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  • br Results br Discussion CCA is


    Discussion CCA is a fatal tumor originating from the intrahepatic bile duct and the prognosis is very poor (Hoyos et al., 2018). CCA is one of the most dangerous primary liver malignant tumors and the most common malignant tumor of the biliary tract worldwide. However, the underlying molecular mechanisms of CCA carcinogenesis remain unclear (Liu et al., 2014). Metastasis and post-surgical recurrence in CCA patients are very high; therefore, the prognosis of CCA patients remains poor (Golan et al., 2017). Unfortunately, few biomarkers exist for the clinical prediction of CCA. To solve this problem, it is necessary to explore novel early diagnostic biomarkers and to find new therapeutic targets (Rizvi and Gores, 2013). This was the first study to clarify that NTS over-expression correlated well with the poor prognosis of CCA patients, suggesting that NTS may be a good prognostic biomarker for CCA patients. NTS is widely distributed throughout the central nervous system, with the highest level in the amygdala, hypothalamus, and nucleus accumbens. NTS has numerous effects, including hypothermia, analgesia, and increased sport activity. It also exerts important roles in regulating the dopamine pathway (Hernandez-Chan et al., 2015). Prospective studies have been conducted in other cancers such as glioma, showing that increased NTS or NTSR1 tie2 were related to a decreased three-year survival rate (Ouyang et al., 2015). The potential of the NTS/NTSR pathway as a novel target for cancer therapies has been advocated in colorectal cancer and some other cancers such as the non-small-cell lung cancer (NSCLC) (Takahashi et al., 2006). NTS has been explored as a diagnostic and therapeutic target in numerous other cancers, including pancreas, breast, and prostate cancers (Wu et al., 2012). However, the role of NTS in CCA metastasis remains ill-defined. The present study found that the NTS level was correlated with the prognosis of CCA patients, which deserves further investigation. Here, we also found that NTS gene knockdown by miRNA inhibited CCA cell metastasis in vitro. Consistently, over-expression of NTS facilitated CCA cell metastasis in vitro. It has been reported that AKT caused constitutive activation in various tumor types (Bo et al., 2018; Sun et al., 2018). AKT was found to be hyper-activated in >60% of cancer types, suggesting it as a novel therapeutic target (West et al., 2002). Activated AKT plays important roles in cellular growth, cell cycle progression, and cell survival (Song et al., 2018). The PI3K/AKT signaling pathway was not only involved in the regulation of tumor development but also as a potential tumor treatment target. Several reports indicated that the constitutive activation of the PI3K/AKT signaling pathway was involved in chemotherapy resistance (Zhou et al., 2017; Zhong et al., 2017) and participated in molecule-targeted treatment (Wendel et al., 2004; Eichhorn et al., 2008). In this study, we found that NTS played a positive role in CCA cells and facilitated CCA metastasis via activating AKT signaling. In addition, these effects could be attenuated by the PI3K inhibitor LY294002 (Han et al., 2015). EGFR has been reported to be associated with most solid cancers, including ovarian cancer, head-and-neck cancer, NSCLC, breast cancer, colon cancer, gliomas, and renal cancer (Herbst and Langer, 2002; Fujino et al., 1996). Over-expression of EGFR was always found in aggressive and invasive cancers. Several EGFR-targeting strategies to interfere with EGFR-mediated malignant behaviors have shown prospective clinical benefits for several solid tumors (Ethier, 2002; Baselga and Arteaga, 2005). Treatment with either gefitinib or erlotinib down-regulated EGRF-TK activity, suppressed tumor cell growth, promoted apoptosis and cell cycle arrest, and reduced HCC-related angiogenesis both in vivo and in vitro (Giaccone, 2005). EGFR inhibitors such as Erlotinib have already been reported to be used in targeted therapy in clinical trials (Wu et al., 2015). Our data show that NTS facilitates CCA cell metastasis by activating EGFR/AKT signaling. Furthermore, these effects can be attenuated by the EGFR inhibitor erlotinib. The findings of the present study shed new light on the mechanism of CCA progression and metastasis, thus providing a potential target for cancer prevention and treatment.