The role of epithelial-mesenchymal transitioin by BMP in malignant melanoma

• Project/Area Number: 17K11622
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Morphological basic dentistry
• Research Institution: Kyushu Dental College
• Principal Investigator: Matsuo Kou 九州歯科大学, 歯学部, 教授 (70238971)
• Co-Investigator(Kenkyū-buntansha): 渡邉 誠之 九州歯科大学, 歯学部, 教授 (10201196) ; 古株 彰一郎 九州歯科大学, 歯学部, 教授 (30448899) ; 自見 英治郎 九州大学, 歯学研究院, 教授 (40276598) ; 矢田 直美 九州歯科大学, 歯学部, 准教授 (60468022)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 悪性黒色腫 / 増殖 / 転写コファクター / TLE3 / BMP / 浸潤 / BMPシグナル / 細胞の形態変化 / がんの浸潤 / 上皮間葉移行 / 骨誘導因子 / 転移

Outline of Final Research Achievements

Melanoma, one of the most aggressive neoplasms, is characterized by rapid cell proliferation. Transducin-like Enhancer of Split (TLE) is an important regulator of cell proliferation via Histone deacetylase (HDAC) recruitment. Given that HDAC activity is associated with melanoma progression, we examined the relationship between TLE3, a TLE family member, and melanoma. TLE3 expression was increased during the progression of human patient melanoma. Overexpression of Tle3 in B16 murine melanoma cells led to an increase in cell proliferation as well as the number of cyclinD1-positive cells. in vivo injection of mice with B16 cells overexpressing Tle3 resulted in larger tumor formation than in mice injected with control cells. In contrast, siRNA-mediated knockdown of Tle3 in B16 cells or TLE3 in HMV-II human melanoma cells decreased proliferation. Treatment of B16 cells with trichostatin A, a class I and II HDAC inhibitor,
prevented the effect s of Tle3 on proliferation.

Academic Significance and Societal Importance of the Research Achievements

近年、免疫チェックポイント阻害剤の登場により悪性黒色腫の治療成績が著しく向上してきたが、これら薬剤は間質性肺炎や大腸炎などの免疫関連有害事象をもたらすこともまた明らかとなってきた。そのため、悪性黒色腫の病態を正確に理解し、新たな治療法を確立する必要性は依然として残っている。HDAC（ヒストン脱アセチル化酵素）阻害剤は悪性黒色腫の新しい治療薬として注目されている。本研究ではHDACを誘導し転写コファクターとして作用するTLE3が悪性黒色腫細胞の増殖を制御するメカニズムを明らかにしたものであり、HDAC阻害剤を利用した悪性黒色腫の治療法に新たなエビデンスを提唱することができた仕事であると考える。

Research Products

• [Int'l Joint Research] McGill University(カナダ)
• [Journal Article] Transducin-like enhancer of split 3 regulates proliferation of melanoma cells via histone deacetylase activity. (2019)
  • Author(s): Ogawa M, Yaginuma T, Nakatomi C, Nakajima T, Tada-Shigeyama Y, Addison WN, Urata M, Matsubara T, Watanabe K, Matsuo K, Sato T, Honda H, Hikiji H, Watanabe S, Kokabu S
  • Journal Title: Oncotarget Volume: 10 Pages: 404-414
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transducin-like Enhancer of Split 3 regulates proliferation of melanoma cells via histone deacetylase activity (2018)
  • Author(s): Ogawa M, Yaginuma T, Nakatomi C, Nakajima T, Tada-Shigeyama Y, Addison WN, Urata M, Matsubara M, Watanabe K, Matsuo K, Sato T, Honda H, Hikiji H, Watanabe S, Kokabu S
  • Journal Title: Oncotarget Volume: 10(3) Issue: 3 Pages: 404-414
  • DOI: 10.18632/oncotarget.26552
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] The role of p130Cas in morphological change, mobility, and invasion ability induced by TGF- β in oral squamous cell carcinoma. (2017)
  • Author(s): Yaginuma T, Matsubara T, Kokabu S, Nakatomi C, Yada N, Matsuo K, Yoshioka Y, Jimi E
  • Organizer: The 10th Japan-Korea joint symposium on bio-microsensing technology and 2nd Asian Symposium on Chemistry-based Biotechnology
  • Int'l Joint Research
• [Presentation] 口腔がんの早期発見と治療 口腔がん検診と治療の現況、検体採取法から基本的な診かたまで 口腔擦過細胞診の基本像 (2017)
  • Author(s): 矢田 直美, 松尾 拡
  • Organizer: 第58回日本臨床細胞学会春期大会