Abstract
Cholangiocarcinoma (CCA) is a malignancy of the bile duct epithelium. The major problems of this cancer are late diagnosis and a high rate of metastasis. CCA patients in advanced stages have poor survival and cannot be cured with surgery. Therefore, targeting molecules involved in the metastatic process may be an effective CCA treatment. Monopolar spindle 1 (MPS1) is a kinase protein that controls the spindle assemble checkpoint in mitosis. It is overexpressed in proliferating cells and various cancers. The functional roles of MPS1 in CCA progression have not been investigated. The aims of this study were to examine the roles and molecular mechanisms of MPS1 in CCA progression. Immunohistochemistry results showed that MPS1 was up-regulated in carcinogenesis of CCA in a hamster model, and positive expression of MPS1 in human CCA tissues was correlated to short survival of CCA patients (n = 185). Small interfering RNA (siRNA)-induced knockdown of MPS1 expression reduced cell proliferation via G2/M arrest, colony formation, migration, and invasion. Moreover, MPS1 controlled epithelial to mesenchymal transition (EMT)-mediated migration via AKT and STAT3 signaling transductions. MPS1 was also involved in MMPs-dependent invasion of CCA cell lines. The current research highlights for the first time that MPS1 has an essential role in promoting the progression of CCA via AKT and STAT3 signaling pathways and could be an attractive target for metastatic CCA treatment.
Highlights
Cholangiocarcinoma (CCA), a primary cancer of bile duct epithelial cells, is associated with infection by the carcinogenic liver fluke (Opisthorchis viverrini, Ov), which is endemic in the Northeastern region of Thailand [1]
These results reveal that Monopolar spindle 1 (MPS1) could be detected early in precancerous lesions (HP/DP) and was highly expressed in CCA
Our findings indicate that MPS1 promotes MMPs-dependent invasion of CCA cells
Summary
Cholangiocarcinoma (CCA), a primary cancer of bile duct epithelial cells, is associated with infection by the carcinogenic liver fluke (Opisthorchis viverrini, Ov), which is endemic in the Northeastern region of Thailand [1]. CCA has a high mortality rate according to its high rate of metastasis, which is due to difficulties with early diagnosis [2]. Treatment of CCA patients with metastasis by surgery or chemotherapy is rarely successful [3,4]. Inhibiting molecules involved in cell progression or metastasis could be an alternative strategy for treatment of metastatic CCA. Monopolar spindle 1 (MPS1), or TTK (Thr/Tyr kinase), is an essential protein in the spindle assembly checkpoint (SAC) during mitosis [5]. MPS1 acts in several aspects of mitotic checkpoint control including mitotic SAC activation, recruitment of SAC components to kinetochores, centrosome duplication, error correction of kinetochoremicrotubule attachment, and chromosome alignment in mitosis [5,6,7].
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