T-box transcription factor BRACHYURY regulate the cancer stem cell phenotype

Research Project

Project/Area Number	17K17263
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	Surgical dentistry
Research Institution	Kyushu University
Principal Investigator	Akimoto Naonari 九州大学, 歯学研究院, 共同研究員 (20772940)
Project Period (FY)	2017-04-01 – 2019-03-31
Project Status	Completed (Fiscal Year 2018)
Budget Amount *help	¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000) Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000) Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords	Brachyury / Sox2 / Sox２ / EMT / 癌幹細胞 / 上皮間葉移行
Outline of Final Research Achievements	Recently, we showed that the T-box transcription factor BRACHYURY could be a strong regulator of EMT and the cancer stem cells (CSCs) 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 stem ness by means of forced expression of BRACHYURY in oral cancer cell lines. BRACHYURY, SOX2, or both were stably transfected into oral carcinoma cell lines. Forced expression of BRACHYURY or SOX2 slightly increased expression of EMT and stem cell markers. 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. These synergistic effects increased expression levels of FIBRONECTIN and TGF-β2. We found that BRACHYURY and SOX2 synergistically promote cancer stemness in oral cancer cells.
Academic Significance and Societal Importance of the Research Achievements	BRACHYURYとSOX2を同時に強制発現させることにより、EMT形質、癌幹細胞形質および細胞の遊走能、浸潤能が促進され、同時にTGFb2とFibronectinの発現が著明に亢進していたことを明らかにした。この相乗効果はBRACHYURY、SOX2、TGFb2、Fibronectinが蛋白、もしくは遺伝子の同一ネットワーク上に存在している可能性を示唆し、これらが癌治療において有効な標的因子となり得るが、応用させていくためには更なる詳細なメカニズムの解析が望まれる。