Elucidate the mechanism of radioresistance via IL-6 in oral squamous cell carcinoma and development of novel therapeutic strategy

• Project/Area Number: 17H06974
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Surgical dentistry
• Research Institution: Kumamoto University
• Principal Investigator: Matsuoka Yuichiro 熊本大学, 医学部附属病院, 非常勤診療医師 (10802100)
• Research Collaborator: Arita Hidetaka
• Project Period (FY): 2017-08-25 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 口腔癌 / 放射線耐性 / がん微小環境 / IL-6 / トシリズマブ / 癌微小環境

Outline of Final Research Achievements

We investigated the mechanism of radioresistance via IL-6 in oral squamous cell carcinoma (OSCC) and developed novel therapies, and obtained the following results. 1) The high expression of IL-6 was associated with the tumor growth in OSCC patients. 2) The extracellular secretion of IL-6 was sequentially increased in OSCC cells. 3) The blockade of IL-6-STAT3 signaling by the inhibitor of STAT3 sensitized OSCC cells to radiation. 4) The radiotherapy that combined tocilizumab significantly suppressed the tumor growth in vivo mice model.

Academic Significance and Societal Importance of the Research Achievements

本研究では、がん微小環境におけるOSCC細胞においてIL-6はSTAT3を活性化することで放射線抵抗性に寄与する可能性を生物学的により明らかにすることができた。
従来の放射線療法と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、OSCC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、トシリズマブを用いた非臨床試験の結果が良好なものであるならば、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。

Research Products

• [Journal Article] Circulating miRNA-1290 as a potential biomarker for response to chemoradiotherapy and prognosis of patients with advanced oral squamous cell carcinoma: A single-center retrospective study (2019)
  • Author(s): Nakashima H, Yoshida R, Hirosue A, Kawahara K, Sakata J, Arita H, Yamamoto T, Toya R, Murakami R, Hiraki A, Shinohara M, Ito T, Kuwahara Y, Nakayama H
  • Journal Title: Tumour Biol Volume: 41(3) Issue: 3 Pages: 1-10
  • DOI: 10.1177/1010428319826853
  • Peer Reviewed / Open Access
• [Journal Article] Severe interstitial pneumonia associated with anti-PD-1 immune checkpoint antibody after talc slurry pleurodesis (2018)
  • Author(s): Sakata Shinya、Matsuoka Yuichiro、Kawahara Kenta、Kakiuchi Yosuke、Takaki Akira、Hirosue Akiyuki、Yoshida Ryoji、Saeki Sho、Fujii Kazuhiko、Nakayama Hideki
  • Journal Title: Respiratory Investigation Volume: 56 Issue: 2 Pages: 195-198
  • DOI: 10.1016/j.resinv.2017.11.006
  • Peer Reviewed / Open Access
• [Journal Article] Tumor budding as a novel predictor of occult metastasis in cT2N0 tongue squamous cell carcinoma (2018)
  • Author(s): Sakata Junki、Yamana Keisuke、Yoshida Ryoji、Matsuoka Yuichiro、Kawahara Kenta、Arita Hidetaka、Nakashima Hikaru、Nagata Masashi、Hirosue Akiyuki、Kawaguchi Sho、Gohara Shunsuke、Nagao Yuka、Hiraki Akimitsu、Shinohara Masanori、Toya Ryo、Murakami Ryuji、Nakayama Hideki
  • Journal Title: Human Pathology Volume: 76 Pages: 1-8
  • DOI: 10.1016/j.humpath.2017.12.021
  • Peer Reviewed / Open Access
• [Journal Article] Predictive value of the combination of SMAD4 expression and lymphocyte infiltration in malignant transformation of oral leukoplakia. (2017)
  • Author(s): Sakata J, Yoshida R, Matsuoka Y, Nagata M, Hirosue A, Kawahara K, Nakamura T, Nakamoto M, Hirayama M, Takahashi N, Nakashima H, Arita H, Ogi H, Hiraki A, Shinohara M, Nakayama H
  • Journal Title: Cancer medicine Volume: 6 Issue: 4 Pages: 730-738
  • DOI: 10.1002/cam4.1005
  • Peer Reviewed / Open Access
• [Journal Article] FBXW7 expression affects the response to chemoradiotherapy and overall survival among patients with oral squamous cell carcinoma: A single-center retrospective study. (2017)
  • Author(s): Hidetaka Arita, Masashi Nagata, Ryoji Yoshida, Yuichiro Matsuoka1, Akiyuki Hirosue, Kenta Kawahara, Junki Sakata, Hikaru Nakashima, Taku Kojima, Ryo Toya, Ryuji Murakami, Akimitsu Hiraki, Masanori Shinohara and Hideki Nakayama.
  • Journal Title: Tumour Biology Volume: 39 Issue: 10 Pages: 1-9
  • DOI: 10.1177/1010428317731771
  • Peer Reviewed / Open Access
• [Presentation] 抗酸化ストレス調節因子であるNrf2は口腔扁平上皮癌の放射線耐性を制御する 松岡祐一郞、吉田遼司、廣末晃之、坂田純基、有田英生、中嶋光、尾木秀直、平木昭光、篠原正徳、中山秀樹 (2018)
  • Author(s): 松岡祐一郞、吉田遼司、廣末晃之、坂田純基、有田英生、中嶋光、尾木秀直、平木昭光、篠原正徳、中山秀樹
  • Organizer: 第36回日本口腔腫瘍学会総会・学術大会
• [Presentation] Nrf2, anti-oxidative stress-regulatory factor, controls resistance to radiation in oral squamous cell carcinoma (2018)
  • Author(s): Yuichiro Matsuoka, Ryoji Yoshida, Akiyuki Hirosue, Masashi Nagata, Kenta Kawahara, Junki Sakata, Hidetaka Arita, Hikaru Nakashima, Akimitsu Hiraki, Masanori Shinohara, Hideki Nakayama
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 抗酸化ストレス調節因子Nrf2は口腔扁平上皮癌の放射線耐性を制御する (2018)
  • Author(s): Yuichiro Matsuoka, Masahiro Maki, Ryoji Yoshida, Akiyuki Hirosue, Kenta Kawahara, Junki Sakata, Hidetaka Arita, Hikaru Nakashima, Masanori Shinohara, Hideki Nakayama
  • Organizer: 第63回日本口腔外科学会総会・学術大会
• [Presentation] 抗酸化ストレス調節因子であるNrf2は口腔扁平上皮癌の放射線耐性を制御する (2018)
  • Author(s): 松岡 祐一郎
  • Organizer: 第36回日本口腔腫瘍学会総会・学術大会
• [Presentation] 抗酸化ストレス調節因子であるNrf2は口腔扁平上皮癌の放射線耐性を制御する (2017)
  • Author(s): 松岡 祐一郎
  • Organizer: 第35回日本口腔腫瘍学会総会・学術大会
• [Presentation] 口腔扁平上皮癌の放射線抵抗性獲得機構における癌微小環境の役割-Interleukin-6/Nrf2 antioxidant pathwayの関与- (2017)
  • Author(s): 松岡 祐一郎
  • Organizer: 第41回日本頭頸部癌学会
• [Presentation] 口腔扁平上皮癌の放射線耐性における癌微小環境の役割-IL-6/Nrf2抗酸化経路の関連- (2017)
  • Author(s): 松岡 祐一郎
  • Organizer: 第62回日本口腔外科学会総会・学術大会