The long term objective of this research is to investigate the molecular mechanisms involved in the malignant conversion of either human normal or premalignant oral cells to tumorigenic phenotype by tobacco-associated carcinogens (TAC). Our preliminary data suggest that this conversion directly involves the participation of a newly discovered tumor suppressor gene, CATR1. This gene appears to be unique and responsible for the conversion of premalignant phenotypes to tumorigenic phenotypes in nude mice. A 1.3 kbp reverse sequence of the 3041 bp CATR1 gene has been prepared and designated as an antisense cDNA construct. When inserted into an RSVLTP promoter and eukaryotic expression vectors and when transfected into non-tumorigenic premalignant or carcinogen-transformed human cells, can convert these cells to tumorigenic phenotypes as tumors. In addition, we have found that the normal levels of transcripts in human oral tumors are also suppressed. Our hypothesis is that the CATR1 message level is inversely related to the degree of malignancy in oral tumors. We wish to investigate in normal oral mucosa cells and in premalignant phenotypes the effect of decreased levels of transcript expression of this gene and modulation of cell cycle regulatory genes, when tobacco carcinogens are used to transform or convert the cells to malignancy. We will pursue this overall CATR1 gene and cell cycle regulatory genes when normal human oral mucosa cells are converted to an anchorage independent growth stage and to a malignant phenotype. S.A. #2 will investigate the changes in TACs. S.A.#.3 will correlate the levels of expression of the CATR1 transcripts with tumor grade in human expression in the establishment and maintenance of human oral tumors by transfection of sense and antisense eukaryotic expression cDNA constructs. It is our intention to evaluate the correlation between malignancy and a levels of expression of CATR1 and cell cycle regulatory gene transcripts in TAC-transformed and converted human cells and premalignant lesions and oral carcinomas from human patients.
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