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Abstract Purpose The molecular signatures of cholangiocarcinoma are not well characterized. Targeting protein for Xenopus kinesin-like protein 2 (TPX2) has been shown to promote oncogenesis in the context of several cancers; however, its' role in cholangiocarcinoma has not been studied. We evaluated the role of TPX2 in cholangiocarcinoma. Methods Expression levels of TPX2 in cholangiocarcinoma were assessed by immunohistochemistry. Potential correlations were assessed by Chi-squared test. Impact of TPX2 expression on cell proliferation, cell cycle, apoptosis, cell invasion and migration was investigated by CCK-8, flow cytometric analysis, and transwell assay, respectively. The expressions of cell-cycle, cell-apoptosis and EMT related target proteins were detected by immunoblotting. Results TPX2 expression in cholangiocarcinoma tissues was significantly higher than that paracancerous tissue (44.3% vs. 5.7%; P <0.01). Overexpression of TPX2 showed a positive correlation with TNM stage, lymph node metastasis, and prognosis of patients. Knockdown of TPX2 expression induced G2-M arrest, apoptosis and inhibited invasion and migration of cholangiocarcinoma cells. Treatment of cholangiocarcinoma cells with TPX2 siRNA resulted in upregulation of cyclin A1, cyclin B1, p53, Bax, and E-cadherin; while downregulation of cyclin D1, CDK2, Bcl-2, N-cadherin, β-cadherin MMP-2, MMP-9, Slug, and Twist1. Conclusions Collectively, these results indicate that TPX2 may serve as a potential biomarker of prognostic relevance and a potential therapeutic target for cholangiocarcinoma. [ABSTRACT FROM AUTHOR]