Extracellular MIF and Wnt and eph/ephrin signaling are involved in WWOX‐regulated cell‐cell recognition and migration

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Loss of tumor suppressor WWOX enhances cancer cell metastasis. Here, we determined that WWOX‐deficient cells fail to recognize the parental wild type cells or any WWOX‐expressing cells of the same or different species. WWOX‐negative cells have loose cell‐cell contacts and migrate individually. WWOX‐positive cells group tightly and migrate collectively. Transiently overexpressed WWOX suppresses cancer cell migration. Knockdown of WWOX by small interfering RNA, or ectopic dominant‐negative WWOX, increases cell migration. WWOX/p53/TIAF1 triad is a known axis of tumor suppression. Ectopic expression of the protein triad suppresses cell migration, anchorage‐independent growth, and induces apoptosis. Mutant p53 at the Ser46 phosphorylation site causes functional loss of the triad. Among all the p53 isoforms, ectopic Δ133p53γ is most potent in inducing apoptosis due, in part, to its activation of the SMAD‐responsive promoter. Time‐lapse microscopy revealed that upon encountering, WWOX‐negative human breast MDA‐MB‐231 cells suppress the migration WWOX‐positive mouse L929 fibroblasts. Few L929 cells undergo apoptosis. Indeed, MDA‐MB‐231 accelerate their migration, contact L929 with protrusions, and then migrate in a retrograde manner. The accelerated migration of MDA‐MB‐231 is associated with rapid activation of the Wnt signaling‐mediated TCF/LEF‐responsive promoter in less than 2 hr. However, L929 exhibit the activation of CRE and NF‐kB promoters in 16 hr and later. Suppression of the Wnt signaling by XAV939 abolishes the retrograde migration of MDA‐MB‐231 and their physical merge with L929. Similarly, inhibition of cell surface ephrin A1, B1 and B2 and extracellular MIF with specific antibodies leads to anterograde migration of MDA‐MB‐231 and restoration of their merge with L929. Together, WWOX‐regulated cell‐to‐cell recognition is associated with cell surface ephrins, extracellular TGF‐β and MIF, and Wnt‐dependent TCF/LEF promoter activation, so as to to avoid unwanted surrounding microenvironment by retrograde migration.Support or Funding InformationResearch was supported by the Department of Defense USA (W81XWH‐08–1‐0682), the Ministry of Science and Education, Taiwan, ROC (NSC99‐2320‐B‐006‐012‐MY3, 102‐2320‐B‐006‐018‐, 102‐2320‐B‐006‐030‐, and 102‐3011‐P‐006‐005‐), and the National Health Research Institute, Taiwan, ROC (NHRI‐EX99–9704BI; NHRI‐EX107‐10734NI) to NS Chang.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.