Identification of novel oncogenes with prognostic relevance and elucidation of their functional role in gastric cancer

Abstract

Identification of novel oncogenes with prognostic relevance and elucidation of their functional role in gastric cancer.

Prior microarray analysis of patient gastric tumors revealed consistent differences in molecular expression patterns in comparison to normal gastric samples. From our comprehensive microarray dataset, we identified 5 genes that are overexpressed and differentially methylated with corresponding significant survival relevance. We hypothesized that genes with these characteristics possibly plays a role in chemotherapeutic drug resistance and hence may result in worse prognosis. In this study, we performed functional validation on XPO1 to evaluate our hypothesis. XPO1 gene expression and methylation was quantified with real time quantitative PCR and methylation specific PCR respectively. Correlation of gene expression to drug response was demonstrated with cell proliferation assay while validation of docetaxel drug response was done via gene and protein quantification of XPO1 downstream targets RAN, RANBP1 and BIRC5 (Survivin) in both docetaxel treated and untreated cells. Our results shows gastric cancer cell lines with upregulated XPO1 gene expression tend to be relatively more sensitive to docetaxel with relatively downregulated expression of RAN, RANBP1 and BIRC5, contrary to literature. In line with our speculation, gene and protein expression of these downstream targets were found to be elevated upon docetaxel drug treatment. We conclude that functional relevance of XPO1 and its downstream targets in the development of docetaxel drug response is probable.