Elucidate the mechanism of radioresistance via Nrf2 anti-oxidative pathway in oral squamous cell carcinoma and development of novel therapeutic strategy

• Project/Area Number: 19K19237
• 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, 病院, 医員 (10802100)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 口腔癌 / 口腔扁平上皮癌 / 放射線耐性 / Nrf2 / IL-6 / トシリズマブ / 癌微小環境

Outline of Research at the Start

口腔扁平上皮癌（OSCC）におけるIL-6依存的な放射線耐性のメカニズムを、申請者らはトシリズマブを用いてin vivo実験系を検討している。また、IL-6とNrf2抗酸化経路との関連性をより検討するためにOSCC患者の生検標本を用いたNrf2、リン酸化Nrf2の免疫組織化学的染色で発現解析を行う。そして、各種臨床病理学的項目との関連性を統計学的に解析する。さらに、本研究ではOSCC培養細胞とこの臨床的放射線耐性株を用いて、OSSC放射線耐性においてKeap1-Nrf2抗酸化経路の活性化のメカニズムを検討する。

Outline of Final Research Achievements

We investigated the mechanism of radioresistance via Nrf2 anti-oxidative pathway in oral squamous cell carcinoma (OSCC) and developed novel therapies, and obtained the following results. 1) The radiotherapy (X-rays 4 Gy/day, total 60 Gy) that combined tocilizumab significantly suppressed the tumor growth in vivo mice model. 2) The tocilizumab sensitized radiosensitivity by suppressing STAT3 pathway and Nrf2 anti-oxidative pathway stimulated by IL-6 in vivo mice model. 3) We analyzed the expression of phosphorylated Nrf2 in the immunohistochemical staining using biopsy specimens of 110 OSCC patients. A high phosphorylated Nrf2 tumour expression was significantly correlated with a poor response to preoperative chemoradiotherapy. A Kaplan–Meier analysis revealed that higher numbers of phosphorylated Nrf2 were significantly correlated with a poor prognosis.

Academic Significance and Societal Importance of the Research Achievements

本研究では、従来のより臨床的なプロトコルの放射線療法とIL-6シグナリングを標的とした治療法の併用の可能性を模索することは、口腔扁平上皮癌の放射線耐性を克服という観点から重要かつ独創的なアプローチである。また、トシリズマブは、関節リウマチなどに対して既に承認されおり、高い効果を示している。従って、このトシリズマブを用いた非臨床試験の良好な結果は、トシリズマブはドラッグ・リ・ポジショニングの観点からも臨床試験のデザインにおいて非常に期待できる。
さらに、本研究ではがん微小環境においてOSCC細胞のNrf2抗酸化経路を介した放射線耐性機構の更なる解明を目指した。

Research Products

• [Journal Article] Enhanced Expression of IGFBP-3 Reduces Radiosensitivity and Is Associated with Poor Prognosis in Oral Squamous Cell Carcinoma (2020)
  • Author(s): Sakata J, Hirosue A, Yoshida R, Matsuoka Y, Kawahara K, Arita H, Nakashima H, Yamamoto T, Nagata M, Kawaguchi S, Gohara S, Nagao Y, Yamana K, Toya R, Murakami R, Kuwahara Y, Fukumoto M, Nakayama H
  • Journal Title: Cancers (Basel) Volume: 12(2) Issue: 2 Pages: 494-494
  • DOI: 10.3390/cancers12020494
  • Peer Reviewed / Open Access
• [Journal Article] BRD4 promotes metastatic potential in oral squamous cell carcinoma through the epigenetic regulation of the MMP2 gene (2020)
  • Author(s): Yamamoto Tatsuro、Hirosue Akiyuki、Nakamoto Masafumi、Yoshida Ryoji、Sakata Junki、Matsuoka Yuichiro、Kawahara Kenta、Nagao Yuka、Nagata Masashi、Takahashi Nozomu、Hiraki Akimitsu、Shinohara Masanori、Nakao Mitsuyoshi、Saitoh Noriko、Nakayama Hideki
  • Journal Title: British Journal of Cancer Volume: 123 Issue: 4 Pages: 580-590
  • DOI: 10.1038/s41416-020-0907-6
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of adjuvant chemotherapy with S-1 in stage II oral squamous cell carcinoma patients: A comparative study using the propensity score matching method (2020)
  • Author(s): Ryoji Yoshida, Masashi Nagata, Akiyuki Hirosue, Kenta Kawahara, Masafumi Nakamoto, Masatoshi Hirayama, Nozomu Takahashi, Yuichiro Matsuoka, Junki Sakata, Hikaru Nakashima, Hidetaka Arita, Akimitsu Hiraki, Masanori Shinohara, Ken Kikuchi, Hideki Nakayama
  • Journal Title: PLoS One Volume: 15 Issue: 4 Pages: e0231656-e0231656
  • DOI: 10.1371/journal.pone.0231656
  • 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
• [Journal Article] Onodera's prognostic nutritional index correlates with tumor immune environment and survival in patients with oral squamous cell carcinoma undergoing chemoradiotherapy (2020)
  • Author(s): Yoshida Ryoji、Gohara Shunsuke、Sakata Junki、Matsuoka Yuichiro、Hirosue Akiyuki、Kawahara Kenta、Kawaguchi Sho、Nagao Yuka、Yamana Keisuke、Nagata Masashi、Fukuma Daiki、Toya Ryo、Murakami Ryuji、Hiraki Akimitsu、Shinohara Masanori、Nakayama Hideki
  • Journal Title: Translational Oncology Volume: 13 Issue: 12 Pages: 100850-100850
  • DOI: 10.1016/j.tranon.2020.100850
  • Peer Reviewed / Open Access
• [Journal Article] A rare intraosseous schwannoma in the maxillary left incisor region: A case report. (2020)
  • Author(s): Matsuoka Y, Iwamoto A, Yoshida R, Kojima T, Hirayama M, Takahashi N, Nakamoto M, Nakayama H.
  • Journal Title: Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology Volume: 32 Pages: 114-119
  • Peer Reviewed
• [Journal Article] FOXP3 lymphocyte status may predict the risk of malignant transformation in oral leukoplakia. (2020)
  • Author(s): Sakata J, Yoshida R, Matsuoka Y, Kawahara K, Arita H, Nakashima H, Hirosue A, Naito H, Takeshita H, Kawaguchi S, Gohara S, Nagao Y, Yamana K, Hiraki A, Shinohara M, Ito T, Nakayama H
  • Journal Title: Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology Volume: 32 Pages: 33-39
  • Peer Reviewed
• [Journal Article] 鎖骨上窩と上縦隔に波及した舌下顎下型ラヌーラの1例 (2020)
  • Author(s): 松岡 祐一郞、吉田 遼司、廣末 晃之、小島 拓、緒方 克守、中山 秀樹
  • Journal Title: 日本口腔外科学会雑誌 Volume: 66 Pages: 261-265
  • NAID: 130007878359
  • Peer Reviewed
• [Journal Article] A rare intraosseous schwannoma in the maxillary left incisor region: A case report. (2020)
  • Author(s): Matsuoka Yuichirou, Asuka Iwamoto, Ryoji Yoshida, Kojima Taku, Hirayama Masatoshi, Nozomu Takahashi, Masafumi Nakamoto and Hideki Nakayama.
  • Journal Title: Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology Volume: -
  • Peer Reviewed
• [Journal Article] HMGA2 Contributes to Distant Metastasis and Poor Prognosis by Promoting Angiogenesis in Oral Squamous Cell Carcinoma. (2019)
  • Author(s): Sakata J,Hirosue A,Yoshida R,Kawahara K,Matsuoka Y,Yamamoto T,Nakamoto M,Hirayama M,Takahashi N,Nakamura T,Arita H,Nakashima H,Nagata M,Hiraki A,Shinohara M,Nakayama H
  • Journal Title: International journal of molecular sciences Volume: 20 Issue: 10 Pages: 2473-2473
  • DOI: 10.3390/ijms20102473
  • Peer Reviewed / Open Access
• [Presentation] 当科における口腔扁平上皮癌患者に対して行った緩和的寡分割放射線治療（QUAD shot）の有効性 (2021)
  • Author(s): 坂田 凛太郎、松岡 祐一郎、川原 健太、永田 将士、廣末 晃之、福間 大喜、吉田 遼司、中山 秀樹
  • Organizer: 第39回日本口腔腫瘍学会総会・学術大会
• [Presentation] 舌の疼痛を契機として診断に至ったSweet症候群の1例 (2020)
  • Author(s): 松岡 祐一郎、川原 健太、永田 将士、廣末 晃之、福間 大喜、吉田 遼司、中山 秀樹
  • Organizer: 第30回日本口腔内科学会学術大会
• [Presentation] IL-6シグナル阻害剤トシリズマブは口腔扁平上皮癌の放射線感受性を増感する (2019)
  • Author(s): Yuichiro Matsuoka, Hidetaka Arita, Ryoji Yoshida, Junki Sakata, Hikaru Nakashima, Kenta Kawahara, Masashi Nagaata, Akiyuki Hirosue, Masanori Shinohara, Hideki Nakayama
  • Organizer: 第64回 日本口腔外科学会総会・学術大会