Analyzes the mechanism of liver tumorigenesis and recurrence through chronic inflammation.

• Project/Area Number: 17K15933
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Kanazawa University
• Principal Investigator: Okada Hikari 金沢大学, 医学系, 博士研究員 (50788916)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: ペレチノイン / オートファジー / 慢性炎症 / 発癌 / 肝線維化 / Atg16L1 / CEBPα / オートファージー / 線維化 / 再発

Outline of Final Research Achievements

The pathogenesis of non-alcoholic steatohepatitis (NASH) is still unclear and the prevention of the development of hepatocellular carcinoma (HCC) has not been established. We found that peretinoin induced autophagy in the liver of mice, which was characterized by the increased co-localized expression of LC3B-II and Lamp2, and increased autophagosome formation and autophagy flux in the liver. Especially, Atg16L1 was repressed at both the mRNA and protein level. Decreased Atg16L1 mRNA expression was also found in the liver of patients with NASH according to disease progression. Interestingly, Atg16L1 overexpression in HepG2 cells inhibited palmitate-induced NF-kB activation and IL6/ STAT3 activation. We showed that Atg16L1 induced the de-phosphorylation of Gp130, a receptor subunit of interleukin-6 family cytokines, which subsequently repressed phosphorylated STAT3 (Tyr705) levels, and this process might be independent of autophagy function.

Academic Significance and Societal Importance of the Research Achievements

1）NASH、肝線維化、肝発がんの影響を、実臨床に即した発がんモデルで解析を行うことで臨床応用に貢献できる。2）ウイルス、腸内細菌、肥満を背景とした肝疾患病態進行による肝組織内のATG16L1 発現回復は、慢性炎症を抑制し、肝線維化の進行や肝細胞癌の再発に対する新規治療標的になり得る可能性がある。Atg16L1 の分子メカニズムを解明は、肝細胞癌の再発率および生存率の改善に貢献できる。

Research Products

• [Journal Article] Induction of Selenoprotein P mRNA during Hepatitis C Virus Infection Inhibits RIG-I-Mediated Antiviral Immunity. (2019)
  • Author(s): Murai K, Honda M, Shirasaki T, Shimakami T, Omura H, Misu H, Kita Y, Takeshita Y, Ishii KA, Takamura T, Urabe T, Shimizu R, Okada H, Yamashita T, Sakai Y, Kaneko S.
  • Journal Title: Cell Host Microbe Volume: 10;25(4) Issue: 4 Pages: 588-601
  • DOI: 10.1016/j.chom.2019.02.015
  • Peer Reviewed / Open Access
• [Journal Article] Characteristics of impaired dendritic cell function in patients with hepatitis B virus infection. (2019)
  • Author(s): Yonejima A, Mizukoshi E, Tamai T, Nakagawa H, Kitahara M, Yamashita T, Arai K, Terashima T, Iida N, Fushimi K, Okada H, Yamashita T, Sakai Y, Honda M, Kaneko S.
  • Journal Title: Hepatology Volume: 10.1002/hep Issue: 1 Pages: 30637-30637
  • DOI: 10.1002/hep.30637
  • Peer Reviewed / Open Access
• [Journal Article] Notch signaling facilitates hepatitis B virus covalently closed circular DNA transcription via cAMP response element-binding protein with E3 ubiquitin ligase-modulation (2019)
  • Author(s): Wang Zijing、Kawaguchi Kazunori、Honda Masao、Hashimoto Shinichi、Shirasaki Takayoshi、Okada Hikari、Orita Noriaki、Shimakami Tetsuro、Yamashita Taro、Sakai Yoshio、Mizukoshi Eishiro、Murakami Seishi、Kaneko Shuichi
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 1621-1621
  • DOI: 10.1038/s41598-018-38139-5
  • Peer Reviewed / Open Access
• [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] Prevention of hepatocellular carcinoma by targeting MYCN-positive liver cancer stem cells with acyclic retinoid (2018)
  • Author(s): Qin XY, Suzuki H, Honda M, Okada H, Kaneko S, Inoue I, Ebisui E, Hashimoto K, Carninci P, Kanki K, Tatsukawa H, Ishibashi N, Masaki T, Matsuura T, Kagechika H, Toriguchi K, Hatano E, Shirakami Y, Shiota G, Shimizu M, Moriwaki H, Kojima S
  • Journal Title: Proc Natl Acad Sci U S A Volume: 115 Issue: 19 Pages: 4969-4974
  • DOI: 10.1073/pnas.1802279115
  • 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] Serum cytokine profiles predict survival benefits in patients with advanced hepatocellular carcinoma treated with sorafenib: a retrospective cohort study. (2017)
  • Author(s): Hayashi T, Yamashita T, Terashima T, Suda T, Okada H, Asahina Y, Hayashi T, Hara Y, Nio K, Sunagozaka H, Takatori H, Arai K, Sakai Y, Yamashita T, Mizukoshi E, Honda M, Kaneko S.
  • Journal Title: BMC Cancer Volume: 17 Issue: 1 Pages: 870-870
  • DOI: 10.1186/s12885-017-3889-x
  • 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] Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma. (2017)
  • Author(s): 4.Hayashi T, Yamashita T, Okada H, Nio K, Hara Y, Nomura Y, Hayashi T, Asahina Y, Yoshida M, Oishi N, Sunagozaka H, Takatori H, Honda M, Kaneko S.
  • Journal Title: Cancer Cell International Volume: 17 Pages: 94-94
  • Peer Reviewed
• [Journal Article] Sorafenib suppresses extrahepatic metastasis de novo in hepatocellular carcinoma through inhibition of mesenchymal cancer stem cells characterized by the expression of CD90. (2017)
  • Author(s): 5.Yoshida M, Yamashita T, Okada H, Oishi N, Nio K, Hayashi T, Nomura Y, Hayashi T, Asahina Y, Ohwada M, Sunagozaka H, Takatori H, Colombo F, Porretti L, Honda M, Kaneko S.
  • Journal Title: Scientific Reports. Volume: 12;7(1) Issue: 1 Pages: 11292-11292
  • DOI: 10.1038/s41598-017-11848-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Novel mTOR Inhibitor; Anthracimycin for the Treatment of Human Hepatocellular Carcinoma. (2017)
  • Author(s): 6.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 Research Volume: vol. 37 no. 7 Pages: 3397-3403
  • Peer Reviewed
• [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] Long-Term Administration of Eicosapentaenoic Acid Improves Post-Myocardial Infarction Cardiac Remodeling in Mice by Regulating Macrophage Polarization. (2017)
  • Author(s): Takamura M, Kurokawa K, Ootsuji H, Inoue O, Okada H, Nomura A, Kaneko S, Usui S.
  • Journal Title: J Am Heart Assoc Volume: 21 Issue: 2
  • DOI: 10.1161/jaha.116.004560
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Levocarnitine improves liver histology and the development of hepatocellular carcinoma in the atherogenic high-fat diet NASH-HCC mouse model (2018)
  • Author(s): Hikari Okada, Masao Honda, Hajime Sunakozaka, Shuichi Kaneko
  • Organizer: アメリカ肝臓学会(AASLD)
  • Int'l Joint Research
• [Presentation] 1.Promoted liver fibrosis and malignant phenotype in HCV/PDGF-C transgenic mice are accompanied by abnormal expression of the glycolysis-related gene pyruvate kinase M (2017)
  • Author(s): 岡田光、本多政夫、Jean S Campbell、酒井佳夫、山下太郎、川口和則、田中卓二、金子周一
  • Organizer: アメリカ肝臓学会（AASLD）
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] 肝細胞癌株、およびそれを用いた肝細胞癌発症動物モデル (2017)
  • Inventor(s): 金子周一、本多政夫、山下太郎、岡田光、村居和寿、院南結香
  • Industrial Property Rights Holder: 金子周一、本多政夫、山下太郎、岡田光、村居和寿、院南結香
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017
• [Patent(Industrial Property Rights)] 抗がん剤及び新規医薬のスクリーニング方法 (2017)
  • Inventor(s): 山下太郎、金子周一、本多政夫、清木元治、岡田光
  • Industrial Property Rights Holder: 山下太郎、金子周一、本多政夫、清木元治、岡田光
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017