Elucidation of the mechanisms of non-response to antiviral treatment in chronic hepatitis C

• Project/Area Number: 25870265
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology; Virology
• Research Institution: Kanazawa University
• Principal Investigator: SHIRASAKI Takayoshi 金沢大学, 保健学系, 助教 (50547180)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: C型肝炎ウイルス / 慢性肝炎 / 自然免疫 / 肝臓学 / 感染防御・制御

Outline of Final Research Achievements

The response of chronic hepatitis C (CHC) to IFN treatment is hampered in patients with advanced liver fibrosis. TGF-β plays an important role in fibrosis development, but its role in IFN signaling is unclear. I investigated the role of TGF-β on IFN signaling in HCV replication. TGF-β impaired IFN signaling by activating Socs3-mediated IFN inhibitory signaling via Foxo3a promoter activation by c-Jun binding. BCAAs could be a new therapeutic candidate to augment IFN signaling in HCV replication in patients with advanced CHC.
I also investigated the functional relevance of IL28B on the innate antiviral system and HCV replication. Gene expression profiling of primary hepatocytes treated with IFNα, IL28B, or both in combination revealed that LECT2, which enhances the innate immune response and suppresses HCV replication, was specifically induced by IL28B. LECT2 might participate in prolonged ISG induction by IL28B and in the unique innate antiviral immune system of IL28B.

Research Products

• [Journal Article] Hepatitis B Virus (HBV) Core-Related Antigen During Nucleos(t)ide Analog Therapy Is Related to Intra-hepatic HBV Replication and Development of Hepatocellular Carcinoma. (2016)
  • Author(s): Honda M, Shirasaki T, Terashima T, Kawaguchi K, Nakamura M, Oishi N, Wang X, Shimakami T, Okada H, Arai K, Yamashita T, Sakai Y, Yamashita T, Mizukoshi E, Kaneko S.
  • Journal Title: Journal of Infectious Diseases Volume: 1;213(7) Pages: 1096-106
  • Peer Reviewed
• [Journal Article] Inhibition of microRNA-214 ameliorates hepatic fibrosis and tumor incidence in platelet-derived growth factor C transgenic mice. (2015)
  • Author(s): Okada H, Honda M, Campbell JS, Takegoshi K, Sakai Y, Yamashita T, Shirasaki T, Takabatake R, Nakamura M, Tanaka T, Kaneko S.
  • Journal Title: Cancer Science Volume: 106(9) Pages: 1143-52
  • NAID: 120005830608
  • Peer Reviewed
• [Journal Article] Small tRNA-derived RNAs are increased and more abundant than microRNAs in chronic hepatitis B and C. (2015)
  • Author(s): Selitsky S, Gale J, Honda M, Yamane D, Masaki T, Fannin E, Guerra B, Shirasaki T, Shimakami T, Kaneko S, Lanford R, Lemon SM, Sethupathy P
  • Journal Title: Scientific Reports Volume: 5 Pages: 7675-7675
  • Peer Reviewed / Open Access
• [Journal Article] The Acyclic Retinoid Peretinoin Inhibits Hepatitis C Virus Replication and Infectious Virus Release in Vitro. (2014)
  • Author(s): Shimakami T, Honda M, Shirasaki T, Takabatake R, Liu F, Murai K, Shiomoto T, Funaki M, Yamane D, Murakami S, Lemon SM, Kaneko S
  • Journal Title: Scientific Reports Volume: 4 Pages: 4688-4688
  • NAID: 120005774911
  • Peer Reviewed / Open Access
• [Journal Article] Impaired IFN signaling in chronic hepatitis C patients with advanced fibrosis via the TGF-β signaling pathway (2014)
  • Author(s): Shirasaki T, Honda M, Shimakami T, Murai K, Shiomoto T, Okada H, Takabatake R, Tokumaru A, Sakai Y, Yamashita T, Lemon SM, Murakami S, Kaneko S
  • Journal Title: Hepatology Volume: 60 (5) Pages: 1519-1530
  • Peer Reviewed
• [Journal Article] Hepatic interferon-stimulated genes are differentially regulated in the liver of chronic hepatitis C patients with different interleukin 28B genotypes. (2014)
  • Author(s): Honda M, Shirasaki T, Shimakami T, Sakai A, Horii R, Arai K, Yamashita T, Sakai Y, Yamashita T, Okada H, Murai K, Nakamura M, Mizukoshi E, Kaneko S
  • Journal Title: Hepatology Volume: 59 (3) Pages: 828-838
  • NAID: 120005447749
  • Peer Reviewed
• [Journal Article] Metformin Suppresses Expression of the Selenoprotein P Gene via an AMP-activated Kinase (AMPK)/FoxO3a Pathway in H4IIEC3 Hepatocytes. (2014)
  • Author(s): Takayama H, Misu H, Iwama H, Chikamoto K, Saito Y, Murao K, Teraguchi A, Lan F, Kikuchi A, Saito R, Tajima N, Shirasaki T, Matsugo S, Miyamoto K, Kaneko S, Takamura T
  • Journal Title: The Journal Of Biological Chemistry Volume: 289 (1) Pages: 335-345
  • Peer Reviewed
• [Journal Article] MicroRNA-27a regulates lipid metabolism and inhibits hepatitis C virus replication in human hepatoma cells. (2013)
  • Author(s): Shirasaki T, Honda M, Shimakami T, Horii R, Yamashita T, Sakai Y, Sakai A, Okada H, Watanabe R, Murakami S, Yi M, Lemon SM, Kaneko S
  • Journal Title: Journal of Virology Volume: 87 (9) Pages: 5270-5286
  • Peer Reviewed
• [Presentation] LECT2 specifically induced by IL28B enhances the innate immune response and HCV replication (2015)
  • Author(s): Takayoshi Shirasaki, Masao Honda, Tetsuro Shimakami, Kazuhisa Murai, Hirofumi Misu, Toshinari Takamura, Stanley Lemon, Seishi Murakami, Shuichi Kaneko
  • Organizer: 66th AASLD The Liver Meeting
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2015-11-13
  • Int'l Joint Research
• [Presentation] LECT2 specifically induced by IL28B enhances the innate immune response and HCV replication (2015)
  • Author(s): Takayoshi Shirasaki, Masao Honda, Tetsuro Shimakami, Kazuhisa Murai, Hirofumi Misu, Toshinari Takamura, Stanley Lemon, Seishi Murakami, Shuichi Kaneko
  • Organizer: 22nd International Symposium on Hepatitis C virus and Related Viruses
  • Place of Presentation: Strasbourg, France
  • Year and Date: 2015-10-09
  • Int'l Joint Research
• [Presentation] LECT2 Specifically Induced by IL28B Regulates Interferon Response and HCV Replication (2014)
  • Author(s): Shirasaki T, Honda M, Shimakami T, Murai K, Shiomoto T, Misu H, Takamura T, Lemon SM, Murakami S, Kaneko S
  • Organizer: 65th Annual Meeting of the American Association for the Study of Liver Disease
  • Place of Presentation: Hynes Veterans Memorial Convention Center (USA)
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] LECT2 Specifically Induced by IL28B Regulates Interferon Response and HCV Replication (2014)
  • Author(s): Shirasaki T, Honda M, Shimakami T, Murai K, Shiomoto T, Misu H, Takamura T, Lemon SM, Murakami S, Kaneko S
  • Organizer: 21st International Symposium on Hepatitis C Viruses and Related Viruses
  • Place of Presentation: The Fairmont Banff Springs (Canada)
  • Year and Date: 2014-09-07 – 2014-09-11
• [Presentation] Impaired IFN signaling in chronic hepatitis C with advanced fibrosis via the TGF-β signaling pathway (2013)
  • Author(s): Takayoshi Shirasaki, Masao Honda, Tetsuro Shimakami, Kazuhisa Murai, Takayuki Shiomoto, Hikari Okada, Riuta Takabatake, Stanley M Lemon, Seishi Murakami, Shuichi Kaneko
  • Organizer: 20th International Symposium on Hepatitis C Virus and Related Viruses
  • Place of Presentation: Melbourne Convention and Exhibition Center (Australia)
• [Presentation] Impaired IFN signaling in chronic hepatitis C with advanced fibrosis via the TGF-β signaling pathway (2013)
  • Author(s): Takayoshi Shirasaki, Masao Honda, Tetsuro Shimakami, Kazuhisa Murai, Takayuki Shiomoto, Hikari Okada, Riuta Takabatake, Stanley M Lemon, Seishi Murakami, Shuichi Kaneko
  • Organizer: The 64th Annual Meeting of the American Association for the Study of Liver Disease
  • Place of Presentation: Walter E. Washington Convention Center (USA)
• [Presentation] A secretory protein specifically induced by IL28B regulates interferon response (2013)
  • Author(s): Takayoshi Shirasaki, Masao Honda, Tetsuro Shimakami, Kazuhisa Murai, Takayuki Shiomoto, Seishi Murakami, Shuichi Kaneko
  • Organizer: 第36回 日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド 他 （兵庫県）