Oncogenic Role of the NFATC2/NEDD4/FBP1 Axis in Cholangiocarcinoma

Nuclear factor of activated T cells 2 (NFATC2) is reported to contribute to the initiation and progression of various cancers; however, its expression and function in cholangiocarcinoma (CCA) remain elusive. Herein, we investigated the expression pattern, clinicopathological characteristics, cell biological functions, and potential mechanisms of NFATC2 in CCA. Real-time PCR and immunohistochemistry were performed to analyze the expression of NFATC2 in human CCA tissues. CCK-8, colony formation, flow cytometry, Western blotting and transwell assays, and in vivo xenograft and pulmonary metastasis models were used to explore the effect of NFATC2 on the proliferation and metastasis of CCA. A dual-luciferase reporter system, oligonucleotide pull down, chromatin immunoprecipitation, immunofluorescence, and coimmunoprecipitation were performed to reveal the potential mechanisms. We found that NFATC2 was upregulated in CCA tissues and cells, and its aberrantly high levels were associated with poorer differentiation pattern. Functionally, NFATC2 overexpression promoted CCA cell proliferation and metastasis, whereas knockdown of NFATC2 led to the opposite results. Mechanistically, NFATC2 could be enriched in the promoter region of neural precursor cell expressed developmentally downregulated 4 (NEDD4) to facilitate its expression. Furthermore, NEDD4 targeted fructose-1, 6-bisphosphatase 1 (FBP1), and inhibited FBP1 expression via ubiquitination. In addition, silencing NEDD4 rescued the effects of NFATC2 overexpression on CCA cells. NEDD4 was upregulated in human CCA tissues, and its expression levels were positively correlated with those of NFATC2. We thus conclude that NFATC2 promotes the progression of CCA via the NEDD4/FBP1 axis, emphasizing the oncogenic role of NFATC2 in CCA progression.

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