Development of novel therapeutic strategies for refractory oral cancer targeting higher-order epigenomic regulation

• Project/Area Number: 18K09727
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Kumamoto University
• Principal Investigator: Hirosue Akiyuki 熊本大学, 病院, 助教 (00638182)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); 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); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 口腔癌 / 治療抵抗性 / エピゲノム / ヒストン修飾 / BRD4 / スーパーエンハンサー / 難治性口腔癌 / 高次エピゲノム

Outline of Final Research Achievements

The morbidity of oral squamous cell carcinoma (OSCC) is increasing with the aging of the population. High malignant potential such as metastasis and therapeutic resistance is a major factor that reduce survival. Therefore, to develop the novel diagnostic and therapeutic methods based on epigenome profiles, we investigated the higher-order epigemomic alterations related treatment resistance in OSCC. It was revealed that BRD4 contributes to metastatic potential in OSCC through the higher-order epigenomic regulation of the MMP2 gene. It was also indicated that IGFBP-3 is involved in radioresistance of OSCC by promoting DNA repair. These findings suggest that an approach targeting epigenome regulation may be a novel therapeutic strategy for refractory oral cancer.

Academic Significance and Societal Importance of the Research Achievements

口腔扁平上皮癌(OSCC)の治療抵抗性に関して高次エピゲノムの制御に着目した研究はほとんどない。そのため、OSCCの転移や放射線耐性に関連する分子メカニズムをエピゲノム制御の観点から解明した本研究は難治性口腔癌の新規の治療戦略に繋がる可能性もあり学術的意義が大きい。また、本研究は現在注目を浴びているがんの個別化治療やPrecision Medicine(精密医療)の発展に貢献できる可能性もあり、さらに幅広い生命現象へ関与している高次エピゲノムの制御機構の解明は、様々な疾患の診断や治療に貢献できる可能性もあり社会的意義も大きい。

Research Products

• [Journal Article] FOXP3 lymphocyte status may predict the risk of malignant transformation in oral leukoplakia (2020)
  • Author(s): Sakata Junki、Yoshida Ryoji、Matsuoka Yuichiro、Kawahara Kenta、Arita Hidetaka、Nakashima Hikaru、Hirosue Akiyuki、Naito Hisaki、Takeshita Hisashi、Kawaguchi Sho、Gohara Shunsuke、Nagao Yuka、Yamana Keisuke、Hiraki Akimitsu、Shinohara Masanori、Ito Takaaki、Nakayama Hideki
  • Journal Title: Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology Volume: 32 Issue: 1 Pages: 33-39
  • DOI: 10.1016/j.ajoms.2019.06.005
  • 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] Hypofractionated palliative volumetric modulated arc radiotherapy with the Radiation Oncology Study Group 8502 “QUAD shot” regimen for incurable head and neck cancer (2020)
  • Author(s): Toya Ryo、Saito Tetsuo、Yamaguchi Kohsei、Matsuyama Tomohiko、Watakabe Takahiro、Matsumoto Tadashi、Yoshida Ryoji、Hirosue Akiyuki、Murakami Daizo、Orita Yorihisa、Nakayama Hideki、Oya Natsuo
  • Journal Title: Radiation Oncology Volume: 15 Issue: 1 Pages: 123-123
  • DOI: 10.1186/s13014-020-01548-w
  • 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] Compositional Shift of Oral Microbiota Following Surgical Resection of Tongue Cancer (2020)
  • Author(s): Kageyama Shinya、Nagao Yuka、Ma Jiale、Asakawa Mikari、Yoshida Ryoji、Takeshita Toru、Hirosue Akiyuki、Yamashita Yoshihisa、Nakayama Hideki
  • Journal Title: Frontiers in Cellular and Infection Microbiology Volume: 10 Pages: 60084-60084
  • DOI: 10.3389/fcimb.2020.600884
  • 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] 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] 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
• [Journal Article] Reliability of MRI-Derived Depth of Invasion of Oral Tongue Cancer (2019)
  • Author(s): Murakami Ryuji、Shiraishi Shinya、Yoshida Ryoji、Sakata Junki、Yamana Keisuke、Hirosue Akiyuki、Uchiyama Yoshikazu、Nakayama Hideki、Yamashita Yasuyuki
  • Journal Title: Academic Radiology Volume: 印刷中 Issue: 7 Pages: 30423-9
  • DOI: 10.1016/j.acra.2018.08.021
  • Peer Reviewed / Open Access
• [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] 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] 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
• [Presentation] Interactions of calcium with mitochondria contribute to cisplatin resistance in oral cancer (2020)
  • Author(s): Mayumi Hirayama, Kenta Kawahara, Akiyuki Hirosue, Satoru Shinriki, Ryoji Yoshida, Hirotaka Matsui, Hideki Nakayama
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Development of a prediction system for delayed neck metastases of tongue cancer (2020)
  • Author(s): Junki Inoue, Ryoji Yoshida, Junki Sakata, Kenta Kawahara, Masatoshi Hirayama, Akiyuki Hirosue, Masashi Nagata, Hideki Nakayama
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] ANGPTL4 is involved in high malignant potential in oral squamous cell carcinoma through the epigenetic regulation. (2019)
  • Author(s): Yuka Nagao, Akiyuki Hirosue, Masafumi Nakamoto,Tatsuro Yamamoto, Junki Sakata, Hidetaka Arita, Hikaru Nakashima, Kenta Kawahara, Ryoji Yoshida, Hideki Nakayama
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 2 型糖尿病を有する口腔扁平上皮癌患者の臨床統計学的，免疫組織学的検討 (2019)
  • Author(s): 永尾優果、廣末晃之、中元雅史、中嶋光、川口翔、郷原俊輔、山名啓介、川原健太、福間大喜、尾木秀直、吉田遼司、平木昭光、篠原正徳、中山秀樹
  • Organizer: 第43回日本頭頸部癌学会
• [Presentation] BRD4 is involved in high malignant potential in oral squamous cell carcinoma through the epigenetic regulation (2018)
  • Author(s): Yuka Nagao, Akiyuki Hirosue, Tatsuro Yamamoto, Junki Sakata, Masafumi Nakamoto, Yuichiro Matsuoka, Hidetaka Arita, Hikaru Nakashima, Kenta Kawahara, Ryoji Yoshida, Noriko Saitoh, Hideki Nakayama
  • Organizer: 日本癌学会
• [Presentation] BRD4はエピジェネティックな調節を介して口腔扁平上皮癌の転移に関与する (2018)
  • Author(s): 山本達郎、廣末晃之、中元雅史、 川原健太、 高橋望、 吉田遼司、 坂田純基、中山秀樹
  • Organizer: 日本口腔外科学会