Identification of biomarkers to predict HCC development after successful treatment of viral hepatitis

2017 Fiscal Year Annual Research Report

• Project/Area Number: 15H04809
• Research Institution: Kanazawa University
• Principal Investigator: 本多 政夫 金沢大学, 保健学系, 教授 (00272980)
• Co-Investigator(Kenkyū-buntansha): 堀本 勝久 国立研究開発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, 副研究センター長 (40238803)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 癌 / ゲノム / マイクロアレイ / メチル化 / 血管内皮 / shear stress

Outline of Annual Research Achievements

肝炎ウイルスの治療は進歩したが、肝炎ウイルス治療後にも肝発がんが認められる。肝炎ウイルス治療後ではウイルス制御により、肝炎が抑制された状態であることから、肝がんの発生にはエピゲノム修飾などによる不可逆的な遺伝子発現異常が大きく関わっている可能性がある。本研究は網羅的メチル化解析並びに遺伝子発現解析を行い、肝炎ウイルス治療後の肝発がん機序の解明と肝発がんを予測するバイオマーカーの同定を行うことを目的とした。
平成29年度は血管内皮細胞HUVEC及び類洞内皮細胞TMNK1細胞を用いてレンチウイルスシステムを用いたGene Xの過剰発現及び発現抑制実験を行った。Gene Xの発現はER及び細胞表面膜上に認められ、Gene Xの過剰発現によりIL6、IL8及びIL1βなどの炎症性サイトカインの発現が強く誘導された。一方、shRNAを用いたノックダウンによりそれらの遺伝子の発現抑制が認められた。また、肝癌細胞株Huh-7を用いたNOD/SCID Xenograftモデルにおいて、Gene X過剰発現HUVECを混合移植した場合の方が、コントロールHUVECを混合移植した場合に比べ、有意に腫瘍増殖が促進された。Gene XはERストレスにより発現誘導され、また、血管伸展刺激であるshear stressでも誘導された。従って、Gene Xは肝線維化進展に伴う血管のshear stressによって誘導されることにより、微小環境における炎症を惹起し、肝発癌及び腫瘍促進に働いていると考えられた。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Peretinoin, an Acyclic Retinoid, Inhibits Hepatitis B Virus Replication by Suppressing Sphingosine Metabolic Pathway In Vitro. (2018)
  • Author(s): Murai K, Shirasaki T, Honda M, Shimizu R, Shimakami T, Nakasho S, Shirasaki N, Okada H, Sakai Y, Yamashita T, Kaneko S
  • Journal Title: Int J Mol Sci Volume: 19 Pages: 108
  • DOI: 10.3390/ijms19020108
  • Peer Reviewed / Open Access
• [Journal Article] Light alcohol consumption has the potential to suppress hepatocellular injury and liver fibrosis in non-alcoholic fatty liver disease. (2018)
  • Author(s): Yamada K, Mizukoshi E, Seike T, Horii R, Kitahara M, Sunagozaka H, Arai K, Yamashita T, Honda M, Kaneko S
  • Journal Title: PLoS One Volume: 13 Pages: e0191026
  • DOI: 10.1371/journal.pone.0191026
  • Peer Reviewed / Open Access
• [Journal Article] Induction of IFN-λ3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection. (2018)
  • 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 YI, Dohi T, Shuno Y, Yano H, Mizokami M
  • Journal Title: Gut Volume: 67 Pages: 362-371
  • DOI: 10.1136/gutjnl-2016-312653
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide association studies identifyPRKCBas a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population (2017)
  • Author(s): Kawashima M, Hitomi Y, Aiba Y, Nishida N, Kojima K, Kawai Y, Nakamura H, 他71名、17番目
  • Journal Title: Hum Mol Genet. Volume: 26 Pages: 650-659
  • DOI: 10.1093/hmg/ddw406
  • Peer Reviewed / Open Access
• [Journal Article] Differential hepatitis C virus RNA target site selection and host factor activities of naturally occurring miR-122 3′ variants (2017)
  • Author(s): Yamane D, Selitsky SR, Shimakami T, Li Y, Zhou M, Honda M, Sethupathy P, Lemon
  • Journal Title: Nucleic Acids Res. Volume: 5 Pages: 4743-4755
  • DOI: 10.1093/nar/gkw1332
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genome-Wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection (2017)
  • Author(s): Matsuura K, Honda M, 他42名、28番目
  • Journal Title: Gastroenterology Volume: 152 Pages: 1383-1394
  • DOI: 10.1053/j.gastro.2017.01.041
  • Peer Reviewed / Open Access
• [Journal Article] Branched-chain amino acids prevent hepatic fibrosis and development of hepatocellular carcinoma in a non-alcoholic steatohepatitis mouse model. (2017)
  • Author(s): Takegoshi K, Honda M, Okada H, Takabatake R, Matsuzawa-Nagata N, Campbell JS,
  • Journal Title: Oncotarget Volume: 8 Pages: 18191-18205
  • DOI: 10.18632/oncotarget.15304
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deficiency of the hepatokine selenoprotein P increases responsiveness to exercise in mice through upregulation of reactive oxygen species and AMP-activated protein kinase in muscle. (2017)
  • Author(s): Misu H, Takayama H, Saito Y, Mita Y, Kikuchi A, Ishii KA, Chikamoto K, Kanamori T, Tajima N, Lan F, Takeshita Y, Honda M, Tanaka M, Kato S, Matsuyama N, Yoshioka Y, Iwayama K, Tokuyama K, Akazawa N, Maeda S, Takekoshi K, Matsugo S, Noguchi N, Kaneko S, Takamura T.
  • Journal Title: Nat Med Volume: 23 Pages: 508-516
  • DOI: 10.1038/nm.4295
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hepatitis B virus X protein induces hepatic stem cell-like features in hepatocellular carcinoma by activating KDM5B. (2017)
  • Author(s): Wang X, Oishi N, Shimakami T, Yamashita T, Honda M, Murakami S, Kaneko S.
  • Journal Title: World J Gastroenterol Volume: 23 Pages: 3252-3261
  • DOI: 10.3748/wjg.v23.i18.3252
  • Peer Reviewed / Open Access
• [Journal Article] De Novo Emergence of Mesenchymal Stem-Like CD105+ Cancer Cells by Cytotoxic Agents in Human Hepatocellular Carcinoma. (2017)
  • Author(s): Nomura Y, Yamashita T, Oishi N, Nio K, Hayashi T, Yoshida M, Hayashi T, Hashiba T, Asahina Y, Okada H, Sunagozaka H, Takatori H, Honda M, Kaneko S.
  • Journal Title: Transl Oncol Volume: 10 Pages: 184-189
  • DOI: 10.1016/j.tranon.2017.01.005
  • Peer Reviewed / Open Access
• [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 Pages: 39978-39993
  • DOI: 10.18632/oncotarget.18116
  • Peer Reviewed / Open Access
• [Journal Article] Beneficial Effect of Maintaining Hepatic Reserve during Chemotherapy on the Outcomes of Patients with Hepatocellular Carcinoma. (2017)
  • Author(s): Terashima T, Yamashita T, Arai K, Kawaguchi K, Kitamura K, Yamashita T, Sakai Y, Mizukoshi E, Honda M, Kaneko S
  • Journal Title: Liver Cancer Volume: 6 Pages: 236-249
  • DOI: 10.1159/000472262
  • Peer Reviewed / Open Access
• [Journal Article] ibavirin suppresses hepatic lipogenesis through inosine monophosphate dehydrogenase inhibition: Involvement of adenosine monophosphate-activated protein kinase-related kinases and retinoid X receptor α. (2017)
  • Author(s): Satoh S, Mori K, Onomura D, Ueda Y, Dansako H, Honda M, Kaneko S, Ikeda M, Kato N
  • Journal Title: Hepatol Commun Volume: 1 Pages: 550-563
  • DOI: 10.1002/hep4.1065
  • Peer Reviewed / Open Access
• [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 T, Shimakami T, Shirasaki T, Yamashita T, Mizukoshi E, Honda M, Kaneko S.
  • Journal Title: J Hepatol Volume: 67 Pages: 1108-1111
  • DOI: 10.1016/j.jhep.2017.07.014
  • 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
  • DOI: 10.21873/anticanres.11706
  • Peer Reviewed / Open Access
• [Journal Article] Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts hepatocellular carcinoma incidence and recurrence in nucleos(t)ide analogue therapy for chronic hepatitis B. (2017)
  • Author(s): Kawaguchi K, Honda M, Ohta H, Terashima T, Shimakami T, Arai K, Yamashita T, Sakai Y, Yamashita T, Mizukoshi E, Komura T, Unoura M, Kaneko S
  • Journal Title: J Gastroenterol Volume: - Pages: in press
  • DOI: 10.1007/s00535-017-1386-2
  • Peer Reviewed / Open Access
• [Journal Article] HBcrAg predicts hepatocellular carcinoma development: An analysis using time-dependent receiver operating characteristics. (2017)
  • Author(s): Kawaguchi K, Honda M, Kaneko S
  • Journal Title: Translational Cancer Research Volume: - Pages: in press
  • Peer Reviewed / Open Access
• [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): 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: Sci Rep Volume: 7 Pages: 11292
  • DOI: 10.1038/s41598-017-11848-z
  • Peer Reviewed / Open Access
• [Journal Article] The in vivo antitumor effects of type I-interferon against hepatocellular carcinoma: the suppression of tumor cell growth and angiogenesis. (2017)
  • Author(s): Enomoto H, Tao L, Eguchi R, Sato A, Honda M, Kaneko S, Iwata Y, Nishikawa H, Imanishi H, Iijima H, Tsujimura T, Nishiguchi S
  • Journal Title: Sci Rep. Volume: 7 Pages: 12189
  • DOI: 10.1038/s41598-017-12414-3
  • Peer Reviewed / Open Access
• [Journal Article] Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma. (2017)
  • Author(s): 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 Int Volume: 17 Pages: 94
  • DOI: 10.1186/s12935-017-0467-x
  • Peer Reviewed / Open Access
• [Journal Article] Clinical features of cystatin A expression in patients with pancreatic ductal adenocarcinoma. (2017)
  • Author(s): Komura T, Takabatake H, Harada K, Yamato M, Miyazawa M, Yoshida K, Honda M, Wada T, Kitagawa H, Ohta T, Kaneko S, Sakai Y
  • Journal Title: Cancer Sci Volume: 108 Pages: 2122-2129
  • DOI: 10.1111/cas.13396
  • 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 Pages: 16978
  • DOI: 10.1038/s41598-017-17285-2
  • Peer Reviewed / Open Access
• [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 Pages: 870
  • DOI: 10.1186/s12885-017-3889-x
  • Peer Reviewed / Open Access
• [Journal Article] The CD45+ fraction in murine adipose tissue derived stromal cells harbors immune-inhibitory inflammatory cells. (2017)
  • Author(s): Nasti A, Sakai Y, Seki A, Buffa GB, Komura T, Mochida H, Yamato M, Yoshida K, Ho TTB, Takamura M, Usui S, Wada T, Honda M, Kaneko S
  • Journal Title: Eur J Immunol Volume: 47 Pages: 2163-2174
  • DOI: 10.1002/eji.201646835
  • Peer Reviewed / Open Access
• [Presentation] Polyprenoic acid, the first-discovered hepatocyte nuclear factor 4 alpha-activating ligand, inhibits liver carcinogenesis. (2017)
  • Author(s): Taro Yamashita, Hikari Okada, Masao Honda, and Shuichi Kaneko
  • Organizer: AASLD 2017
  • Int'l Joint Research
• [Presentation] Unexpected Enhancement of Replication Capacity by Simeprevir for Simeprevir-Resistant Variants in Genotype 1a Hepatitis C Virus (2017)
  • Author(s): Tetsuro Shimakami, Kazuhisa Murai, Christoph Welsh, Takayosi Shirasaki, Masao Honda, and Shuichi Kaneko
  • Organizer: AASLD 2017
  • Int'l Joint Research
• [Presentation] Genome-wide methylation analysis identified a new intrahepatic angiogenesis marker associated with induction of tumorigenesis after successful eradication of HCV (2017)
  • Author(s): Masashi Nishikawa, Masao Honda, Hikari Okada, Kazunori Kawaguchi, Rika Horii, Tetsuro Shimakami, Kuniaki Arai, Taro Yamashita, Yoshio Sakai, Tatsuya Yamashita, Eishiro Mizukoshi, and Shuichi Kaneko
  • Organizer: AASLD 2017
  • Int'l Joint Research
• [Presentation] Nucleos(t)ide analogues and interferon affect intranuclear HBV genome in vitro via Notch signaling modification, independent of the ubiquitin-proteasome system (2017)
  • Author(s): Kazunori Kawaguchi, Zijing Wang, Masao Honda, Takayoshi Shirasaki, Hikari Okada, Tetsuro Shimakami, Kouki Nio, Kuniaki Arai, Taro Yamashita, Yoshio Sakai, Tatsuya Yamashita, Eishiro Mizukoshi, Shuichi Kaneko
  • Organizer: AASLD 2017
  • Int'l Joint Research
• [Presentation] Notch signaling inhibition is associated with degradation of intrahepatic HBV by ITCH in an ubiquitin-dependent manner (2017)
  • Author(s): Zijing Wang, Kazunori Kawaguchi, Masao Honda, Hikari Okada, Takayoshi Shirasaki, Tetsuro Shimakami, Shuichi Kaneko
  • Organizer: AASLD 2017
  • 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, Miwako Narita, Hirofumi Misu, Toshinari Takamura, Seishi Murakami, Shuichi Kaneko
  • Organizer: AASLD 2017
  • Int'l Joint Research
• [Presentation] Inhibitory effect of acyclic retinoid on hepatitis B virus replication (2017)
  • Author(s): Ryogo Shimizu, Masao Honda, Takayoshi Shirasaki, Tetsuro Shimakami, Kazuhisa Murai, Shuichi Kaneko
  • Organizer: AASLD 2017
  • Int'l Joint Research
• [Presentation] Osteopontin regulates IFN signaling and HCV replication in cancer stem cells (2017)
  • Author(s): Ryougo Shimizu, Masao Honda, Takayoshi Shirasaki, Tetsuro Shimakami, Taro Yamashita, Shuichi Kaneko
  • Organizer: AASLD 2017
  • Int'l Joint Research
• [Presentation] MicroRNA-10a is associated with the impaired liver functions in patients with advanced stage of chronic hepatitis C (2017)
  • Author(s): Rika Horii, Masao Honda, Takayoshi Shirasaki, Tetsuro Shimakami, Ryogo Shimizu, Shuichi Kaneko
  • Organizer: AASLD 2017
  • Int'l Joint Research
• [Presentation] Identification of novel HLA-A24-restricted endogenous CTL epitopes derived from HBV genotype C (2017)
  • Author(s): Eishiro Mizukosh, Kiichiro Kaji, Kazumi Fushimi, MasaakiKithara, Noriho Iida, Masao Honda, Shuichi Kaneko
  • Organizer: AASLD 2017
  • Int'l Joint Research
• [Presentation] Regulation of Hepatitis C Virus Infection by Long Non-Coding RNA (2017)
  • Author(s): Jyuria Kitabayashi, Tetsuro Shimakami, Takayosi Shirasaki, Kazuhisa Murai, Masao Honda, and Shuichi Kaneko
  • Organizer: AASLD 2017
  • Int'l Joint Research
• [Presentation] The utility of the serum C16:1n7/C16:0 ratio as a diagnostic marker of non-alcoholic steatohepatitis (2017)
  • Author(s): Eishiro Mizukoshi, Takuya Seike, Rika Horii, Takeshi Terashima, Norio iida, Masaaki Kitahara, Hajime Sunagozaka, Kuniaki Arai, Tatsuya Yamashita, Masao Honda, Shuichi Kaneko
  • Organizer: AASLD 2017
  • Int'l Joint Research
• [Presentation] Immunomodulation of aggressive liver cancer by EpCAM+ cancer stem cells thorough the activation of CCL20-CCR6 axis. (2017)
  • Author(s): Mika Ohwada, TaroYamashita, Hikari Okada, Kouki Nio, Masao Honda and Shuichi Kaneko
  • Organizer: AASLD 2017
  • Int'l Joint Research
• [Presentation] Serum Cytokine Profiles Predict Survival Benefits in Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib: a Retrospective Cohort Study (2017)
  • Author(s): Tsuyoshi Suda, Tomoyuki Hayashi, Taro Yamashita, Hikari Okada,Yoshirou Asahina, Takehiro Hayashi, Yasumasa Hara, Kouki Nio, Takeshi Terashima, Hajime Sunagozaka,Hajime Takatori, Kuniaki Arai1, Yoshio Sakai, Tatsuya Yamashita, Eishiro Mizukoshi, Masao Honda, Shuichi Kaneko
  • Organizer: AASLD 2017
  • Int'l Joint Research
• [Presentation] 7. mRNA for selenoprotein P, a hepatokine, binds RIG-I protein and inhibits the RIG-I-mediated type I interferon response (2017)
  • Author(s): Kazuhisa Murai, Masao Honda, Tetsuro Shimakami, Takayoshi Shirasaki, Hirofumi Misu, Toshinari Takamura, Stanley M. Lemon, Seishi Murakami, Shuichi Kaneko
  • Organizer: AASLD 2017
  • Int'l Joint Research
• [Presentation] IFN-λ3 induces dendritic cell maturation independent of type I IFN (2017)
  • Author(s): Shiho Tanaka, Masao Honda, Kazuhisa Murai, Tetsuro Shimakami, Takayoshi Shirasaki, Seishi Murakami, Shuichi Kaneko
  • Organizer: AASLD 2017
  • Int'l Joint Research
• [Presentation] Promoted liver fibrosis and malignant phenotype in HCV/PDGF-C transgenic mouse are accompanied by abnormal expression of the glycolysis-related gene pyruvate kinase M (2017)
  • Author(s): Hikari Okada, Masao Honda, Jean S Campbell, Yoshio Sakai, Taro Yamashita, Kazunori Kawaguchi, Takuji Tanaka, Shuichi Kaneko
  • Organizer: AASLD 2017
  • Int'l Joint Research