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  • br Acknowledgments br Introduction The


    Introduction The incidence of cholangiocarcinoma (CCA), a malignant tumor found in both intra- and extra-hepatic biliary epithelia [1], has been increased worldwide over the past two decades [2]. The prognosis of CCA patients are generally poor, due to the lack of early detection and effective therapeutic regimens. The median post-surgical survival of patients with CCA was 4 months and 2-year survival was only 8.1% [3]. In addition, CCA recurrence can be as high as 50–70% even after surgery [4]. So, there is an urgent need to search for a novel treatment for early targeting of aberrantly expressed genes in the carcinogenesis and/or progression of CCA. Nowadays, there are several targeted molecules for cancer therapy based on the hallmarks of cancer [5]. In 1924, Otto Warburg described glucose metabolism in cancer called the “Warburg effect” or “aerobic glycolysis” [6] which has recently been indicated as general hallmark of cancer. Cancer SB-505124 hydrochloride mg aberrantly express some specific proteins involved in glucose metabolism such as glucose transporter 1 (GLUT1), pyruvate kinase M2 (PKM2) and hexokinase 2 (HKII) [7]. Hexokinase is the first enzyme and the first rate limiting step of glycolysis pathway that converts glucose to glucose-6-phosphate. Overexpression of HKII has been reported in several cancer cells such as ovarian [8], liver [9], colon [10], including non-Opisthorchis viverrini (Ov) associated CCA [11]. High levels of HKII have been associated with poor outcomes of cancer patients, e.g., tumor size, metastasis, and short survival rates, etc. [12]. Moreover, the inhibition of HKII using a specific inhibitor, namely lonidamine (LND) effectively suppressed the proliferation and metastasis of various cancers in in vitro, in vivo as well as clinical trials [13]. However, the information on HKII in Ov associated CCA is limited. The aim of the present study was to investigate the expression of HKII in Ov associated hamster and patient tissues. In addition, the functional roles of HKII in Ov associated CCA cell lines were to be determined using siRNA and HKII inhibitor.
    Materials and methods
    Discussion In aerobic condition, normal cells mostly rely on mitochondrial oxidative phosphorylation to produce energy. In contrast, cancer cells, although in aerobic atmosphere, depend mostly on glycolysis, the aerobic breakdown of glucose into ATP, known as the “Warburg effect” [22]. Based on this contrary finding, the specific isoform of glycolytic enzymes which is unique to cancer metabolism should be an effective target for cancer therapy. In the present study, the aberrant expression of HKII in tumor tissues from Ov associated CCA patients was observed. The contribution of HKII in CCA was confirmed in Ov induced hamster model. Lastly, it was shown that inhibiting expression or activity of HKII in CCA cells using small interfering RNA (siRNA) or HKII inhibitor, LND, gave a good promising as the target therapy for CCA. In the current study, HKII was overexpressed in precancerous and tumor tissues in more than 80% (68/82 cases) of Ov associated intrahepatic CCA. The result was similar to those reported for non Ov associated CCA (77%, 20/26 cases) [23] and extrahepatic CCA (84.6%, 22/26 cases) [11]. Contribution of HKII in the development of cholangiocarcinoma was noted in the Ov induced CCA hamster model in the present study. Aberrant expression of HKII was detected only in the tumor tissues from the Ov plus NDMA induced CCA hamsters but not observed in those from other hamster groups. The influence of HKII in carcinogenesis of CCA, however, may be at late stage, as there was no HKII expression in the bile duct epithelia observed before CCA was fully developed (at 6 months). In addition, HKII is possibly specific to malignant cells as it was detected only in the CCA but not in other cell types found in the liver. This assumption is supported by the fact that HKII was found mainly in the CCA tissues of the patients. On this basis, HKII might be a good target for therapy of CCA.