title: Tetraspanin CD63 acts as a pro-metastatic factor via β-catenin stabilization.
abstract: The tetraspanin CD63 is implicated in pro-metastatic signaling pathways but, so far, it is unclear, how CD63 levels affect the tumor cell phenotype. Here, we investigated the effect of CD63 modulation in different metastatic tumor cell lines. In vitro, knock down of CD63 induced a more epithelial-like phenotype concomitant with increased E-cadherin expression, downregulation of its repressors Slug and Zeb1, and decreased N-cadherin. In addition, β-catenin protein was markedly reduced, negatively affecting expression of the target genes MMP-2 and PAI-1. β-catenin inhibitors mimicked the epithelial phenotype induced by CD63 knock down. Inhibition of β-catenin upstream regulators PI3K/AKT or GSK3β could rescue the mesenchymal phenotype underlining the importance of the β-catenin pathway in CD63-regulated cell plasticity. CD63 knock down-induced phenotypical changes correlated with a decrease of experimental metastasis whereas CD63 overexpression enhanced the tumor cell-intrinsic metastatic potential. Taken together, our data show that CD63 is a crucial player in the regulation of the tumor cell-intrinsic metastatic potential by affecting cell plasticity.
authors.affiliation: Institute for Experimental Oncology and Therapy Research and Institute of Molecular Immunology, Klinikum rechts der Isar der Technische Universität München, München, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Seubert
authors.forename: Haissi
authors.initials: H
authors.lastname: Cui
authors.forename: Nicole
authors.initials: N
authors.lastname: Simonavicius
authors.forename: Katja
authors.initials: K
authors.lastname: Honert
authors.forename: Sandra
authors.initials: S
authors.lastname: Schäfer
authors.forename: Ute
authors.initials: U
authors.lastname: Reuning
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.forename: Bernard
authors.initials: B
authors.lastname: Mari
authors.forename: Achim
authors.initials: A
authors.lastname: Krüger
mesh_terms: D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D060149:Tetraspanin 30 / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C554586:CD63 protein, human; C554587:Cd63 protein, mouse; D060149:Tetraspanin 30; D051176:beta Catenin
keywords: CD63; E-cadherin; GSK3; PI3K; beta-catenin; cancer; epithelial mesenchymal transition (EMT); mesenchymal to epithelial transition (MET); metastasis; tetraspanin