Establishment of molecular basis for improving the treatment efficacy of chronic hepatitis C and preventing the occurrence of hepatocellular carcinoma.

• Project/Area Number: 24390187
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kanazawa University
• Principal Investigator: HONDA Masao 金沢大学, 保健学系, 教授 (00272980)
• Co-Investigator(Kenkyū-buntansha): HORIMOTO Katsuhisa 独立行政法人産業技術総合研究所, 創薬分子プロファイリング研究センター, 副センター長 (40238803)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2014: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000); Fiscal Year 2012: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: 肝炎 / 肝癌 / 自然免疫 / C型肝炎ウイルス / 肝浸潤リンパ球 / IL28B / 治療抵抗性 / C型肝炎 / 肝細胞癌

Outline of Final Research Achievements

The aim of this study is to investigate how IL28B is involved in the IFN resistance in patients of chronic hepatitis C. Comparison of gene expression profiling in PBMC and liver showed that the loss of correlation of ISGs expression between PBMC and liver in IL28B minor patients. Laser capture micro dissection analysis (LCM) of hepatocyte and liver infiltrated lymphocytes combined with immune-staining of surface marker of immune cells showed that infiltration of lymphocyte into the liver was impaired in patients with IL28B minor patients. Interestingly, non-canonical wnt ligand, WNT5A was up-regulated in the liver of IL28B minor patients and WNT5A induced ISGs and stress granule protein G3BP1, and increased HCV replication. WN5A repressed the expression of chemokines and play roles in the impairment of lymphocytes infiltration in liver. The analysis of newly developed IL28B knockout mouse showed that IL28B was directly involved in the lymphocytes infiltration in liver.

Research Products

• [Journal Article] Small tRNA-derived RNAs are increased and more abundant than microRNAs in chronic hepatitis B and C. (2015)
  • Author(s): Selitsky SR, Baran-Gale J, Honda M, Yamane D, Masaki T, Fannin EE, Guerra B, Shirasaki T, Shimakami T, Kaneko S, Lanford RE, Lemon SM, Sethupathy P.
  • Journal Title: Sci Rep. Volume: 5 Issue: 1 Pages: 7675-7675
  • DOI: 10.1038/srep07675
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide association study identifies a PSMD3 variant associated with neutropenia in interferon-based therapy for chronic hepatitis C. (2015)
  • Author(s): Iio E, Matsuura K, Nishida N, Maekawa S, Enomoto N, Nakagawa M, Sakamoto N, Yatsuhashi H et al.
  • Journal Title: Hum Genet Volume: 134 Issue: 3 Pages: 279-289
  • DOI: 10.1007/s00439-014-1520-7
  • Peer Reviewed / Open Access
• [Journal Article] Characteristics of hepatic fatty acid compositions in patients with nonalcoholic steatohepatitis. (2015)
  • Author(s): Yamada K, Mizukoshi E, Sunagozaka H, Arai K, Yamashita T, Takeshita Y, Misu H, Takamura T, Kitamura S, Zen Y, Nakanuma Y, Honda M, Kaneko S.
  • Journal Title: Liver Int. Volume: 35(2) Issue: 2 Pages: 582-90
  • DOI: 10.1111/liv.12685
  • Peer Reviewed / Open Access
• [Journal Article] Blood neutrophil to lymphocyte ratio as a predictor in patients with advanced hepatocellular carcinoma treated with hepatic arterial infusion chemotherapy. (2014)
  • Author(s): Terashima T, Yamashita T, Iida N, Yamashita T, Nakagawa H, Arai K, Kitamura K, Kagaya T, Sakai Y, Mizukoshi E, Honda M, Kaneko S.
  • Journal Title: Hepatol Res. Volume: - Issue: 9 Pages: 949-959
  • DOI: 10.1111/hepr.12436
  • Peer Reviewed / Open Access
• [Journal Article] Impaired interferon signaling in chronic hepatitis C patients with advanced fibrosis via the transforming growth factor beta 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) Issue: 5 Pages: 1519-30
  • DOI: 10.1002/hep.27277
  • Peer Reviewed
• [Journal Article] Autoantibody status and histological variables influence biochemical response to treatment and long-term outcomes in Japanese patients with primary biliary cirrhosis. (2014)
  • Author(s): Nakamura M, Kondo H, Tanaka A, Komori A, Ito M, Yamamoto K, Ohira H, Zeniya M, Hashimoto E, Honda M, Kaneko S, Ueno Y, Kikuchi K, Shimoda S, Harada K, Arai K, Miyake Y, Abe M, Taniai M, Saibara T, Sakisaka S, Takikawa H, Onji M, Tsubouchi H, Nakanuma Y, Ishibashi H.
  • Journal Title: Hepatol Res. Volume: - Issue: 8 Pages: 846-855
  • DOI: 10.1111/hepr.12423
  • Peer Reviewed / Open Access
• [Journal Article] The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism : a randomised controlled trial (2014)
  • Author(s): Y Takeshita, T Takamura, M Honda, Y Kita, Y Zen, KI Kato, H Misu, T Ota, M Nakamura, K Yamada, H Sunagozaka, K Arai, T Yamashita, E Mizukoshi, S Kaneko
  • Journal Title: Diabetologia Volume: 57(5) Issue: 5 Pages: 878-90
  • DOI: 10.1007/s00125-013-3149-9
  • Peer Reviewed / Open Access
• [Journal Article] P53, hTERT, WT-1, and VEGFR2 are the most suitable targets for cancer vaccine therapy in HLA-A24 positive pancreatic adenocarcinoma. (2014)
  • Author(s): Terashima T, Mizukoshi E, Arai K, Yamashita T, Yoshida M, Ota H, Onishi I, Kayahara M, Ohtsubo K, Kagaya T, Honda M, Kaneko S.
  • Journal Title: Cancer Immunol Immunother. Volume: 63(5) Issue: 5 Pages: 479-89
  • DOI: 10.1007/s00262-014-1529-8
  • NAID: 120005464870
  • 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: Sci Rep. Volume: 4 Issue: 1 Pages: 4688-4688
  • DOI: 10.1038/srep04688
  • NAID: 120005774911
  • Peer Reviewed / Open Access
• [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): M Honda, T Shirasaki, T Shimakami, A Sakai, R Horii, K Arai, T Yamashita, Y Sakai, T Yamashita, H Okada, K Murai, M Nakamura, E Mizukoshi, S Kaneko
  • Journal Title: Hepatology Volume: 59(3) Issue: 3 Pages: 828-38
  • DOI: 10.1002/hep.26788
  • NAID: 120005447749
  • Peer Reviewed / Open Access
• [Journal Article] Gd-EOB-DTPA-enhanced magnetic resonance imaging and alpha-fetoprotein predict prognosis of early-stage hepatocellular carcinoma. (2014)
  • Author(s): Yamashita T, Kitao A, Matsui O, Hayashi T, Nio K, Kondo M, Ohno N, Miyati T, Okada H, Yamashita T, Mizukoshi E, Honda M, Nakanuma Y, Takamura H, Ohta T, Nakamoto Y, Yamamoto M, Takayama T, Arii S, Wang XW, Kaneko S
  • Journal Title: Hepatology Volume: in press Issue: 5 Pages: 1674-85
  • DOI: 10.1002/hep.27093
  • Peer Reviewed / Open Access
• [Journal Article] New susceptibility and resistance HLA-DP alleles to HBV-related diseases identified by a trans-ethnic association study in Asia. (2014)
  • Author(s): Nishida N, Sawai H, Kashiwase K, Minami M, Sugiyama M, Seto WK, Yuen MF, Posuwan N, Poovorawan Y, Ahn SH, Han KH, Matsuura K, Tanaka Y, Kurosaki M, Asahina Y, Izumi N, Kang JK, （省略）, Tokunaga K, and Mizokami M
  • Journal Title: PLoS One Volume: 9 Issue: 2 Pages: e86449-e86449
  • DOI: 10.1371/journal.pone.0086449
  • Peer Reviewed / Open Access
• [Journal Article] The transcription factor SALL4 regulates stemness of EpCAM-positive hepatocellular carcinoma. (2014)
  • Author(s): Zeng SS, Yamashita T, Kondo M, Nio K, Hayashi T, Hara Y, Nomura Y, Yoshida M, Hayashi T, Oishi N, Ikeda H, Honda M, and Kaneko S.
  • Journal Title: Journal of Hepatology Volume: 60 Issue: 1 Pages: 127-134
  • DOI: 10.1016/j.jhep.2013.08.024
  • NAID: 120005349158
  • Peer Reviewed
• [Journal Article] Feasibility and efficacy of hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma after sorafenib. (2013)
  • Author(s): Terashima T, Yamashita T, Arai K, Sunagozaka H, Kitahara M, Nakagawa H, Kagaya T, Mizukoshi E, Honda M, Kaneko S.
  • Journal Title: Hepatol Res. Volume: Oct 31 Issue: 12 Pages: 1-7
  • DOI: 10.1111/hepr.12266
  • NAID: 120005537892
  • Peer Reviewed / Open Access
• [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: J Virol Volume: 87(9) Issue: 9 Pages: 5270-5286
  • DOI: 10.1128/jvi.03022-12
  • Peer Reviewed
• [Journal Article] Gene expression profiling of hepatitis B- and hepatitis C-related hepatocellular carcinoma using graphical Gaussian modeling. (2013)
  • Author(s): Ueda T, Honda M, Horimoto K, Aburatani S, Saito S, Yamashita T, Sakai Y, Nakamura M, Takatori H, Sunagozaka H, Kaneko S.
  • Journal Title: Genomics. Volume: Apr;101(4) Issue: 4 Pages: 238-48
  • DOI: 10.1016/j.ygeno.2013.02.007
  • Peer Reviewed
• [Journal Article] Peretinoin, an acyclic retinoid, improves the hepatic gene signature of chronic hepatitis C following curative therapy of hepatocellular carcinoma. (2013)
  • Author(s): Honda M, Yamashita T, Yamashita T, Arai K, Sakai Y, Sakai A, Nakamura M, Mizukoshi E, Kaneko S.
  • Journal Title: BMC Cancer. Volume: 15 Issue: 1 Pages: 191-191
  • DOI: 10.1186/1471-2407-13-191
  • Peer Reviewed
• [Journal Article] ER stress induced impaired TLR signaling and macrophage differentiation of human monocytes. (2013)
  • Author(s): Komura T, Sakai Y, Honda M, Takamura T, Wada T, Kaneko S.
  • Journal Title: Cell Immunol Volume: 282(1) Issue: 1 Pages: 44-52
  • DOI: 10.1016/j.cellimm.2013.04.006
  • Peer Reviewed
• [Journal Article] Discrete nature of EpCAM(+) and CD90(+) cancer stem cells in human hepatocellular carcinoma. (2013)
  • Author(s): Yamashita T, Nakamoto Y, et al.
  • Journal Title: Hepatology Volume: 57 Issue: 4 Pages: 1484-1497
  • DOI: 10.1002/hep.26168
  • Peer Reviewed
• [Journal Article] Association of interleukin-28B genotype and hepatocellular carcinoma recurrence in patients with chronic hepatitis C. (2013)
  • Author(s): Hodo Y, Honda M, Tanaka A, Nomura Y, Arai K, Yamashita T, Sakai Y, Yamashita T, Mizukoshi E, Sakai A, Sasaki M, Nakanuma Y, Moriyama M, Kaneko S.
  • Journal Title: Clin Cancer Res. Volume: 19 Issue: 7 Pages: 1827-37
  • DOI: 10.1158/1078-0432.ccr-12-1641
  • Peer Reviewed
• [Journal Article] Adipose tissue-derived stem cells as a regenerative therapy for a mouse steatohepatitis-induced cirrhosis model (2013)
  • Author(s): A Seki, S Y akai, T Komura, A Nasti, K Yoshida, M Higashimoto, M Honda, S Usui, M Takamura, T Takamura, T Ochiya, K Furuichi, T Wada, S Kaneko
  • Journal Title: Hepatology Volume: 58(3) Issue: 3 Pages: 1133-42
  • DOI: 10.1002/hep.26470
  • Peer Reviewed
• [Journal Article] Adipose tissue derived stromal stem cell therapy in murine ConA-derived hepatitis is dependent on myeloid-lineage and CD4+ T-cell suppression. (2013)
  • Author(s): Higashimoto M, Sakai Y, Takamura M, Usui S, Nasti A, Yoshida K, Seki A, Komura T, Honda M, Wada T, Furuichi K, Ochiya T, Kaneko S.
  • Journal Title: Eur J Immunol Volume: 43 Issue: 11 Pages: 2956-68
  • DOI: 10.1002/eji.201343531
  • Peer Reviewed
• [Journal Article] Pro-angiogenic cytokines for prediction of outcomes in patients with advanced hepatocellular carcinoma. (2013)
  • Author(s): Miyahara K, Nouso K, Morimoto Y, Takeuchi Y, Hagihara H, Kuwaki K, Onishi H, Ikeda F, Miyake Y, Nakamura S, Shiraha H, Takaki A, Honda M, Kaneko S, Sato T, Sato S, Obi S, Iwadou S, Kobayashi Y, Takaguchi K, Kariyama K, Takuma Y, Takabatake H, Yamamoto K
  • Journal Title: Br J Cancer. Volume: 109(8) Issue: 8 Pages: 2072-8
  • DOI: 10.1038/bjc.2013.554
  • Peer Reviewed
• [Journal Article] microRNA-122 Abundance in Hepatocellular Carcinoma and Non-Tumor Liver Tissue from Japanese Patients with Persistent HCV versus HBV Infection. (2013)
  • Author(s): Spaniel C, Honda M, Selitsky SR, Yamane D, Shimakami T, Kaneko S, Lanford RE, Lemon SM.
  • Journal Title: PLoS One Volume: 8(10) Issue: 10 Pages: e76867-e76867
  • DOI: 10.1371/journal.pone.0076867
  • Peer Reviewed
• [Journal Article] Characterization of naturally occurring protease inhibitor-resistance mutations 1n genotype lb hepatitis C virus patients. (2012)
  • Author(s): Shindo H, Maekawa S, Komase K, Sueki R, Miura M, Kadokura M, Shindo K, Amemiya F; Kitamura T, Nakayama y Inoue T, S akamoto M, Okada SI, Asahina Y, Izumi N, Honda M, Kaneko S, Enomoto N.
  • Journal Title: Hepatol Int. Volume: 6(2) Pages: 482-490
  • Peer Reviewed
• [Journal Article] Guideline on the use of new anticancer drugs for the treatment of Hepatocellular Carcinoma 20 10 update. (2012)
  • Author(s): Kaneko S, Furuse J, Kudo M, Ikeda K, Honda M, et al.
  • Journal Title: Hepatol Res. Volume: 42(6) Pages: 523-542
  • NAID: 10031144267
  • Peer Reviewed
• [Journal Article] Coexpression network analysis in chronic hepatitis B and C hepatic lesion reveals distinct patterns of disease progression to hepatocellular carcinoma (2012)
  • Author(s): He D, Liu ZP, Honda M, Kaneko S, Chen L.
  • Journal Title: J Mol Cell Biol Volume: (Epub ahead of print) Issue: 3 Pages: 140-152
  • DOI: 10.1093/jmcb/mjs011
  • Peer Reviewed
• [Journal Article] Heterogeneous nuclear ribonucleoprotein A2/B1 in association with hTERT is a potential biomarker for hepatocellular carcinoma (2012)
  • Author(s): Mizuno H, Honda M, 他5名
  • Journal Title: Epub ahead of print Volume: (Epub ahead of print) Issue: 7 Pages: 1146-1155
  • DOI: 10.1111/j.1478-3231.2012.02778.x
  • Peer Reviewed
• [Journal Article] Acyclic retinoid targets platelet-derived growth factor signaling in the prevention of hepatic fibrosis and hepatocellular carcinoma development. (2012)
  • Author(s): Okada H, Honda M, Campbell JS, Sakai Y, Yamashita T, Takebuchi Y, Hada K, Shirasaki T, Takabatake R, Nakamura M, Sunagozaka H, Tanaka T, Fausto N, Kaneko S.
  • Journal Title: Cancer Res. Volume: 72 Issue: 17 Pages: 4459-4471
  • DOI: 10.1158/0008-5472.can-12-0028
  • Peer Reviewed
• [Journal Article] Beneficial effect of branched-chain amino acid supplementation on glycemic control in chronic hepatitis C patients with insulin resistance : Implications for type 2 diabetes. Metabolism (2012)
  • Author(s): Honda M, (他12名, 12番目)
  • Journal Title: Epub ahead of print Volume: (Epub ahead of print) Issue: 10 Pages: 1388-94
  • DOI: 10.1016/j.metabol.2012.03.011
  • Peer Reviewed
• [Journal Article] Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population. (2012)
  • Author(s): Nakamura M
  • Journal Title: Am J Hum Genet. Volume: 91 Issue: 4 Pages: 721-728
  • DOI: 10.1016/j.ajhg.2012.08.010
  • Peer Reviewed
• [Journal Article] Expression of Chondroitin-glucuronate C5-epimerase and Cellular Immune Responses in Patients with Hepatocellular Carcinoma (2012)
  • Author(s): 水腰英四郎, 伏見一美
  • Journal Title: Liver International Volume: 32 Issue: 10 Pages: 1516-1526
  • DOI: 10.1111/j.1478-3231.2012.02853.x
  • NAID: 120004997021
  • Peer Reviewed
• [Journal Article] Genome-wide association study confirming association of HLA-DP with protection against chronic hepatitis B and viral clearance in Japanese and Korean. (2012)
  • Author(s): Nishida N, Asahina Y, Mizokami M et al
  • Journal Title: PLoS One Volume: 7 Issue: 6 Pages: 1-8
  • DOI: 10.1371/journal.pone.0039175
  • Peer Reviewed
• [Journal Article] No association for Chinese HBV-related hepatocellular carcinoma susceptibility SNP in other East Asian populations. (2012)
  • Author(s): Sawai H, Asahina Y, Tokunaga K et al
  • Journal Title: BMC Med Genet Volume: 13 Issue: 1 Pages: 47-47
  • DOI: 10.1186/1471-2350-13-47
  • Peer Reviewed
• [Journal Article] A randomized phase II trial of intra-arterial chemotherapy using SM-11355 (Miriplatin) for hepatocellular carcinoma (2011)
  • Author(s): Okusaka T, Kasugai H, Ishii H, Kudo M, Sata M, Tanaka K, Shioyama Y, Chayama K, Kumada H, Yoshikawa M, Seki T, Saito H, Hayashi N, Shiratori K, Okita K, Sakaida I, Honda M, Kusumoto Y, Tsutsumi T, Sakata K
  • Journal Title: Invest New Drugs (Epub 21 Dec.) Volume: (E-pub) Issue: 5 Pages: 2015-2025
  • DOI: 10.1007/s10637-011-9776-4
  • Peer Reviewed
• [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(HCV2014)
  • Place of Presentation: バンフ（カナダ）
  • Year and Date: 2014-09-09
• [Presentation] Hepatic interferon-stimulated genes are differentially regulated in the liver of chronic hepatitis C patients with different interleukin 28B genotypes. (2013)
  • Author(s): Honda M, Shirasaki T, Shimakami T, Sakai A, Horii R, Arai K, Yamashita T, Sakai Y, Yamashita T, Okada H, Nakamura M, Mizukoshi E, Kaneko S.
  • Organizer: HCV Meeting2013(第20回C型肝炎ウイルス及び関連ウイルスに関する国際会議)
  • Place of Presentation: Melbourne Convention and Exhibition Centre（オーストラリア）
• [Presentation] Hepatic interferon-stimulated genes are differentially regulated in the liver of chronic hepatitis C patients with different interleukin 28B genotypes. (2013)
  • Author(s): Honda M, Shirasaki T, Shimakami T, Sakai A, Horii R, Arai K, Yamashita T, Sakai Y, Yamashita T, Okada H, Nakamura M, Mizukoshi E, Kaneko S.
  • Organizer: AASLD2013(第64回米国肝臓学会)
  • Place of Presentation: Walter E. Washington Convention Center（アメリカ）
• [Presentation] Impaired infiltration of immune regulatory cells into liver lobules of chronic hepatitis C patients with interferon-resistant IL28B genotype. (2012)
  • Author(s): Masao Honda
  • Organizer: the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
  • Place of Presentation: Hynes Convention Center(USA)
  • Year and Date: 2012-11-11
• [Presentation] 次世代シークエンサーを用いた肝細胞癌の全エクソーム解析 (2012)
  • Author(s): 本多 政夫
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 石川県立音楽堂(石川県)
  • Year and Date: 2012-06-07
• [Presentation] 非環式レチノイド投与に伴う肝組織遺伝子発現変化と肝線維化・発癌抑制機構 (2012)
  • Author(s): 本多 政夫
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル(東京都)
  • Year and Date: 2012-04-20