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To investigate the effect of fructose-1,6-bisphosphatase 1 (FBP1) on the malignant phenotypes of cholangiocarcinoma (CCA) cells, and to explore the underlying mechanism.The expression of FBP1 in clinical CCA tissues was detected by real-time PCR, Western blot and immunohistochemistry staining. FBP1 was overexpressed by transfection of a forced expression plasmid. MTT, plate colony formation assay, Hoechst staining, flow cytometry, Western blot, wound healing, transwell assays and xenograft were performed to detect the growth, proliferation, cell cycle, apoptosis, migration, invasion and tumorigenesis in RBE and HCCC-9801 cells. In addition, the Wnt/β-catenin signaling was detected.FBP1 was downregulated in clinical CCA specimens and cell lines, compared to paired para-carcinoma tissues or normal cholangetic epithelial cells. Gain-of-function experiments demonstrated that the forced expression of FBP1 inhibited the proliferation, colony formation, and blocked cell cycle of RBE and HCCC-9801 cells. Apoptosis of CCA cells was significantly enhanced by FBP1 overexpression, evidenced by upregulation of cleaved caspase-3, cleaved PARP and Bax levels, while downregulation of Bcl-2 level. Moreover, overexpression of FBP1 decreased the migratory and invasive ability in RBE and HCCC-9801 cells. However, FBP1-induced phenotypic changes were eliminated by overexpression of β-catenin. Finally, the forced overexpression of FBP1 inhibited tumorigenesis in vivo.Our findings demonstrate that FBP1 is downregulated in CCA tissues and cell lines, and the overexpression of FBP1 inhibits the proliferation, migration, invasion and tumorigenesis of CCA cells partly via inactivation of Wnt/β-catenin pathway. FBP1 may be a novel early diagnosis marker and therapeutic target for CCA.