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

Chiba,Takahiro; Ishisaki,Akira; Kyakumoto,Seiko; Shibata,Toshiyuki; Yamada,Hiroyuki; Kamo,Masaharu

doi:10.3892/or.2016.5338

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

Authors:
- Takahiro Chiba
- Akira Ishisaki
- Seiko Kyakumoto
- Toshiyuki Shibata
- Hiroyuki Yamada
- Masaharu Kamo
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Affiliations: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Yahaba-cho, Iwate 028-3694, Japan, Department of Oral and Maxillofacial Surgery, Gifu University Graduate School of Medicine, Gifu-shi, Gifu 501-1194, Japan, Division of Oral and Maxillofacial Surgery, Department of Reconstructive Oral and Maxillofacial Surgery, Iwate Medical University School of Dentistry, Morioka, Iwate 020-8505, Japan
Published online on: December 28, 2016 https://doi.org/10.3892/or.2016.5338
Pages: 713-720
Copyright: © Chiba et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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