title: Critical role of Wnt5a-Ror2 signaling in motility and invasiveness of carcinoma cells following Snail-mediated epithelial-mesenchymal transition.
abstract: Expression of Snail has been shown to mediate epithelial-mesenchymal transition (EMT) of epithelial cells and carcinomas, characterized by morphological alterations with disappearance and appearance of E-cadherin and vimentin, respectively. Here, we show that ectopic expression of Snail in human epidermoid carcinoma A431 cells (Snail/A431) induces the representative EMT, resulting in remarkable motile and invasive properties of the cells. Expression of Wnt5a, its receptor Ror2 and matrix metalloproteinase (MMP)-2 is induced in Snail/A431, but not in control A431 cells. Interestingly, suppressed expression of either Wnt5a or Ror2 in Snail/A431 cells results in the inhibition of in vitro cell motility and invasiveness, at least partly mediated by MMP-2, without affecting characteristics of EMT, i.e., mesenchymal morphology, and down- and up-regulations of E-cadherin and vimentin, respectively. We further show that endogenous Snail is required for sustained expression of Wnt5a, Ror2 and MMP-13 in human osteosarcoma SaOS-2 cells. The results indicate that expression of both Wnt5a and Ror2 is induced during Snail-mediated EMT or malignant progression of cancer cells and that consequently activated Wnt5a-Ror2 signaling confers highly motile and invasive properties on cancer cells. Thus, Wnt5a-Ror2 signaling can be a target of cancer therapies to prevent cancer cells from undergoing invasion and metastasis.
authors.affiliation: Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Dayong
authors.initials: D
authors.lastname: Ren
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Minami
authors.forename: Michiru
authors.initials: M
authors.lastname: Nishita
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein
chemical_list: D011518:Proto-Oncogene Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C078717:ROR2 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors