title: Semaphorin-7a reverses the ERF-induced inhibition of EMT in Ras-dependent mouse mammary epithelial cells.
abstract: Epithelial-to-mesenchymal transition (EMT) is a key process in cancer progression and metastasis, requiring cooperation of the epidermal growth factor/Ras with the transforming growth factor-β (TGF-β) signaling pathway in a multistep process. The molecular mechanisms by which Ras signaling contributes to EMT, however, remain elusive to a large extent. We therefore examined the transcriptional repressor Ets2-repressor factor (ERF)-a bona fide Ras-extracellular signal-regulated kinase/mitogen-activated protein kinase effector-for its ability to interfere with TGF-β-induced EMT in mammary epithelial cells (EpH4) expressing oncogenic Ras (EpRas). ERF-overexpressing EpRas cells failed to undergo TGF-β-induced EMT, formed three-dimensional tubular structures in collagen gels, and retained expression of epithelial markers. Transcriptome analysis indicated that TGF-β signaling through Smads was mostly unaffected, and ERF suppressed the TGF-β-induced EMT via Semaphorin-7a repression. Forced expression of Semaphorin-7a in ERF-overexpressing EpRas cells reestablished their ability to undergo EMT. In contrast, inhibition of Semaphorin-7a in the parental EpRas cells inhibited their ability to undergo TGF-β-induced EMT. Our data suggest that oncogenic Ras may play an additional role in EMT via the ERF, regulating Semaphorin-7a and providing a new interconnection between the Ras- and the TGF-β-signaling pathways.
authors.affiliation: Medical School, University of Crete, Crete, Greece.
authors.forename: Maryline
authors.initials: M
authors.lastname: Allegra
authors.forename: Andreas
authors.initials: A
authors.lastname: Zaragkoulias
authors.forename: Elena
authors.initials: E
authors.lastname: Vorgia
authors.forename: Marina
authors.initials: M
authors.lastname: Ioannou
authors.forename: Gabriele
authors.initials: G
authors.lastname: Litos
authors.forename: Hartmut
authors.initials: H
authors.lastname: Beug
authors.forename: George
authors.initials: G
authors.lastname: Mavrothalassitis
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D020935:MAP Kinase Signaling System; D008321:Mammary Glands, Animal / Q000166:cytology*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C522019:Erf protein, mouse; D012097:Repressor Proteins; C485571:Sema7a protein, mouse; D039961:Semaphorins; D016212:Transforming Growth Factor beta; D018631:ras Proteins