title: Transforming growth factor-β1 induces epithelial-mesenchymal transition and integrin α3β1-mediated cell migration of HSC-4 human squamous cell carcinoma cells through Slug.
abstract: We investigated whether transforming growth factor (TGF)-β1 promoted epithelial-mesenchymal transition (EMT) and migration of human oral squamous cell carcinoma (hOSCC) cells. Among 6 hOSCC cell lines investigated, Smad2 phosphorylation and TGF-β target genes expression were most clearly upregulated following TGF-β1 stimulation in HSC-4 cells, indicating that HSC-4 cells were the most responsive to TGF-β1. In addition, the expression levels of the mesenchymal markers N-cadherin and vimentin were most clearly induced in HSC-4 cells among the hOSCC cell lines by TGF-β1 stimulation. Interestingly, E-cadherin and β-catenin at the cell surface were internalized in HSC-4 cells stimulated with TGF-β1. In addition, the expression levels of the EMT-related transcription factor Slug was significantly upregulated on TGF-β1 stimulation. Moreover, the downregulation of Slug by RNA interference clearly inhibited the TGF-β1-induced expression of mesenchymal marker and the migration of HSC-4 cells. Proteomics analysis also revealed that the expression levels of integrin α3β1-targeted proteins were upregulated in TGF-β1-stimulated HSC-4 cells. Neutral antibodies against integrin α3 and β1, as well as a focal adhesion kinase (FAK) inhibitor, clearly suppressed TGF-β1-induced cell migration. These results suggest that the EMT and integrin α3β1/FAK pathway-mediated migration of TGF-β1-stimulated HSC-4 hOSCC cells is positively controlled by Slug.
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Nishitokuta, Yahaba-cho, Iwate 028-3694, Japan.
authors.forename: Daishi
authors.initials: D
authors.lastname: Saito
authors.forename: Seiko
authors.initials: S
authors.lastname: Kyakumoto
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Chosa
authors.forename: Miho
authors.initials: M
authors.lastname: Ibi
authors.forename: Noriko
authors.initials: N
authors.lastname: Takahashi
authors.forename: Naoto
authors.initials: N
authors.lastname: Okubo
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Sawada
authors.forename: Akira
authors.initials: A
authors.lastname: Ishisaki
authors.forename: Masaharu
authors.initials: M
authors.lastname: Kamo
mesh_terms: D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D039201:Integrin alpha3beta1 / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D015820:Cadherins; D039201:Integrin alpha3beta1; C497806:SMAD7 protein, human; C000604407:SNAI1 protein, human; D051906:Smad7 Protein; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1