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

Abstract

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.

Functional genetic variant in the Kozak sequence of WW domain-containing oxidoreductase (WWOX) gene is associated with oral cancer risk

“…In addition, we observed a high frequency of the homozygous 121 TT genotype and its combination with the heterozygous WWOX CT in patients, suggesting that changes in the translation initiation rate generally explains the differences in protein expression among the participants. The WWOX expression also suppresses tumor growth and induces cell apoptosis [45]. We observed that rs11545028 was associated with a higher risk of stage III and IV cancers, lymph node metastasis, and the cell differentiation grade.…”

Angiomotin Counteracts the Negative Regulatory Effect of Host WWOX on Viral PPxY-Mediated Egress

“…Indeed, we demonstrate that WW-domain #1 of WWOX, a multi-functional tumor suppressor, specifically interacts with the PPxY motifs of eVP40, mVP40, and LASV Z proteins to inhibit VLP egress. Our identification of WWOX as the newest negative regulator of viral PPxY-mediated budding is particularly intriguing since like YAP/TAZ and BAG3, WWOX plays a key role in regulating physiologically important cellular pathways, such as transcription (Hippo pathway), apoptosis, cytoskeletal dynamics, and tight junctions (TJ) formation, via PPxY/WW-domain interactions (34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44).…”

The Roles of p38 MAPK and ERK1/2 in Coplanar Polychlorinated Biphenyls-Induced Apoptosis of Human Extravillous Cytotrophoblast-Derived Transformed Cells

“…MAPK signaling pathways mediate the intracellular signaling associated with a variety of cellular physiological process, including the morphological and functional differentiation of villous trophoblasts, and have been proven to be important for the induction of cytotoxicity responses [28][29][30][31]. Thus, to identify the potential mechanisms that lead to cytotoxic responses of HTR-8/SVneo and HPT-8 cells to Co-PCBs, we demonstrated the roles members of the MAPK signal cascades, including ERK1/2 and p38 kinase.…”