Elucidation of the radioresistance mechanism via Nrf2 antioxidant pathway in oral squamous cell carcinoma controlled by cancer metabolism

• Project/Area Number: 21K17145
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Kumamoto University
• Principal Investigator: Matsuoka Yuichiro 熊本大学, 大学院生命科学研究部(医), 特定研究員 (10802100)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 口腔癌 / 放射線耐性 / Nrf2 / がん糖代謝 / 口腔がん / 口腔扁平上皮癌 / 代謝リプログラミング

Outline of Research at the Start

臨床的放射線抵抗性(CRR)細胞を用いて、がん糖代謝においてNrf2が制御する代謝リプログラミングに着眼し、放射線耐性機機序を解明することを目指す。
まず、OSCC細胞、CRR細胞でのNrf2の発現意義およびNrf2活性化の放射線耐性への影響を明らかにすることで、放射線耐性OSCCにおけるNrf2の機能解析へと繋げる。
次に、OSCC細胞とCRR細胞を用いることで、放射線耐性OSCC細胞においてNrf2と代謝機構や抗酸化能との関連などを検討する。その結果より、放射線治療によるがんの根絶には、がん細胞のエネルギー代謝、代謝リプログラミングの抑制が有効となる可能性を追求する。

Outline of Final Research Achievements

Our research aimed to elucidate the biological effects of tNrf2 anti-oxidant pathway on radioresistance in oral squamous cell carcinoma (OSCC) and Nrf2-dependent radioresistance mechanism in cancer glucose metabolism. Nrf2 was upregulated in clinical radioresistant cells in in vitro and in vivo experiments, and increased Nrf2 expression was associated with radioresistance. In addition, Nrf2-dependent glycolysis was involved in the development of radioresistance. Furthermore, phosphorylated Nrf2 expression was associated with histopathological response to chemoradiotherapy, and its expression correlated with poor prognosis in patients with advanced OSCC. These results suggested that Nrf2 plays an important role in OSCC radioresistance accompanied with metabolic modulation.

Academic Significance and Societal Importance of the Research Achievements

継続的放射線照射によって耐性を獲得した臨床的放射線耐性細胞（CRR細胞）は、標準的な放射線治療線量である2GyのX線を毎日照射しても安定して生存し続けることから、放射線耐性機序を解析するための臨床的なモデルがん細胞として非常に有用な資材であり、学術的独自性が高いと考えられる。そのため、CRR細胞を用いて放射線耐性におけるNrf2依存的な代謝経路を解析し、Nrf2の代謝調節を標的とした放射線抵抗性口腔扁平上皮癌に対する治療戦略は新規治療の開発の観点で意義が深い。

Research Products

• [Journal Article] 舌の腫脹と疼痛を主訴としSweet病が疑われた1例 (2023)
  • Author(s): 坂田 純基, 松岡 祐一郎, 有田 英生, 平山 真敏, 高橋 望, 中山 秀樹
  • Journal Title: 日本口腔科学会雑誌 Volume: 72 Pages: 9-14
  • Peer Reviewed
• [Journal Article] FOXM1-Mediated Regulation of Reactive Oxygen Species and Radioresistance in Oral Squamous Cell Carcinoma Cells (2023)
  • Author(s): Takeshita Hisashi、Yoshida Ryoji、Inoue Junki、Ishikawa Kohei、Shinohara K、Hirayama M、Oyama T、Kubo R、Yamana K、Nagao Y、Gohara S、Sakata J、Nakashima H、Matsuoka Y、Nakamoto M、Hirayama M、Kawahara K、Takahashi N、Hirosue A、Kuwahara Y、Fukumoto M、Toya R、Murakami R、Nakayama H
  • Journal Title: Laboratory Investigation Volume: 103 Issue: 5 Pages: 100060-100060
  • DOI: 10.1016/j.labinv.2022.100060
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The antioxidative stress regulator Nrf2 potentiates radioresistance of oral squamous cell carcinoma accompanied with metabolic modulation (2022)
  • Author(s): Matsuoka Yuichiro、Yoshida Ryoji、Kawahara Kenta、Sakata Junki、Arita Hidetaka、Nkashima Hikaru、Takahashi Nozomu、Hirayama Masatoshi、Nagata Masashi、Hirosue Akiyuki、Kuwahara Yoshikazu、Fukumoto Manabu、Toya Ryo、Murakami Ryuji、Nakayama Hideki
  • Journal Title: Laboratory Investigation Volume: 102 Issue: 8 Pages: 896-907
  • DOI: 10.1038/s41374-022-00776-w
  • Peer Reviewed / Open Access
• [Journal Article] An oncolytic virus as a promising candidate for the treatment of radioresistant oral squamous cell carcinoma. (2022)
  • Author(s): Gohara S, Shinohara K, Yoshida R, Kariya R, Tazawa H, Hashimoto M, Inoue J, Kubo R, Nakashima H, Arita H, Kawaguchi S, Yamana K, Nagao Y, Iwamoto A, Sakata J, Matsuoka Y, Takeshita H, Hirayama M, Kawahara K, Nagata M, Hirosue A, Kuwahara Y, Fukumoto M, Okada S, Urata Y, Fujiwara T, and Nakayama H.
  • Journal Title: Molecular Therapy Oncolytics Volume: 27 Pages: 141-156
  • DOI: 10.1016/j.omto.2022.10.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Postoperative delirium in patients undergoing tumor resection with reconstructive surgery for oral cancer (2021)
  • Author(s): Takahashi Nozomu、Hiraki Akimitsu、Kawahara Kenta、Nagata Masashi、Yoshida Ryoji、Matsuoka Yuichiro、Tanaka Takuya、Obayashi Yuko、Sakata Junki、Nakashima Hikaru、Arita Hidetaka、Shinohara Masanori、Nakayama Hideki
  • Journal Title: Molecular and Clinical Oncology Volume: 14 Issue: 3 Pages: 60-60
  • DOI: 10.3892/mco.2021.2222
  • Peer Reviewed / Open Access
• [Journal Article] Extracellular vesicles derived from radioresistant oral squamous cell carcinoma cells contribute to the acquisition of radioresistance via the miR‐503‐3p‐BAK axis (2021)
  • Author(s): K Yamana,J Inoue,R Yoshida,J Sakata,H Nakashima,H Arita,S Kawaguchi,S Gohara,Y Nagao,H Takeshita,M Maeshiro,R Liu,Y Matsuoka,M Hirayama,K Kawahara,M Nagata,A Hirosue,R Toya,R Murakami,Y Kuwahara,M Fukumoto,H Nakayama
  • Journal Title: Journal of Extracellular Vesicles Volume: 10 Issue: 14
  • DOI: 10.1002/jev2.12169
  • Peer Reviewed / Open Access
• [Journal Article] miR-30a attenuates drug sensitivity to 5-FU by modulating cell proliferation possibly by downregulating cyclin E2 in oral squamous cell carcinoma. (2021)
  • Author(s): Kenta Kawahara, Masashi Nagata, Ryoji Yoshida, Akiyuki Hirosue, Takuya Tanaka, Yuichiro Matsuoka, Hidetaka Arita, Hikaru Nakashima, Junki Sakata, Keisuke Yamana, Sho Kawaguchi, Shunsuke Gohara, Yuka Nagao, Masatoshi Hirayama, Nozomu Takahashi, Mayumi Hirayama, Hideki Nakayama
  • Journal Title: Biochemistry Biophysics Reports Volume: 21 Pages: 28-28
  • DOI: 10.1016/j.bbrep.2021.101114
  • Peer Reviewed / Open Access
• [Journal Article] Role of serum amylase and salivary cytokines in oral complications during chemoradiotherapy (2020)
  • Author(s): Kawahara Kenta、Hiraki Akimitsu、Arita Hidetaka、Takeshita Hisashi、Hirosue Akiyuki、Matsuoka Yuichiro、Sakata Junki、Obayashi Yuko、Nakashima Hikaru、Hirayama Mayumi、Nagata Masashi、Yoshida Ryoji、Shinohara Masanori、Nakayama Hideki
  • Journal Title: Oral Diseases Volume: Online ahead of print Issue: 6 Pages: 1564-1571
  • DOI: 10.1111/odi.13686
  • Peer Reviewed / Open Access
• [Presentation] Promotion of iron-mediated cell death ferroptosis enhances radiosensitivity in oral squamous cell carcinoma) (2023)
  • Author(s): 石川 紘平、松岡 祐一郎、吉田 遼司、川原 健太、平山 真敏、高橋 望、大山 徹、久保 隆太、井上 淳貴、篠原 光佑、関 祐紀、中山 秀樹
  • Organizer: 第82回日本癌学会学術総会
• [Presentation] 口腔扁平上皮癌における鉄介在性細胞死フェロトーシス の促進は放射線感受性を高める (2023)
  • Author(s): 石川 紘平、松岡 祐一郎 、大山 徹、久保 隆太、井上 淳貴、篠原 光佑、関 祐紀、平山 真敏、高橋 望、中元 雅史、川原 健太、吉田 遼司、中山 秀樹
  • Organizer: 第68回公益社団法人 日本口腔外科学会総会・学術大会