WWOX Suppresses Cell Growth and Induces Cell Apoptosis via Inhibition of P38 Nuclear Translocation in Cholangiocarcinoma

Background: Extrahepatic cholangiocarcinoma (EHCC) is the second most common primary hepatic malignancy, and is associated with high morbidity and mortality. We previously reported the decreased expression of WWOX in EHCC samples, but the underlying mechanism remained unclear. Methods: Immunoprecipitation and immunofluorescence were performed to examine the interaction of WWOX and P38 MAPK. Western blot was carried out to detect the expression of ATF2 and eIF-4E. MTT, colony formation, and Annexin V-FITC assays were performed to detect the cell proliferation and apoptosis. IHC was performed to detect the protein expression in clinical samples. Results: WWOX interacted with P38 and modulated its sub-cellular localization, leading to the cytoplasmic retention of P38. WWOX over-expression inhibited the phosphorylation of ATF2 and eIF-4E, while exogenous P38 reversed this reduction in phosphorylation. Ectopic expression of WWOX in EHCC cells led to inhibited proliferation and stimulated apoptosis in a P38 MAPK-dependent manner. In addition, we found a negative association of WWOX with nuclear localization of P38 and expression of phosphorylated ATF2 in EHCC samples. Conclusion: Our data demonstrated the role of WWOX in EHCC progression, revealing the potential of WWOX/p-ATF2 as a novel diagnostic and prognostic marker, and therapeutic target for EHCC.

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