Expression and functional analysis of let-7 for the establishment of new diagnostic and therapeutic methods for liver fibrosis

• Project/Area Number: 17K09435
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• 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), 講師 (30580576)
• Project Period (FY): 2017-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 肝線維化 / microRNA / miRNA / let-7

Outline of Final Research Achievements

Using stored samples from several chronic hepatitis C cohorts in Japan, we found that the expression level of let-7a in serum decreased with the progression of liver fibrosis and correlated well with other fibrosis markers. Cytokine and chemokine analysis was performed using stored sera from patients whose hepatitis C virus had been eliminated by treatment, and we found that serum Angiopoietin-2 and CXCL10 expression levels after completion of treatment were associated with subsequent improvement or deterioration of liver fibrosis. The expression level of let-7 in liver tissue was significantly decreased after activation of a human hepatic stellate cell line (LX-2) with several cytokines. When let-7 was transfected into LX-2, there was a trend toward suppression of gene expression related to inflammation and liver fibrosis.

Academic Significance and Societal Importance of the Research Achievements

末梢血中のlet-7発現レベルが肝線維化診断マーカーとして応用できる可能性を見出した。血清サイトカイン・ケモカイン解析により、HCV排除後の肝線維化改善・非改善に関わる機構の解明につながることが期待される。細胞株を用いた検討から、let-7が肝線維化機構を抑制的に制御していること見出し、今後さらなる検討によりlet-7補充療法を肝線維化治療に応用できる可能性が考えられた。これらの期待される新規治療法は、HCV排除後や非アルコール性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非常に大きい。

Research Products

• [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
• [Journal Article] TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus by interferon-free therapy. (2019)
  • Author(s): Iio E, Matsuura K (co-first author), Shimada N, Atsukawa M, Itokawa N, Abe H, Kato K, Takaguchi K, Senoh T, Eguchi Y, Nomura H, Yoshizawa K, Kang JH, Matsui T, Hirashima N, Kusakabe A, Miyaki T, Fujiwara K, Matsunami K, Tsutsumi S, Iwakiri K, Tanaka Y.
  • Journal Title: J Gastroenterol. Volume: 54 Issue: 4 Pages: 339-346
  • DOI: 10.1007/s00535-018-1526-3
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel Genetic Rearrangements Termed "Structural Variation Polymorphisms" Contribute to the Genetic Diversity of Orthohepadnaviruses (2019)
  • Author(s): Fujiwara K, Matsuura K, Matsunami K, Iio E, Nagura Y, Nojiri S, Kataoka H.
  • Journal Title: Viruses Volume: 11 Issue: 9 Pages: 871-871
  • DOI: 10.3390/v11090871
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ウイルス性肝炎の今後の課題 (2019)
  • Author(s): 松浦健太郎、田中靖人
  • Journal Title: BIO Clinica Volume: 34 Pages: 6-10
• [Journal Article] Circulating let-7 levels in serum correlate with the severity of hepatic fibrosis in chronic hepatitis C. (2018)
  • Author(s): Matsuura K, Aizawa N, Enomoto H, Nishiguchi S, Toyoda H, Kumada T, Iio E, Ito K, Ogawa S, Isogawa M, Alter HJ, Tanaka Y.
  • Journal Title: Open Forum Infct Dis. Volume: 5 Issue: 11 Pages: 268-268
  • DOI: 10.1093/ofid/ofy268
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Evaluation of Hepatocarcinogenesis and Outcome Using a Novel Glycobiomarker <i>Wisteria floribunda</i> Agglutinin-Positive Mac-2 Binding Protein (WFA⁺-M2BP) in Chronic Hepatitis C with Advanced Fibrosis (2018)
  • Author(s): Inoue T, Tsuzuki Y, Iio E, Shinkai N, Matsunami K, Fujiwara K, Matsuura K, Nojiri S, Tanaka Y.
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 71 Issue: 3 Pages: 177-183
  • DOI: 10.7883/yoken.JJID.2017.459
  • NAID: 130006743926
  • ISSN: 1344-6304, 1884-2836
  • Peer Reviewed
• [Journal Article] Characterization of hepatitis B virus with complex structural variations. (2018)
  • Author(s): Fujiwara K, Matsuura K, Matsunami K, Iio E, Nojiri S.
  • Journal Title: BMC Microbiol. Volume: 18 Issue: 1 Pages: 202-202
  • DOI: 10.1186/s12866-018-1350-1
  • Peer Reviewed / Open Access
• [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
• [Presentation] ゲノムワイド研究から臨床応用へ ～肝炎診療の現状と今後の展開 (2019)
  • Author(s): 松浦健太郎，田中靖人
  • Organizer: 第11回日本臨床検査医学会特別例会
• [Presentation] C型慢性肝疾患におけるDAA治療後初発肝発癌リスク因子の検討 (2019)
  • Author(s): 飯尾悦子、松浦健太郎、田中靖人
  • Organizer: 第105回日本消化器病学会総会
• [Presentation] 門脈圧亢進症患者におけるB-RTOおよびPSE治療前後の肝予備能の検討 (2019)
  • Author(s): 名倉義人、松浦健太郎、田中靖人
  • Organizer: 日本消化器病学会東海支部第130回例会
• [Presentation] C型慢性肝疾患におけるDAA治療後予後因子の検討 (2019)
  • Author(s): 飯尾悦子、松浦健太郎、田中靖人
  • Organizer: 第43回日本肝臓学会西部会
• [Presentation] 肝硬変患者におけるB-RTO治療後の肝予備能及び生命予後の成因別評価 (2019)
  • Author(s): 名倉義人、松波加代子、飯尾悦子、松浦健太郎、藤原圭、野尻俊輔、田中靖人
  • Organizer: 第23回日本肝臓学会大会
• [Presentation] C型慢性肝炎患者の血清におけるlet-7発現解析 (2018)
  • Author(s): 松浦健太郎、飯尾悦子、榎本平之、西口修平、豊田秀徳、熊田卓、松波加代子、藤原圭、野尻俊輔、田中靖人
  • Organizer: 第54回日本肝臓学会総会
• [Presentation] C型肝炎ウイルス排除後の肝癌発症に関連するTLL1遺伝子多型の同定および機能解析 (2018)
  • Author(s): 松浦健太郎、堤進、田中靖人
  • Organizer: 第22回日本肝臓学会大会
• [Presentation] The role of TLL1 in hepatic fibrogenesis and carcinogenesis. (2018)
  • Author(s): Kentaro Matsuura, Susumu Tsutsumi, Etsuko Iio, Masanori Isogawa, Yasuhito Tanaka.
  • Organizer: American Association for the Study of Liver Diseases
  • Int'l Joint Research
• [Presentation] C型慢性肝炎患者の肝線維化進展に関連するlet-7発現・機能解析 (2017)
  • Author(s): 松浦健太郎、飯尾悦子、会澤信弘、榎本平之、西口修平、豊田秀徳、熊田卓、松波加代子、藤原圭、野尻俊輔、城卓志、田中靖人
  • Organizer: 日本肝臓学会大会
• [Presentation] Circulating let-7 levels in serum and extracellular vesicles correlate with hepatic fibrosis progression in chronic hepatitis C (2017)
  • Author(s): Kentaro Matsuura, Etsuko Iio, Nobuhiro Aizawa, Hirayuki Enomoto, Shuhei Nishiguchi, Hidenori Toyoda, Takashi Kumada, Kayoko Matsunami, Kei Fujiwara, Shunsuke Nojiri, Valeria De Giorgi, Richard Y. Wang, Kazi Salam, Aparna Vuppala, Robert D. Allison, Patrizia Farci, Harvey J. Alter, and Yasuhito Tanaka
  • Organizer: 米国肝臓学会
  • Int'l Joint Research