Elucidation on the molecular mechanisms of the carcinogenesis, invasion, and metastasis of oral cancer via DeltaNp63-mediated epithelial-mesenchymal transition

• Project/Area Number: 17K11845
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Kyushu University
• Principal Investigator: Matsubara Ryota 九州大学, 歯学研究院, 共同研究員 (60615798)
• Co-Investigator(Kenkyū-buntansha): 川野 真太郎 九州大学, 大学病院, 准教授 (00398067) ; 神野 哲平 九州大学, 大学病院, 助教 (60755247)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 口腔扁平上皮癌 / 上皮ー間葉転換 / ΔNp63 / PAR1 / 口腔扁平上皮癌（OSCC） / 上皮-間葉転換（EMT） / 浸潤・転移 / 歯学 / 癌

Outline of Final Research Achievements

We investigated the relationship between ΔNp63 and protease-activated protein (PAR) 1, a G protein-coupled 7-transmembrane receptor, also known as thrombin receptor, which has been reported to be expressed in several cancer types. As a result, the incidence of cervical lymph node metastasis and histological grade were significantly higher in cases with PAR1 expression in tumor and stromal cells, and PAR1 expression in tumor cells at the invasive tip was inversely correlated with ΔNp63 expression. These results suggest that PAR expression is enhanced by reduced expression of ΔNp63 and contributes to the progression of OSCC by inducing EMT.

Academic Significance and Societal Importance of the Research Achievements

口腔扁平上皮癌に特異的なマーカーを発見し、その機能を解明することで口腔扁平上皮癌患者の生存率を改善できること。

Research Products

• [Journal Article] Elevated expression of protease-activated receptor 1 via ΔNp63 down-regulation contributes to nodal metastasis in oral squamous cell carcinoma (2021)
  • Author(s): Hattori T.、Kawano S.、Tanaka S.、Matsubara R.、Sakamoto T.、Hashiguchi Y.、Kaneko N.、Mikami Y.、Morioka M.、Maruse Y.、Kitamura R.、Hamada E.、Hiwatashi M.、Oobu K.、Kiyoshima T.、Nakamura S.
  • Journal Title: International Journal of Oral and Maxillofacial Surgery Volume: 50 Issue: 2 Pages: 163-170
  • DOI: 10.1016/j.ijom.2020.04.021
  • Peer Reviewed / Open Access
• [Journal Article] Cytokeratin 19 as a biomarker of highly invasive oral squamous cell carcinoma with metastatic potential (2020)
  • Author(s): Shoichi Tanaka, Shintaro Kawano, Taichi Hattori, Ryota Matsubara, Taiki Sakamoto, Yuma Hashiguchi, Naoki Kaneko, Yurie Mikami, Masahiko Morioka, Yasuyuki Maruse, Ryoji Kitamura, Eiki Hamada, Megumi Hiwatashi, Kazunari Oobu, Tamotsu Kiyoshima, Seiji Nakamura
  • Journal Title: Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology Volume: 32(1) Pages: 1-7
  • Peer Reviewed
• [Journal Article] Significant association of increased PD-L1 and PD-1 expression with nodal metastasis and a poor prognosis in oral squamous cell carcinoma. (2018)
  • Author(s): Maruse Y, Kawano S, Jinno T, Matsubara R, Goto Y, Kaneko N, Sakamoto T, Hashiguchi Y, Moriyama M, Toyoshima T, Kitamura R, Tanaka H, Oobu K, Kiyoshima T, Nakamura S.
  • Journal Title: International Journal of Oral and Maxillofacial Surgery Volume: － Issue: 7 Pages: 836-845
  • DOI: 10.1016/j.ijom.2018.01.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Differential roles of kallikrein-related peptidase 6 in malignant transformation and ΔNp63β-mediated epithelial-mesenchymal transition of oral squamous cell carcinoma. (2017)
  • Author(s): Naoki Kaneko, Shintaro Kawano, Kaori Yasuda, Yuma Hashiguchi, Taiki Sakamoto, Ryota Matsubara, Yuichi Goto, Teppei Jinno, Yasuyuki Maruse, Masahiko Morioka, Taichi Hattori, Shoichi Tanaka, Hideaki Tanaka, Ryoji Kitamura, Tamotsu Kiyoshima, Seiji Nakamura
  • Journal Title: Oral Oncology Volume: 75 Pages: 148-157
  • DOI: 10.1016/j.oraloncology.2017.11.004
  • Peer Reviewed / Open Access
• [Journal Article] Cytokeratin 17 mRNA as a prognostic marker of oral squamous cell carcinoma. (2017)
  • Author(s): Ryoji Kitamura, Takeshi Toyoshima, Hideaki Tanaka, Shintaro Kawano, Ryota Matsubara, Yuichi Goto, Teppei Jinno, Yasuyuki Maruse, Kazunari Oobu, Seiji Nakamura
  • Journal Title: Oncology Letters Volume: 14 Pages: 6735-6743
  • DOI: 10.3892/ol.2017.7066
  • Peer Reviewed / Open Access
• [Journal Article] Tumor-suppressive roles of ΔNp63β-miR-205 axis in epithelial-mesenchymal transition of oral squamous cell carcinoma via targeting ZEB1 and ZEB2. (2017)
  • Author(s): Yuma Hashiguchi, Shintaro Kawano, Yuichi Goto, Kaori Yasuda, Naoki Kaneko, Taiki Sakamoto, Ryota Matsubara, Teppei Jinno, Yasuyuki Maruse, Hideaki Tanaka, Masahiko Morioka, Taichi Hattori, Shoichi Tanaka, Tamotsu Kiyoshima, Seiji Nakamura
  • Journal Title: Journal of Cellular Physiology Volume: － Issue: 10 Pages: 6565-6577
  • DOI: 10.1002/jcp.26267
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Critical roles of Wnt5a-Ror2 signaling in aggressiveness of tongue squamous cell carcinoma and production of matrix metalloproteinase-2 via ΔNp63β-mediated epithelial-mesenchymal transition. (2017)
  • Author(s): Taiki Sakamoto, Shintaro Kawano, Ryota Matsubara, Yuichi Goto, Teppei Jinno, Yasuyuki Maruse, Naoki Kaneko, Yuma Hashiguchi, Taichi Hattori, Shoichi Tanaka, Ryoji Kitamura, Tamotsu Kiyoshima, Seiji Nakamura
  • Journal Title: Oral Oncology Volume: 69 Pages: 15-25
  • DOI: 10.1016/j.oraloncology.2017.03.019
  • Peer Reviewed / Open Access
• [Presentation] 口腔扁平上皮癌における ΔNp63 を介したKRT19 の発現についての検討 (2018)
  • Author(s): 田中 翔一, 川野 真太郎, 松原 良太, 坂本 泰基, 金子 直樹, 橋口 有真, 服部 多市, 大部 一成, 中村 誠司
  • Organizer: 日本口腔外科学会
• [Presentation] 口腔扁平上皮癌における ΔNp63 を介したkallikrein-related peptidase 5 の発現 (2018)
  • Author(s): 服部多市, 川野真太郎, 松原良太, 坂本泰基, 橋口有真, 金子直樹, 田中翔一, 大部一成, 中村誠司
  • Organizer: 日本口腔外科学会