title: Transforming growth factor-β1 suppresses bone morphogenetic protein-2-induced mesenchymal-epithelial transition in HSC-4 human oral squamous cell carcinoma cells via Smad1/5/9 pathway suppression.
abstract: Squamous cell carcinoma is the most common cancer in the oral cavity. We previously demonstrated that transforming growth factor-β1 (TGF-β1) promotes the epithelial-mesenchymal transition (EMT) of human oral squamous cell carcinoma (hOSCC) cells; however, it remains to be clarified whether the TGF-β superfamily member bone morphogenetic protein (BMP) affects this process in hOSCC cells. Here, we examined the independent and collective effects of TGF-β1 and BMP-2 on EMT and mesenchymal‑epithelial transition (MET) in a panel of four hOSCC cell lines. Notably, we found that HSC-4 cells were the most responsive to BMP-2 stimulation, which resulted in the upregulation of Smad1/5/9 target genes such as the MET inducers ID1 and cytokeratin 9 (CK9). Furthermore, BMP-2 downregulated the mesenchymal marker N-cadherin and the EMT inducer Snail, but upregulated epithelial CK9 expression, indicating that BMP-2 prefers to induce MET rather than EMT. Moreover, TGF-β1 dampened BMP-2-induced epithelial gene expression by inhibiting Smad1/5/9 expression and phosphorylation. Functional analysis revealed that TGF-β1 and BMP-2 significantly enhanced HSC-4 cell migration and proliferation, respectively. Collectively, these data suggest that TGF-β positively regulates hOSCC invasion in the primary tumor, whereas BMP-2 facilitates cancer cell colonization at secondary metastatic sites. Thus, the invasive and metastatic characteristics of hOSCC appear to be reciprocally regulated by BMP and TGF-β.
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba-cho, Iwate 028-3694, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Chiba
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba-cho, Iwate 028-3694, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ishisaki
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba-cho, Iwate 028-3694, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Kyakumoto
authors.affiliation: Department of Oral and Maxillofacial Surgery, Gifu University Graduate School of Medicine, Gifu-shi, Gifu 501-1194, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Division of Oral and Maxillofacial Surgery, Department of Reconstructive Oral and Maxillofacial Surgery, Iwate Medical University School of Dentistry, Morioka, Iwate 020-8505, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba-cho, Iwate 028-3694, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Kamo
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism*; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism; D051904:Smad8 Protein / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D012333:RNA, Messenger; C497399:SMAD1 protein, human; C497797:SMAD5 protein, human; C107514:SMAD9 protein, human; D051785:Smad Proteins; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; D053773:Transforming Growth Factor beta1