| Summary: | 博士 === 國立成功大學 === 基礎醫學研究所 === 95 === Oral cancer is one of the most common types of human cancer in the world. Although the risk factors for oral cancer are well-recognized in different countries, the molecular mechanism responsible for this malignancy remains elusive particularly in the countries where betel quid chewing is prevalent. To clarify the genes involved in the oral cancer, especially in patients with betel-quid chewing habit, the cDNA microarray analysis was used to analyze the mRNA expression patterns of 1177 genes in ten oral cancer patients with betel quid chewing history. Eighty-four genes involving cell adhesion, cell shape, growth, apoptosis, angiogenesis, metastasis, and metabolism were deregulated. Although the expression profile of these genes was shared by certain clinical patients, there was no significant association of the expression profile with clinical staging. Overexpression of STAT-1, caspase-1 and COX-2 in the precancer lesions, suggesting that deregulation of these genes might occur early even before malignancy occurred. To further dig out the deregulated genes in oral carcinogenesis, larger scale cDNA microarray was used to screen 7500 human cDNA clones for genes differentially expressed in two Taiwanese oral cancer lines, OEC-M1 and OC-2, compared to normal oral keratinocytes (NOK). The expression level of S100A2 in oral cancer cell lines was found to be only one-third of that in NOK. Although S100A2 is considered a putative tumor suppressor due to its loss or down-regulation in several cancer types, no mechanism has been described for the tumor suppressor role of S100A2. To clarify this role, we employed stable clones of squamous cell carcinoma (SCC) ectopically expressing S100A2. The ectopic expression of S100A2 resulted in a significant inhibition of proliferation, migration, and invasion of cancer cells. Moreover, S100A2 significantly reduced the number of colonies (≧0.5 mm) formed in semisolid agar and decreased the growth of tumor burden in nude mice. Moreover, we found that such potent anti-tumor role of S100A2 in squamous cell carcinoma was partly via reduced expression of COX-2. By the study of epigenetic mechanisms, we found the disagreement from previous studies. The restoration of S100A2 expression by 5’-azaC and/or TSA treatment was not found in every cancer cell line we examined. It implies that there are still other upstream regulatory mechanisms other than methylation and deacetylation for regulating the expression of S100A2. By sequencing the coding region of S100A2, we found a G/A polymorphism in nucleotide 182 of S100A2 that results in asparagines substitution of serine in oral squamous cell carcinoma. No strict correlation in the genotype of S100A2 and the mRNA expression or the tumor suppression role of S100A2 in vitro could be identified. Together, S100A2 indeed behaves as a tumor suppressor partly via repression of COX-2. More studies are needed to examine if other proteins or signaling pathways are involved in the anti-tumor effect of S100A2.
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