Upregulation of topoisomerase IIα expression in advanced gallbladder carcinoma: a potential chemotherapeutic target

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Abstract
The lack of treatment options other than surgical resection results in unfavourable prognosis of advanced gallbladder carcinoma. The aim of this study was to identify cancer-specific cellular targets that would form the basis for some therapeutic approaches for this disease. Twelve advanced gallbladder carcinoma tissue samples and three samples of normal gallbladder epithelium were screened to identify differentially expressed genes by DNA microarray analysis. The results obtained were validated in an independent sample set by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR). Among the genes picked-up, one molecule, topoisomerase IIα (TOPO IIα), was further assessed immunohistochemically as a potential chemotherapeutic target, and the growth inhibitory effects of etoposide, doxorubicin and idarubicin, representative TOPO IIα inhibitors, on two different gallbladder carcinoma cell lines were compared with that of gemcitabine and 5-fulorouracil. Five upregulated genes were identified: four cell cycle-related genes (TOPO IIα, cyclin B2, CDC28 protein kinase regulatory subunit 2, ubiquitin-conjugating enzyme E2C) and a metabolism-related gene (γ-glutamyl hydrolase). Immunohistochemically, TOPO IIα was expressed in gallbladder cancer cells, and 16 of 35 cases (46%) had strong TOPO IIα expression defined as having a labeling index of >50%. In in vitro growth inhibition assay, etoposide, as well as doxorubicin and idarubicin, was the most effective for OCUG-1 cells that had strong TOPO IIα expression, while gemicitabine was the most effective for NOZ cells with weak TOPO IIα expression. Etoposide induced apoptosis of OCUG-1 cells. TOPO IIα might be an effective chemotherapeutic target in advanced gallbladder carcinoma, especially when it is expressed strongly.