Establishment of novel diagnostic method and development of treatment for liver fibrosis using miRNA

• Project/Area Number: 20K08314
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Nagoya City University
• Principal Investigator: Matsuura Kentaro 名古屋市立大学, 医薬学総合研究院(医学), 准教授 (30580576)
• Project Period (FY): 2020-04-01 – 2025-03-31
• Project Status: Completed (Fiscal Year 2024)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: miRNA / HCV / SVR / 細胞外小胞 / 肝線維化 / 核酸創薬

Outline of Research at the Start

miRNAは、肝疾患における炎症、線維化、発癌機構に深く関与しており、疾患バイオマーカー、創薬の標的として期待されている。申請者はこれまでの研究から、末梢血中のmiRNA発現レベルは肝線維化進展度のバイオマーカーとなる可能性を見出している。本研究では、新規の細胞外小胞（Extracellular vesicles: EVs ）精製技術を用い、血清EVs中のmiRNA発現解析を行い、新規の肝線維化バイオマーカーの確立を目指す。さらに、同定したmiRNAの肝線維化進展および線維化改善に与える影響について機能解析し、新規の核酸創薬：肝線維化改善薬を開発する。

Outline of Final Research Achievements

We collected extracellular vesicles (EVs) from the serum of patients with liver cirrhosis and advanced fibrosis who had achieved HCV elimination by treatment, and performed comprehensive RNA-seq analysis of miRNAs in EVs in patients with and without improved liver fibrosis and function over time. We found that miR-223-3p expression level after completion of antiviral therapy was associated with improvement of liver fibrosis after HCV elimination. We also found that the expression levels of serum CXCL10 and Angiopoietin-2 after antiviral therapy were associated with improved liver fibrosis after HCV elimination. These are not only potential biomarkers for predicting improvement in liver fibrosis and function after HCV elimination, but also potential therapeutic targets.

Academic Significance and Societal Importance of the Research Achievements

本研究で見出したEVs中のmiRNA、サイトカイン/ケモカインは肝臓における炎症、線維化、血管新生、発癌において機能的にも関与している可能性があり、HCV排除後の肝線維化進展・肝発癌を予測するバイオマーカーとしてのみならず、これらの機構の解明にもつながる大変興味深い知見である。さらに、これらは肝線維化の治療標的となる可能性を秘めており、HCV排除後や脂肪性肝疾患など極めて多くの患者が対象となり得、実現されればその社会的貢献は大きい。

Research Products

• [Journal Article] MicroRNA-223-3p levels in serum-derived extracellular vesicles predict regression of M2BPGi-based liver fibrosis after hepatitis C virus eradication by direct-acting antiviral agents (2024)
  • Author(s): Suzuki Takanori、Matsuura Kentaro、Nagura Yoshihito、Ito Kyoko、Ogawa Shintaro、Kawamura Hayato、Fujiwara Kei、Nagaoka Katsuya、Iio Etsuko、Watanabe Takehisa、Kataoka Hiromi、Tanaka Yasuhito
  • Journal Title: Journal of Gastroenterology Volume: 59 Issue: 8 Pages: 719-731
  • DOI: 10.1007/s00535-024-02115-w
  • Peer Reviewed
• [Journal Article] Serum Angiopoietin-2 Levels Predict the Development of Hepatocellular Carcinoma following Hepatitis C Virus Eradication Using Direct-Acting Antiviral Agents (2024)
  • Author(s): Suzuki Takanori、Matsuura Kentaro、Nagura Yoshihito、Kawamura Hayato、Fujiwara Kei、Ogawa Shintaro、Nagaoka Katsuya、Iio Etsuko、Watanabe Takehisa、Kataoka Hiromi、Tanaka Yasuhito
  • Journal Title: Oncology Volume: - Issue: 7 Pages: 1-10
  • DOI: 10.1159/000536154
  • Peer Reviewed
• [Journal Article] Serum inducible protein 10?kDa/C‐X‐C motif chemokine?10 levels predict regression of M2BPGi‐based liver fibrosis after hepatitis?C virus eradication by direct‐acting antiviral agents (2023)
  • Author(s): Nagura Yoshihito、Suzuki Takanori、Matsuura Kentaro、Ogawa Shintaro、Kawamura Hayato、Kuno Kayoko、Fujiwara Kei、Nojiri Shunsuke、Nagaoka Katsuya、Iio Etsuko、Watanabe Takehisa、Kataoka Hiromi、Tanaka Yasuhito
  • Journal Title: Hepatology Research Volume: 54 Issue: 1 Pages: 32-42
  • DOI: 10.1111/hepr.13962
  • Peer Reviewed
• [Journal Article] Serum angiopoietin‐2 levels predict regression of Mac‐2 binding protein glycosylation isomer‐based liver fibrosis after hepatitis C virus eradication by direct‐acting antiviral agents (2022)
  • Author(s): Suzuki Takanori、Matsuura Kentaro、Nagura Yoshihito、Ogawa Shintaro、Fujiwara Kei、Nojiri Shunsuke、Watanabe Takehisa、Kataoka Hiromi、Tanaka Yasuhito
  • Journal Title: Hepatology Research Volume: 52 Issue: 11 Pages: 919-927
  • DOI: 10.1111/hepr.13823
  • Peer Reviewed
• [Journal Article] International multicenter validation of GES score for HCC risk stratification in chronic hepatitis C patients (2022)
  • Author(s): Shiha Gamal、Soliman Reham、Mikhail Nabiel N. H.、Carrat Fabrice、Azzi Jessica、Nathalie Ganne‐Carrie、Toyoda Hidenori、Uojima Haruki、Nozaki Akito、Takaguchi Koichi、Hiraoka Atsushi、Atsukawa Masanori、Abe Hiroshi、Matsuura Kentaro、 et al.
  • Journal Title: Journal of Viral Hepatitis Volume: 29 Issue: 9 Pages: 807-816
  • DOI: 10.1111/jvh.13717
  • Peer Reviewed
• [Journal Article] Liver-related events after direct-acting antiviral therapy in patients with hepatitis C virus-associated cirrhosis (2022)
  • Author(s): Tahata Y, Hikita H, Mochida S, Enomoto N, Kawada N, Kurosaki M, Ido A, Miki D, Yoshiji H, Takikawa Y, Sakamori R, Hiasa Y, Nakao K, Kato N, Ueno Y, Yatsuhashi H, Itoh Y, Tateishi R, Suda G, Takami T, Nakamoto Y, Asahina Y, et al.
  • Journal Title: Journal of Gastroenterology Volume: 57 Issue: 2 Pages: 120-132
  • DOI: 10.1007/s00535-021-01845-5
  • Peer Reviewed
• [Journal Article] Characteristics and Prognosis of De Novo Hepatocellular Carcinoma After Sustained Virologic Response (2021)
  • Author(s): Toyoda Hidenori、Watanabe Tsunamasa、Tanaka Junko
  • Journal Title: Hepatology Communications Volume: 5 Issue: 7 Pages: 1290-1299
  • DOI: 10.1002/hep4.1716
  • Peer Reviewed / Open Access
• [Journal Article] A novel noninvasive formula for predicting cirrhosis in patients with chronic hepatitis C (2021)
  • Author(s): Atsukawa M, Tsubota A, Kondo C, Uchida-Kobayashi S, Takaguchi K, Tsutsui A, Nozaki A, Chuma M, Hidaka I, Ishikawa T, Iwasa M, Tamai Y, Tobari M, Matsuura K, Nagura Y, Abe H, Kato K, Suzuki K, Okubo T, Arai T, Itokawa N, Toyoda H, Enomoto M, Tamori A, Tanaka Y, Kawada N, Takei Y, Iwakiri K.
  • Journal Title: PLOS ONE Volume: 16 Issue: 9 Pages: e0257166-e0257166
  • DOI: 10.1371/journal.pone.0257166
  • Peer Reviewed / Open Access
• [Journal Article] Time‐course changes in liver functional reserve after successful sofosbuvir/velpatasvir treatment in patients with decompensated cirrhosis (2021)
  • Author(s): Atsukawa Masanori、Watanabe Tsunamasa、Iwakiri Katsuhiko
  • Journal Title: Hepatology Research Volume: 52 Issue: 3 Pages: 235-246
  • DOI: 10.1111/hepr.13739
  • Peer Reviewed
• [Journal Article] Clinical efficacy of a novel, high-sensitivity HBcrAg assay in the management of chronic hepatitis B and HBV reactivation (2021)
  • Author(s): Inoue Takako、Kusumoto Shigeru、Iio Etsuko、Ogawa Shintaro、Suzuki Takanori、Yagi Shintaro、Kaneko Atsushi、Matsuura Kentaro、Aoyagi Katsumi、Tanaka Yasuhito
  • Journal Title: Journal of Hepatology Volume: in press Issue: 2 Pages: 302-310
  • DOI: 10.1016/j.jhep.2021.02.017
  • Peer Reviewed
• [Journal Article] Inhibitory Effect of a Human MicroRNA, miR-6133-5p, on the Fibrotic Activity of Hepatic Stellate Cells in Culture (2020)
  • Author(s): Hamada-Tsutsumi Susumu、Onishi Masaya、Matsuura Kentaro、Isogawa Masanori、Kawashima Keigo、Sato Yusuke、Tanaka Yasuhito
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 19 Pages: 7251-7251
  • DOI: 10.3390/ijms21197251
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sofosbuvir plus velpatasvir treatment for hepatitis C virus in patients with decompensated cirrhosis: a Japanese real-world multicenter study (2020)
  • Author(s): Tahata Yuki、Hikita Hayato、Matsuura Kentaro、Takehara Tetsuo, et al.
  • Journal Title: Journal of Gastroenterology Volume: 56 Issue: 1 Pages: 67-77
  • DOI: 10.1007/s00535-020-01733-4
  • Peer Reviewed / Open Access
• [Presentation] 血清由来細胞外小胞中のmiR-223-3p発現レベルはHCV排除後の肝線維化改善に関連する (2024)
  • Author(s): 鈴木孝典、松浦健太郎、田中靖人
  • Organizer: 第60回日本肝臓学会総会
• [Presentation] DAA治療後の血清CXCL10高値はSVR後の肝線維化非改善に関連する (2023)
  • Author(s): 松浦健太郎，名倉義人，田中靖人
  • Organizer: 第59回日本肝臓学会総会
• [Presentation] HCV排除後の肝硬変患者における血清サイトカイン/ケモカイン発現解析 (2021)
  • Author(s): 名倉義人、松浦健太郎、鈴木孝典、藤原圭、野尻俊輔、田中靖人
  • Organizer: 第57回日本肝臓学会総会
• [Presentation] B型慢性肝疾患に対する核酸アナログ投与中および中止後の肝発癌に関する検討 (2020)
  • Author(s): 松浦健太郎，飯尾悦子，田中靖人
  • Organizer: 第106回日本消化器病学会総会
• [Presentation] C型慢性肝疾患におけるDAA治療後の肝予備能・予後に関連する因子 (2020)
  • Author(s): 飯尾悦子、松浦健太郎、田中靖人
  • Organizer: 第106回日本消化器病学会総会
• [Presentation] C型肝硬変患者におけるDAA治療後発癌と生命予後の検討～未治療群と比較して (2020)
  • Author(s): 飯尾悦子、松浦健太郎、島田紀朋、田中靖人
  • Organizer: 第56回日本肝臓学会総会