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Int. J. Mol. Sci. 2018, 19(11), 3620; https://doi.org/10.3390/ijms19113620

Transfection of T-Box Transcription Factor BRACHYURY and SOX2 Synergistically Promote Self-Renewal and Invasive Phenotype in Oral Cancer Cells

1
Section of Oral and Maxillofacial Surgery, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan
2
Department of Maxillofacial Diagnostic and Surgical Science, Field of Oral and Maxillofacial Rehabilitation, Graduate school of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 8 October 2018 / Revised: 6 November 2018 / Accepted: 8 November 2018 / Published: 16 November 2018
(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)
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Abstract

Recent studies suggest that epithelial–mesenchymal transition (EMT) correlates with cancer metastasis. In addition, there is growing evidence of the association of EMT with cancer stem cells (CSCs). Recently, we showed that the T-box transcription factor BRACHYURY could be a strong regulator of EMT and the CSC phenotype, which were effectively suppressed by a BRACHYURY knockdown in an adenoid cystic carcinoma cell line. In this study, we further tested whether BRACHYURY is a regulator of cancer stemness by means of forced expression of BRACHYURY in oral cancer cell lines. BRACHYURY, SOX2, or both were stably transfected into oral carcinoma cell lines. We analysed these transfectants with respect to self-renewal phenotypes using a sphere-formation assay, and we assessed the expression levels of EMT markers and stem cell markers using real-time reverse transcription-polymerase chain reaction (RT-PCR). Cell migration and invasiveness in vitro were evaluated using a wound healing assay and a tumour cell dissemination assay, respectively. Forced expression of BRACHYURY or SOX2 slightly increased expression of EMT and stem cell markers and the self-renewal phenotype. The expression levels, however, were much lower compared to those of cancer stem cell-like cells. Forced co-expression of BRACHYURY and SOX2 strongly upregulated EMT and stem cell markers and the self-renewal phenotype. Cell migration and invasiveness in vitro were also remarkably enhanced. These synergistic effects increased expression levels of FIBRONECTIN, SNAIL, SLUG, ZEB1, and TGF-β2. In particular, the effects on FIBRONECTIN and TGF-β2 were significant. We found that BRACHYURY and SOX2 synergistically promote cancer stemness in oral cancer cells. This finding points to the importance of gene or protein networks associated with BRACHYURY and SOX2 in the development and maintenance of the CSC phenotype. View Full-Text
Keywords: BRACHYURY; SOX2; Epithelial–Mesenchymal transition (EMT); cancer stem cell; oral cancer BRACHYURY; SOX2; Epithelial–Mesenchymal transition (EMT); cancer stem cell; oral cancer
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Akimoto, N.; Nakamura, K.; Hijioka, H.; Kume, K.; Matsumura, Y.; Sugiura, T. Transfection of T-Box Transcription Factor BRACHYURY and SOX2 Synergistically Promote Self-Renewal and Invasive Phenotype in Oral Cancer Cells. Int. J. Mol. Sci. 2018, 19, 3620.

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