Tumor suppressor WWOX participates in cell/cell recognition and migration

Abstract

Metastatic cancer cells are essentially devoid of tumor suppressor WWOX expression, and this appears to be associated with their enhanced migration. A portion of WWOX is localized at the cell membrane/cytoskeleton area. By time‐lapse microscopy, we showed that wild type Wwox+/+ mouse embryonic fibroblast (MEF) cells migrated collectively, whereas the knockout Wwox−/− cells migrated individually. When wild type MEF cells encountered knockout cells, the knockout cells failed to recognize the wild type, although they are from the same mouse strain. The knockout Wwox−/− MEF cells reached out with their pseudopodia to touch the wild type from a distance (5–20 μm), and then moved backward significantly faster and divided simultaneously. The event was also shown in many WWOX‐negative malignant cancer cells upon encountering with WWOX‐expressing cells. Restoration of WWOX with ectopic gene expression or treatment with an inhibitor of DNA methylation restored collective migration. Molecular analysis revealed that when cells overexpressing a short N‐terminal segment of WWOX, they attracted upcoming visiting cells. But, they repelled the visitors if a short segment in the C‐terminal SDR domain of WWOX was overexpressed. Thus, WWOX participates in cell/cell recognition, and conformational alteration of membrane‐associated WWOX affects cell behavior. (Supported in part by NHRI, NSC and DOH, Taiwan, and DoD, USA)