Molecular mechanisms and biological, clinical significance of IFNL4

• Project/Area Number: 16K21058
• 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): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: IFNλ4 / ウイルス / 感染症 / 癌

Outline of Final Research Achievements

Molecular mechanisms and the biological, clinical significance of IFNλ4 is poorly understood.
(1) We examined the expression of IFNλ4 in patients’ samples and evaluated its clinical significance. Hepatic IFNλ4 expression is related to the response to the chemotherapy to advanced HCC. (2) We revealed that IFNλ4 has functional roles quite different from other IFNs. We revealed that IFNλ4 has a strong anti-viral activity and has a strong anti-tumor activity. We identified IFNλ4-dependent gene expression patterns that support the specific phenotype of IFNλ4. (3) We identified new IFNλ4 receptors; A and B. Detailed signaling pathway down streaming of receptor A and B are now under investigating. (4) Anti-tumor activity of IFNλ4 in vivo was evaluated by using xenograft model to NOD-SCID mice. IFNλ4 expressing HepG2 cells established significant small tumors compared to the control tumors or IFNλ3 expressing tumors.

Academic Significance and Societal Importance of the Research Achievements

IFNλ4の詳細な機能的役割の解明は、C型慢性肝炎の治療抵抗性の機序、持続感染、発癌機序の解明に繋がる。更に、本研究成果は、C型肝炎のみならず、種々の感染症、感染免疫、病態形成、発癌、抗癌作用等の研究に重要な情報を提供できるため学術的にも大いに意義がある。

Research Products

• [Journal Article] The osteopontin-CD44 axis in hepatic cancer stem cells regulates IFN signaling and HCV replication. (2018)
  • Author(s): Shirasaki T, Honda M, Yamashita T, Nio K, Shimakami T, Shimizu R, Nakasyo S, Murai K, Shirasaki N, Okada H, Sakai Y, Sato T, Suzuki T, Yoshioka K, Kaneko S.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 13143-13143
  • DOI: 10.1038/s41598-018-31421-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Unexpected Replication Boost by Simeprevir for Simeprevir-resistant Variants in Genotype 1a Hepatitis C Virus (2018)
  • Author(s): Murai K, Shimakami T, Welsch C, Shirasaki T, Liu F, Kitabayashi J, Tanaka S, Funaki M, Omura H, Nishikawa T, Suminyadorj A, Honda M, Kaneko S.
  • Journal Title: Antimicrob Agents Chemother Volume: 印刷中 Issue: 7
  • DOI: 10.1128/aac.02601-17
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Peretinoin, an Acyclic Retinoid, Inhibits Hepatitis B Virus Replication by Suppressing Sphingosine Metabolic Pathway In Vitro. (2018)
  • Author(s): 1.Murai K, Shirasaki T, Honda M, Shimizu R, Shimakami T, Nakasho S, Shirasaki N, Okada H, Sakai Y, Yamashita T, Kaneko S.
  • Journal Title: International Journal of Molecular Sciences. Volume: 19(2) Issue: 2 Pages: 108-108
  • DOI: 10.3390/ijms19020108
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Branched-chain amino acids prevent hepatic fibrosis and development of hepatocellular carcinoma in a non-alcoholic steatohepatitis mouse model. (2017)
  • Author(s): K Takegoshi, M Honda, H Okada, R Takabatake, N Matsuzawa-Nagata, JS Campbell, M Nishikawa, T Shimakami, T Shirasaki, Y Sakai, T Yamashita, T Takamura, T Tanaka, S Kaneko.
  • Journal Title: Oncotarget Volume: 印刷中 Issue: 11 Pages: 18191-18205
  • DOI: 10.18632/oncotarget.15304
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Eicosapentaenoic acid down-regulates expression of the selenoprotein P gene by inhibiting SREBP-1c protein independently of the AMP-activated protein kinase pathway in H4IIEC3 hepatocytes. (2017)
  • Author(s): Tajima-Shirasaki N, Ishii KA, Takayama H, Shirasaki T, Iwama H, Chikamoto K, Saito Y, Iwasaki Y, Teraguchi A, Lan F, Kikuchi A, Takeshita Y, Murao K, Matsugo S, Kaneko S, Misu H, Takamura T.
  • Journal Title: J Biol Chem. Volume: 292 Issue: 26 Pages: 10791-10800
  • DOI: 10.1074/jbc.m116.747006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Peretinoin, an acyclic retinoid, suppresses steatohepatitis and tumorigenesis by activating autophagy in mice fed an atherogenic high-fat diet (2017)
  • Author(s): Okada H, Takabatake R, Honda M, Takegoshi K, Yamashita T, Nakamura M, Shirasaki T, Sakai Y, Shimakami T, Nagata N, Takamura T, Tanaka T, Kaneko S.
  • Journal Title: Oncotarget Volume: 8 Issue: 25 Pages: 39978-39993
  • DOI: 10.18632/oncotarget.18116
  • Peer Reviewed / Open Access
• [Journal Article] A Novel mTOR Inhibitor; Anthracimycin for the Treatment of Human Hepatocellular Carcinoma. (2017)
  • Author(s): Hayashi T, Yamashita T, Okada H, Oishi N, Sunagozaka H, Nio K, Hayashi T, Hara Y, Asahina Y, Yoshida M, Hashiba T, Suda T, Shirasaki T, Igarashi Y, Miyanouchi K, Yamashita T, Honda M, Kaneko S.
  • Journal Title: Anticancer Res Volume: 37 Pages: 3397-3403
  • Peer Reviewed
• [Journal Article] Reactivation of hepatitis B virus from an isolated anti-HBc positive patient after eradication of hepatitis C virus with direct-acting antiviral agents (2017)
  • Author(s): Suda Tsuyoshi、Shimakami Tetsuro、Shirasaki Takayoshi、Yamashita Tatsuya、Mizukoshi Eishiro、Honda Masao、Kaneko Shuichi
  • Journal Title: J Hepatol Volume: 67 Issue: 5 Pages: 1108-1111
  • DOI: 10.1016/j.jhep.2017.07.014
  • Peer Reviewed / Open Access
• [Journal Article] Peretinoin, an acyclic retinoid, inhibits hepatocarcinogenesis by suppressing sphingosine kinase 1 expression in vitro and in vivo. (2017)
  • Author(s): Funaki M, Kitabayashi J, Shimakami T, Nagata N, Sakai Y, Takegoshi K, Okada H, Murai K, Shirasaki T, Oyama T, Yamashita T, Ota T, Takuwa Y, Honda M, Kaneko S.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 16978-16978
  • DOI: 10.1038/s41598-017-17285-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Induction of IFN-lambda3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection (2016)
  • Author(s): Murata, K. Asano, M. Matsumoto, A. Sugiyama, M. Nishida, N. Tanaka, E. Inoue, T. Sakamoto, M. Enomoto, N. Shirasaki, T. Honda, M. Kaneko, S. Gatanaga, H. Oka, S. Kawamura, Y. I. Dohi, T. Shuno, Y. Yano, H. Mizokami, M.
  • Journal Title: Gut Volume: - Issue: 2 Pages: 362-371
  • DOI: 10.1136/gutjnl-2016-312653
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Efficient Suppression of Hepatitis C Virus Replication by Combination Treatment with miR-122 Antagonism and Direct-acting Antivirals in Cell Culture Systems. (2016)
  • Author(s): Liu F, Shimakami T, Murai K, Shirasaki T, Funaki M, Honda M, Murakami S, Yi M, Tang H, Kaneko S.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 30939-30939
  • DOI: 10.1038/srep30939
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Jagged1 DNA Copy Number Variation Is Associated with Poor Outcome in Liver Cancer. (2016)
  • Author(s): Kawaguchi K, Honda M, Yamashita T, Okada H, Shirasaki T, Nishikawa M, Nio K, Arai K, Sakai Y, Yamashita T, Mizukoshi E, Kaneko S.
  • Journal Title: Am J Pathol. Volume: 186(8) Issue: 8 Pages: 2055-2067
  • DOI: 10.1016/j.ajpath.2016.04.011
  • NAID: 120005899105
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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: J Infect Dis Volume: 213 Issue: 7 Pages: 1096-1106
  • DOI: 10.1093/infdis/jiv572
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] A liver-derived secretory protein, LECT2, restores the impaired plasmacytoid dendritic cells function by HBV and protects hepatocytes against HBV infection. (2018)
  • Author(s): Takayoshi Shirasaki, Masao Honda, Tetsuro Shimakami, Kazunori Kawaguchi, Ying-Yi Li, Kouki Nio, Taro Yamashita, Shuichi Kaneko
  • Organizer: 2018 International HBV Meeting Molecular Biology of Hepatitis B Viruses
  • Int'l Joint Research
• [Presentation] A liver-derived secretory protein, LECT2, enhances the innate immune response and suppresses RIG-I mediated virus infection. (2018)
  • Author(s): Takayoshi Shirasaki, Masao Honda, Kazuhisa Murai, Tetsuro Shimakami, Hirofumi Misu, Toshinari Takamura, Shuichi Kaneko
  • Organizer: 69th AASLD The Liver Meeting
  • Int'l Joint Research
• [Presentation] A liver-derived secretory protein, LECT2, activates plasmacytoid dendritic cells and protects hepatocytes from HBV infection (2017)
  • Author(s): Takayoshi Shirasaki, Masao Honda, Kazuhisa Murai, Tetsuro Shimakami, Ryogo Shimizu, Hirofumi Misu, Toshinari Takamura, Shuichi Kaneko
  • Organizer: 2017 International HBV Meeting Molecular Biology of Hepatitis B Viruses
  • Int'l Joint Research
• [Presentation] Differential microRNA expression in the liver during the advanced stage of chronic hepatitis C (2017)
  • Author(s): Takayoshi Shirasaki, Masao Honda, Rika Horii, Tetsuro Shimakami, Kazuhisa Murai, Ryogo Shimizu, Shuichi Kaneko
  • Organizer: 24th International Symposium on Hepatitis C virus and Related Viruses
• [Presentation] A liver-derived secretory protein, LECT2, activates plasmacytoid dendritic cells and protects hepatocytes from HBV infection (2017)
  • Author(s): Takayoshi Shirasaki, Masao Honda, Kazuhisa Murai, Tetsuro Shimakami, Miwako Narita, Hirofumi Misu, Toshinari Takamura, Seishi Murakami, Shuichi Kaneko
  • Organizer: 68th AASLD The Liver Meeting
• [Presentation] A liver-derived secretory protein, LECT2, enhances the innate immune response and suppresses HCV replication (2017)
  • Author(s): Takayoshi Shirasaki
  • Organizer: 5th Annual Meeting of the International Cytokine and Interferon Society, ICIS 2017
• [Presentation] A liver-derived secretory protein, LECT2, enhances the innate immune response and suppresses HCV replication (2016)
  • Author(s): Takayoshi Shirasaki, Masao Honda, Kazuhisa Murai, Tetsuro Shimakami, Hirofumi Misu, Toshinari Takamura, Seishi Murakami, Shuichi Kaneko
  • Organizer: 67th AASLD The Liver Meeting
  • Place of Presentation: Boston (米国)
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] A liver-derived secretory protein, LECT2, activates pDCs and protects hepatocytes against HBV infection. (2016)
  • Author(s): Takayoshi Shirasaki, Masao Honda, Kazuhisa Murai, Miwako Narita, Hirofumi Misu, Toshinari Takamura, Seishi Murakami, Shuichi Kaneko
  • Organizer: 67th AASLD The Liver Meeting
  • Place of Presentation: Boston (米国)
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] A liver-derived secretory protein, LECT2, enhances the innate immune response and suppresses HCV replication. (2016)
  • Author(s): Takayoshi Shirasaki, Masao Honda, Kazuhisa Murai, Tetsuro Shimakami, Hirofumi Misu, Toshinari Takamura, Seishi Murakami, Shuichi Kaneko
  • Organizer: 23rd International Symposium on Hepatitis C virus and Related Viruses
  • Place of Presentation: Kyoto (Japan)
  • Year and Date: 2016-10-11
  • Int'l Joint Research