Development of a therapeutic agent for oral cancer applying a naturally derived component with EGFR signal inhibitory effect.

• Project/Area Number: 16K11707
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Kanagawa Dental College
• Principal Investigator: MAEHATA YOJIRO 神奈川歯科大学, 大学院歯学研究科, 特任講師 (80410009)
• Co-Investigator(Kenkyū-buntansha): 畑 隆一郎 神奈川歯科大学, 大学院歯学研究科, 特任教授 (10014276)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 口腔癌 / CXCL14/BRAK / 癌幹細胞 / CXCL14/BRAk / 口腔癌細胞 / 分子標的治療薬 / CXCL14 (BRAK) / EGF受容体 / 細胞・組織、歯学 / 癌

Outline of Final Research Achievements

At the beginning of this study, we planned to find regulation mechanisms of CXCL14/BRAK by fatty acid acetogenins in head and neck squamous cell carcinoma cell (HSC-3), but we could not find conditions that regulates BRAK expression in the cells. Therefore, the research program has been changed to investigate effect of BRAK on the gene expression of oral carcinoma cells.Because we found that BRAK transgenic mice suppressed various types of cancer, we examined the effects BRAK on the stem cell factors and cancer stem cell factor expression using HSC-3 cells and BRAK over expressed HSC-3 cells and BRAK knock downed cells. As a result, we found that BRAK over expression suppresses tumor progression, together with the decreased expression in stem cell factors and cancer stem cell factor. These results indicate that BRAK may regulate tumor progression through regulation of cancer stem cell factor expression. These data are useful for future development of cancer progression by use of BRAK.

Academic Significance and Societal Importance of the Research Achievements

ヒトの癌組織中には，自己複製能，多分化能および無制限な増殖能を併せ持つ癌幹細胞が存在することが報告されている。また，癌幹細胞は癌の再発, 転移および薬剤耐性の獲得に関与する事が知られている。口腔癌においても，癌幹細胞マーカー（CD44V）陽性の口腔癌幹細胞の存在が報告されている。本研究結果から，口腔癌において，発癌，癌細胞増殖および転移を抑制する多段階癌抑制因子であるCXCL14/BRAKの発現上昇により，CD44Vおよび幹細胞因子NANOG，KLF4の発現が抑制されることが示された。口腔癌におけるBRAKの発現を上昇させる分子の検索は，口腔癌の分子標的治療に有用であると考えられる。

Research Products

• [Journal Article] C-X-C Motif Chemokine Ligand 14 is a Unique Multifunctional Regulator of Tumor Progression. International Journal of Molecular (2019)
  • Author(s): Xiao-Yan Yang,Shigeyuki Ozawa, Yasumasa Kato, Yojiro Maehata, Kazuhito Izukuri1, Takeharu Ikoma, Keisuke Kanamori, Tetsu Akasaka, Kenji Suzuki, Hiroshi Iwabuchi, Shun-Ichi Kurata, Iyoko Katoh,, Takashi Sakurai, Tohru Kiyono, Ryu-Ichiro Hata
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 8 Pages: 1872-1872
  • DOI: 10.3390/ijms20081872
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TRPM5 mediates acidic extracellular pH signaling and TRPM5 inhibition reduces spontaneous metastasis in mouse B16-BL6 melanoma cells. (2017)
  • Author(s): Maeda T, Suzuki A, Koga K, Miyamoto C, Maehata Y, Ozawa S, Ikoma T, Hata R-I, Nagashima Y, Nabeshima K, Miyazaki K, Kato Y
  • Journal Title: Oncotarget Volume: 8(45) Pages: 78312-78326
  • Peer Reviewed / Open Access
• [Journal Article] Expression of the chemokine CXCL14 and cetuximab-dependent tumour suppression in head and neck squamous cell carcinoma. (2016)
  • Author(s): Kondo T, Ozawa S, Ikoma T1, Yang XY, Kanamori K, Suzuki K, Iwabuchi H, Maehata Y, Miyamoto C, Taguchi T, Kiyono T, Kubota E, Hata RI
  • Journal Title: Oncogenesis Volume: 5 Issue: 7 Pages: 1-10
  • DOI: 10.1038/oncsis.2016.43
  • Peer Reviewed / Open Access
• [Presentation] Low-intensity Pulsed Ultrasound (LIPUS) Prevents Development of BRONJ-like Pathophysiology in Rat Alveolar Bone Defect Induced by Tooth Removal after Alendronate and Porphyromonas Gingivalis Challenges. (2018)
  • Author(s): Hidaka K, Mikuni-Takagaki Y, Wada-Takahashi S, Saita M, Kawamata R, Sato T, Kawata A, Miyamoto C, Maehata Y, Watabe H, Tani-Ishii N, Hamada N, Takahashi S-S, Deguchi S, Takeuchi R
  • Organizer: ASBMR 2018 Annual Meeting,
  • Int'l Joint Research
• [Presentation] 口腔癌細胞において癌抑制性ケモカインCXCL14の発現は幹細胞マーカーの発現を制御する. (2018)
  • Author(s): 畑隆一郎，陽暁艶，小澤重幸，居作和人，生駒丈晴，金森慶亮，鈴木健司，前畑洋次郎，服部俊治，水野一乘，清野透
  • Organizer: 第51回日本結合組織学会学術大会
• [Presentation] ヒト細胞のUV 照射による癌抑制分子CXCL14の発現上昇はp38δ特異的シグナル経路による (2017)
  • Author(s): 陽暁艶, 小澤重幸, 生駒丈晴, 鈴木健司, 岩渕博史, 前畑洋次郎, 宮本千央, 久保田英朗, 畑隆一郎
  • Organizer: 第49回日本結合組織学会学術大会
• [Presentation] MAP kinase specific pathway stimulates gene expression of chemokine CXCL14, a multistep tumor suppressor (2017)
  • Author(s): Yang X-Y, Ozawa Y, Ikoma T, Maehata Y, Kato Y, Hata R-Y
  • Organizer: 第59回歯科基礎医学会学術大会
• [Presentation] Therapeutic ultrasound prevents delayed healing of socket, possibly BRONJ humorally (2017)
  • Author(s): Hidaka K, Miyamoto C, Wada-Takahashi1 S, Kawamata R,Kawata A, Maehata Y, Saita M, Sato T, Watabe H, Tani-Ishii N, Takahashi S-S, Hamada N, Deguchi S, Mikuni-Takagaki Y
  • Organizer: CED-IADR/NOF Oral Health Research Congress 2017
  • Int'l Joint Research
• [Presentation] 低出力超音波パルス(LIPUS)刺激によりビスフォスフォネート関連顎骨壊死(BRONJ)を予防できるか―ステージ0を想定したモデルラットによる検討 (2017)
  • Author(s): 日髙恒輝，宮本千央，高橋聡子，川股亮太，河田亮，前畑洋次郎，斉田牧子，佐藤武則，渡部博隆，石井信之，高橋俊介，浜田信城，出口眞二，高垣裕子
  • Organizer: 日本歯周病学会60周年記念京都大会
• [Presentation] Scavenger of oxidative stress effective for the inhibition of angiogenesis and tumor proliferation in human head and neck squamous cell carcinoma cells by regulation gene expression of chemokines, (2016)
  • Author(s): Maehata Y, Miyamoto C, Tsukinoki K
  • Organizer: Pharmacology 2016
  • Place of Presentation: London
  • Year and Date: 2016-12-13
  • Int'l Joint Research
• [Presentation] 多段階癌抑制分子のケモカインCXCL14/BRAKは扁平上皮組織の分化制御分子か? (2016)
  • Author(s): 生駒 丈晴, 陽 暁艶, 小澤 重幸, 前畑 洋次郎, 畑 隆一郎
  • Organizer: 第58回歯科基礎医学会学術大会
  • Place of Presentation: 札幌
  • Year and Date: 2016-08-24
• [Presentation] ケモカインCXCL14の発現がセツキシマブ(抗上皮増殖因子受容体抗体)による腫瘍抑制活性を決定する (2016)
  • Author(s): 陽 暁艶, 近藤 忠稚, 小澤 重幸, 生駒 丈晴, 鈴木 健司, 岩淵 博史, 前畑 洋次郎, 宮本 千央, 久保田 英朗, 畑 隆一郎
  • Organizer: 第48回日本結合組織学会学術大会
  • Place of Presentation: 長崎
  • Year and Date: 2016-06-24
• [Presentation] Rock inhibitor fasudil suppresses growth of tumor by stimulating gene expression and secretion of CXCL14/BRAK, (2016)
  • Author(s): Miyamoto C and Maehata Y
  • Organizer: Pharmacology 2016
  • Place of Presentation: London
  • Int'l Joint Research