GENES INVOLVED IN PRENEOPLASTIC PROGRESSION

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The overall aim of this research is to identify and characterize four classes of genes involved in multistage carcinogenesis. The first class includes genes associated with susceptibility to tumor promoter-induced neoplastic transformation. The second class includes genes that specify expression of tumor cell phenotype. The third class is tumor suppressor genes, and the fourth, apoptosis-causing genes. Mouse JB6 promotion-resistant (P-), promotion-sensitive (P+), and tumorigenic (Tx) JB6-derived epidermal cell lines have been found to differ in the expression or activity of several susceptibility-related genes described in the accompanying project, Z01CP05383-12 LVC, "Membrane Signal Transduction in Tumor Promotion." Human nasopharyngeal carcinomas (NPCs) from China show a heterozygous expressed mutation in codon 280 of the tumor suppressor gene, p53. The novel mutated p53 has oncogenic activity and functions dominantly in the presence of wild-type p53 to inhibit transcriptional activation and to cause progression toward neoplastic phenotype in two models. Since a high proportion of human NPCs and tumorigenic mouse JB6 cells express only wild-type p53, we have inquired as to whether events downstream of p53 might be inactivated, thus losing p53-dependent tumor suppressor activity as if a p53 mutation had occurred. WAF-1/CIP-1, a gene transcriptionally controlled by p53 that regulates complexes involved in the G1 checkpoint, has been found not to be mutated in NPC or in JB6 tumor cells. A codon 31 polymorphism in WAF-1 has been found, however, that offers utility for following allele distribution in Chinese populations. A new candidate tumor suppressor gene has been identified by the differential mRNA display technique applied to the mouse JB6 P- to P+ to Tx progression series. This gene, identified as tissue inhibitor of metalloproteinase-3 (TIMP-3), is expressed in preneoplastic, but not neoplastic (Tx), JB6 cells. When expressed in colon carcinoma cells that lack it, TIMP-3 suppresses carcinoma growth in nude mice and produces G1 arrest.