Blood microRNAs as a predictive biomarker of chemosensitivity, and a target of nucleic therapy in oesophageal cancer

• Project/Area Number: 20K09062
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Fujiwara Hitoshi 京都府立医科大学, 医学(系)研究科(研究院), 准教授 (20332950)
• Co-Investigator(Kenkyū-buntansha): 大辻 英吾 京都府立医科大学, 医学(系)研究科(研究院), 教授 (20244600) ; 小松 周平 京都府立医科大学, 医学(系)研究科(研究院), 特任准教授 (40578978)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 食道癌 / microRNA / 抗がん剤 / 抗がん核酸治療 / バイオマーカー / リキッドバイオプシー / 遊離核酸 / 抗癌核酸治療

Outline of Research at the Start

これまでの研究成果で、一部の癌抑制型miRNAは正常細胞からも癌細胞の増殖抑制を目的として血中に分泌されるが、それらが枯渇することで癌の増殖、浸潤、転移などの悪性化、抗癌剤への耐性化が導かれる可能性がある。また枯渇した癌抑制型miRNAを生体内に再導入し血中濃度を回復させて維持することで、抗腫瘍効果、抗癌剤感受性回復効果を得ることができる可能性がある。本研究は食道癌の体液中の分泌型の癌抑制型miRNA濃度による癌の悪性度診断や抗癌剤感受性診断のみならず、分泌型の癌抑制型miRNAを用いた血液・体液を介した抗腫瘍効果や抗癌剤感受性回復効果を目的とした新たな癌治療の可能性を世界に先駆けて検証する。

Outline of Final Research Achievements

We selected four miRNA candidates (miR-323, 345, 409 and 1254) based on the microRNA microarray comparing pre-treatment plasma levels in ESCC patients with high and low histopathological responses to neoadjuvant chemotherapy (NAC). Among these miRNA candidates, miR-1254 was more highly elevated in pre-treatment plasma of ESCC patients with a high histopathological response than in those with a low histopathological response (P=0.0021; AUC 0.7621). High plasma miR-1254 levels tended to correlate with the absence of venous invasion (P= 0.0710) and were an independent factor predicting a higher response to chemotherapy (P= 0.0022; Odds ratio 7.86) and better prognosis (P = 0.0235; Hazard ratio 0.23). Overexpressing miR-1254 in ESCC cells significantly enhanced chemosensitivity to cisplatin through the transcriptional regulation of ABCC1 in vitro. Moreover, increased plasma miR-1254 levels by subcutaneous injection significantly improved responses to CDDP in mice.

Academic Significance and Societal Importance of the Research Achievements

本研究成果から、一部の癌抑制型miRNAは正常細胞からも癌細胞の増殖抑制を目的として血中に分泌されるが、それらが枯渇することで癌の増殖、浸潤、転移などの悪性化、抗癌剤への耐性化が導かれる可能性がある。また、枯渇した癌抑制型miRNAを生体内に再導入し血中濃度を回復させて維持することで、抗腫瘍効果、抗癌剤感受性回復効果を得ることができる可能性がある。食道癌の体液中の分泌型癌抑制型miRNA濃度による癌の悪性度診断や抗癌剤感受性診断のみならず、分泌型の癌抑制型miRNAを用いた血液・体液を介した抗腫瘍効果や抗癌剤感受性回復効果を目的とした新たな癌治療の可能性を世界に先駆け報告するものである。

Research Products

• [Journal Article] microRNA-192-5p can predict the response to neoadjuvant chemotherapy and prognosis in esophageal cancer. (2023)
  • Author(s): Furuke H, Konishi H, Arita T, Komatsu S, Shiozaki A, Otsuji E et al.
  • Journal Title: Cancer Science Volume: 114(4) Issue: 4 Pages: 1686-1696
  • DOI: 10.1111/cas.15703
  • Peer Reviewed / Open Access
• [Journal Article] Overexpression of Tetraspanin31 contributes to malignant potential and poor outcomes in gastric cancer. (2022)
  • Author(s): Takashima Y, Komatsu S, Otsuji E et al.
  • Journal Title: Cancer Science Volume: 113(6) Issue: 6 Pages: 1984-1998
  • DOI: 10.1111/cas.15342
  • Peer Reviewed / Open Access
• [Journal Article] Anoctamin 5 regulates the cell cycle and affects prognosis in gastric cancer (2022)
  • Author(s): Fukami Tomoyuki、Shiozaki Atsushi、Kosuga Toshiyuki、Kudou Michihiro、Shimizu Hiroki、Ohashi Takuma、Arita Tomohiro、Konishi Hirotaka、Komatsu Shuhei、Kubota Takeshi、Fujiwara Hitoshi、Okamoto Kazuma、Kishimoto Mitsuo、Morinaga Yukiko、Konishi Eiichi、Otsuji Eigo
  • Journal Title: World Journal of Gastroenterology Volume: 28 Issue: 32 Pages: 4649-4667
  • DOI: 10.3748/wjg.v28.i32.4649
  • Peer Reviewed / Open Access
• [Journal Article] NADPH Oxidase 2 Has a Crucial Role in Cell Cycle Progression of Esophageal Squamous Cell Carcinoma (2022)
  • Author(s): Shimizu Hiroki、Katsurahara Keita、Inoue Hiroyuki、Shiozaki Atsushi、Kosuga Toshiyuki、Kudou Michihiro、Arita Tomohiro、Konishi Hirotaka、Komatsu Shuhei、Fujiwara Hitoshi、Morinaga Yukiko、Konishi Eiichi、Otsuji Eigo
  • Journal Title: Annals of Surgical Oncology Volume: 29 Issue: 13 Pages: 8677-8687
  • DOI: 10.1245/s10434-022-12384-5
  • Peer Reviewed / Open Access
• [Journal Article] Functions and Clinical Significance of CACNA2D1 in Gastric Cancer (2022)
  • Author(s): Inoue Hiroyuki、Shiozaki Atsushi、Kosuga Toshiyuki、Shimizu Hiroki、Kudou Michihiro、Ohashi Takuma、Arita Tomohiro、Konishi Hirotaka、Komatsu Shuhei、Kubota Takeshi、Fujiwara Hitoshi、Okamoto Kazuma、Kishimoto Mitsuo、Konishi Eiichi、Otsuji Eigo
  • Journal Title: Annals of Surgical Oncology Volume: - Issue: 7 Pages: 4522-4535
  • DOI: 10.1245/s10434-022-11752-5
  • Peer Reviewed
• [Journal Article] TRPV2 Promotes Cell Migration and Invasion in Gastric Cancer via the Transforming Growth Factor-β Signaling Pathway (2021)
  • Author(s): Kato Shunji、Shiozaki Atsushi、Kudou Michihiro、Shimizu Hiroki、Kosuga Toshiyuki、Ohashi Takuma、Arita Tomohiro、Konishi Hirotaka、Komatsu Shuhei、Kubota Takeshi、Fujiwara Hitoshi、Okamoto Kazuma、Kishimoto Mitsuo、Konishi Eiichi、Otsuji Eigo
  • Journal Title: Annals of Surgical Oncology Volume: 29 Issue: 5 Pages: 2944-2956
  • DOI: 10.1245/s10434-021-11132-5
  • Peer Reviewed
• [Journal Article] Depletion of tumor suppressor miRNA-148a in plasma relates to tumor progression and poor outcomes in gastric cancer (2021)
  • Author(s): Shuhei Komatsu , Taisuke Imamura , Jun Kiuchi , Yusuke Takashima , Hajime Kamiya , Takuma Ohashi , Hirotaka Konishi , Atsushi Shiozaki , Takeshi Kubota , Kazuma Okamoto , Eigo Otsuji
  • Journal Title: Am J Cancer Res Volume: 11(12) Pages: 2944-2956
  • Peer Reviewed / Open Access
• [Journal Article] MiR-3663-3p Inhibits the Progression of Gastric Cancer Through the CCND1 Pathway (2021)
  • Author(s): Koji Takao , Hirotaka Konishi , Daiki Matsubara , Katsutoshi Shoda , Tomohiro Arita , Hiroki Shimizu , Shuhei Komatsu , Atsushi Shiozaki , Yusuke Yamamoto , Takeshi Kubota , Hitoshi Fujiwara , Kazuma Okamoto , Eigo Otsuji
  • Journal Title: Anticancer Res Volume: 41(5) Pages: 2441-2449
  • Peer Reviewed
• [Journal Article] Anterior gradient 2 regulates cancer progression in TP53 wild type esophageal squamous cell carcinoma (2021)
  • Author(s): Takabatake K, Konishi H, Komatsu S, Fujiwara H, Otsuji E et al.
  • Journal Title: Oncol Rep Volume: 46(6) Issue: 6 Pages: 260-260
  • DOI: 10.3892/or.2021.8211
  • Peer Reviewed / Open Access
• [Journal Article] Expression and Role of CFTR in Human Esophageal Squamous Cell Carcinoma (2021)
  • Author(s): Matsumoto Yoshihisa、Shiozaki Atsushi、Kosuga Toshiyuki、Kudou Michihiro、Shimizu Hiroki、Arita Tomohiro、Konishi Hirotaka、Komatsu Shuhei、Kubota Takeshi、Fujiwara Hitoshi、Okamoto Kazuma、Kishimoto Mitsuo、Konishi Eiichi、Otsuji Eigo
  • Journal Title: Annals of Surgical Oncology Volume: - Issue: 11 Pages: 6424-6436
  • DOI: 10.1245/s10434-021-09752-y
  • Peer Reviewed
• [Journal Article] Functional Analysis and Clinical Significance of Chloride Channel 2 Expression in Esophageal Squamous Cell Carcinoma (2021)
  • Author(s): Mitsuda Masato、Shiozaki Atsushi、Kudou Michihiro、Shimizu Hiroki、Arita Tomohiro、Kosuga Toshiyuki、Konishi Hirotaka、Komatsu Shuhei、Kubota Takeshi、Fujiwara Hitoshi、Okamoto Kazuma、Kishimoto Mitsuo、Konishi Eiichi、Otsuji Eigo
  • Journal Title: Annals of Surgical Oncology Volume: - Issue: 9 Pages: 5384-5397
  • DOI: 10.1245/s10434-021-09659-8
  • Peer Reviewed
• [Journal Article] Plasma microRNA profiles: identification of miR-1229-3p as a novel chemoresistant and prognostic biomarker in gastric cancer (2020)
  • Author(s): Nishibeppu K, Komatsu S et al.
  • Journal Title: Sci Rep Volume: 10 Issue: 1 Pages: 3161-3161
  • DOI: 10.1038/s41598-020-59939-8
  • Peer Reviewed / Open Access
• [Journal Article] Circulating circERBB2 as a potential prognostic biomarker for gastric cancer: An investigative study. (2020)
  • Author(s): Nanishi K, Konishi H, Shoda K, Arita T, Kosuga T, Komatsu S, Shiozaki A, Kubota T, Fujiwara H, Okamoto K, Ichikawa D, Otsuji E.
  • Journal Title: Cancer Science Volume: 111 Issue: 11 Pages: 4177-4186
  • DOI: 10.1111/cas.14645
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of Intracellular and Extracellular High-Mobility Group Box-1 in the Progression of Esophageal Squamous Cell Carcinoma. (2020)
  • Author(s): Matsubara D, Konishi H, Arita T, Shoda K, Fujita Y, Ogino S, Takao K, Nanishi K, Kosuga T, Komatsu S, Shiozaki A, Fujiwara H, Okamoto K, Otsuji E.
  • Journal Title: Ann Surg Oncol. Volume: ー Issue: 9 Pages: 3233-3244
  • DOI: 10.1245/s10434-020-08363-3
  • Peer Reviewed
• [Journal Article] ANO9 Regulated Cell Cycle in Human Esophageal Squamous Cell Carcinoma. (2020)
  • Author(s): Katsurahara K, Shiozaki A, Kosuga T, Kudou M, Shoda K, Arita T, Konishi H, Komatsu S, Kubota T, Fujiwara H, Okamoto K, Kishimoto M, Konishi E, Marunaka Y, Otsuji E.
  • Journal Title: Ann Surg Oncol. Volume: ー Issue: 9 Pages: 3218-3230
  • DOI: 10.1245/s10434-020-08368-y
  • Peer Reviewed
• [Presentation] New era of myomiR-133b in blood for sarcopenia-related tumor progression and nucleic acid therapy in gastric cancer (2021)
  • Author(s): 小松周平、藤原 斉、大辻英吾 他
  • Organizer: 日本癌学会総会
• [Presentation] The restoration of the depleted miR-143 in plasma is a novel anticancer treatment for esophageal squamous cell carcinoma (2021)
  • Author(s): 木内 純、小松周平、藤原 斉、大辻英吾 他
  • Organizer: 日本癌学会総会
• [Presentation] Histological heterogeneity contributes to lymph node metastasis via intercellular transfer of miR-21 in gastric cancer (2021)
  • Author(s): 神谷 肇、小松周平、藤原 斉、大辻英吾 他
  • Organizer: 日本癌学会総会
• [Presentation] 血中分泌型microRNAを用いた胃癌の抗がん剤感受性診断予測と抗がん核酸治療 (2020)
  • Author(s): 小松周平、藤原 斉 他
  • Organizer: 日本癌学会総会
• [Presentation] 分化・未分化混在型胃癌におけるmicroRNAを介した悪性化機序の解明 (2020)
  • Author(s): 高嶋 祐助、小松周平、藤原 斉 他
  • Organizer: 日本癌学会総会
• [Presentation] 消化器癌における筋由来血中miR-133bを用いたサルコペニア病態診断とその治療応用 (2020)
  • Author(s): 木内 純、小松周平、藤原 斉 他
  • Organizer: 日本癌学会総会
• [Presentation] 食道胃接合部腺癌における新規癌関連遺伝子CDCA3の癌化機構の解明と臨床応用 (2020)
  • Author(s): 神谷 肇、小松周平、藤原 斉 他
  • Organizer: 日本癌学会総会
• [Presentation] 胃食道接合部癌における新規の癌関連遺伝子SMYD2の発現意義と臨床応用 (2020)
  • Author(s): 大橋拓馬、小松周平、藤原 斉 他
  • Organizer: 日本癌学会総会