Novel sensitivity genes to 5-FU and CDDP in esophageal squamous cell carcinoma

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Existing chemotherapy is palliative for advanced esophageal squamous cell carcinoma (ESCC), and the therapeutic outcome significantly varies, even among patients given the same therapy. The prediction of sensitivity to anticancer drugs and clinical outcomes of chemotherapy is urgently required to improve survival for ESCC patients. Using 20 human cancer cell lines, we sort out genes responsible for drug-sensitivity in ESCC, through 2 different genome-wide microarray analyses and subsequent real-time RT-PCR, and identified 7 genes as novel potent markers for 5-FU and CDDP. cDNA and oligonucleotide microarray analyses and MTT assay was first performed to select genes whose expression levels correlated with sensitivity to 5-FU and CDDP. Each array screening analysis provided numerous candidates, but they included few genes showing high correlation in both array screening analyses (P<0.01). After the confirmation of correlations between their expression levels quantified by real-time RT-PCR, we finally selected 7 genes as the most potent markers of sensitivity to the drugs: B4GALT5, UGCG, XBP1 for 5-FU and ARFRP11, IFITM1, KIAA0685, SIPAIL for CDDP. The fact that drug sensitivity is determined by multiple genes required a better understanding of the intricate network of the selected genes in the expression levels. We performed, therefore, multiple regression analysis and reached the prediction formulae of in vitro drug activity and clinical response to the drugs. Despite the limited data, the fixed prediction formulae appeared to be of highly predictive, which suggest that simultaneous performance of two different types of comprehensive gene expression analysis may provide way to identify potent marker genes, and evaluation of the variable expression of the 2 sets of selected genes can work well in the prediction model. To clarify the functional significance in the drug sensitivity, we established stable B4GALT5 gene transfectants. Although the other 6 genes are still under investigation, we found that overexpression of B4GALT5 caused an increase of 5-FU resistance. Our selected genes may be better current candidates for prediction markers of response to 5-FU and CDDP in ESCC.