aim of this is to obtain the full-length cDNA of the three putative oral TSGs. In the second Aim, methodologies will be established in order to re-express and obtain full-length cDNAs in malignant hamster oral keratinocytes. The availability of the necessary reagents for the re- expression of these putative oral TSGs will then permit us, in future applications, to systematically examine the functional significance of each of these genes in the suppression of various transformation phenotypes.
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