Comprehensive analyses for the mechanism of PIVKA-II production from hepatocellular carcinoma

• Project/Area Number: 23591005
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Research Institute, International Medical Center of Japan
• Principal Investigator: MURATA Kazumoto 独立行政法人国立国際医療研究センター, その他部局等, その他 (40345971)
• Co-Investigator(Kenkyū-buntansha): IMAMURA Masatoshi 国立国際医療研究センター, 国府台病院, 医長 (60445129)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 肝癌 / 腫瘍マーカー / PIVKA-II / EMT

Research Abstract

PIVKA-II is generally used in hepatocellular carcinoma (HCC) clinic, but precise mechanism of PIVKA-II production is still unkown. We have demonstrated that PIVKA-II was produced when HCC became metastatic phenotype (epithelial mesenchymal transition: EMT) that was impaired uptake of vitamin K by actin rearrangement. In this project, we demonstrated that further EMT caused impairment of liver specific protein synthesis, resulting in impairment of PIVKA-II production even though HCC still grew. Moreover, findings in enhanced ultrasonography well-correlated with PIVKA-II production in surgically resected HCC. Taken together, PIVKA-II could be an biological marker for HCC as well as a tumor marker of HCC.

Research Products

• [Journal Article] Ex vivo induction of IFN-λ3 by a TLR7 agonist determines response to Peg-IFN/ ribavirin therapy in chronic hepatitis C patients (2014)
  • Author(s): Murata K, Sugiyama M, Kimura T, Yoshio S, Kanto T, Kirikae I, Saito H, Aoki Y, Hiramine S, Matsui T, Ito K, Korenaga M, Imamura M, Masaki N, Mizokami M
  • Journal Title: J Gastroenterol Volume: 49(1) Issue: 1 Pages: 126-37
  • DOI: 10.1007/s00535-013-0814-1
  • Peer Reviewed
• [Journal Article] Risk factors for long-term persistence of serum hepatitis B surface antigen following acute hepatitis B virus infection in Japanese adults (2014)
  • Author(s): Ito K, Yotsuyanagi H, Yatsuhashi H, Karino Y, Takikawa Y, Saito T, Arase Y, Imazeki F, Kurosaki M, Umemura T, Ichida T, Toyoda H, Yoneda M, Mita E, Yamamoto K, Michitaka K, Maeshiro T, Tanuma J, Tanaka Y, Sugiyama M, Murata K, Masaki N, Mizokami M; Japanese AHB Study Group
  • Journal Title: Hepatology Volume: 59 Issue: 1 Pages: 89-97
  • DOI: 10.1002/hep.26635
  • Peer Reviewed
• [Journal Article] Human blood dendritic cell antigen 3 (BDCA3)(+) dendritic cells are a potent producer of interferon-λ in response to hepatitis C virus (2013)
  • Author(s): Yoshio S, Kanto T, Kuroda S, Matsubara T, Higashitani K, Kakita N, Ishida H, Hiramatsu N, Nagano H, Sugiyama M, Murata K, Fukuhara T, Matsuura Y, Hayashi N, Mizokami M, Takehara T
  • Journal Title: Hepatology Volume: 57 Issue: 5 Pages: 1705-15
  • DOI: 10.1002/hep.26182
  • Peer Reviewed
• [Journal Article] In vitroの系からみたPIVKA-IIと脈管侵襲 (2013)
  • Author(s): 村田一素
  • Journal Title: 肝胆膵 Volume: 66 Pages: 909-915
• [Journal Article] PIVKA-IIの産生機序と癌転移能との関連.ウイルス肝炎 (2013)
  • Author(s): 村田一素
  • Journal Title: 肝癌の病態と治療(第29回犬山シンポジウム)
• [Journal Article] Scirrhous colonic metastasis from lobular carcinoma of breast (2013)
  • Author(s): Takeda T, Murata K, Chatani N, Aoki Y, Yada T, Aoki Y, Koizuka H, Korenaga M, Imamura M, Kanto T, Masaki N, Ishida T, Watanabe S, Mizokami M, Uemura N
  • Journal Title: Clin J Gastroenterol Volume: 6 Pages: 291-294
  • Peer Reviewed
• [Journal Article] B型肝炎ウイルス感染における宿主免疫応答の重要性－特にNKT細胞の関与について－ (2013)
  • Author(s): 村田一素
  • Journal Title: 肝臓 Volume: 54 Pages: 7-18
  • NAID: 10031144315
  • Peer Reviewed
• [Journal Article] Hepatitis B virus-induced lipid alterations contribute to natural killer T cell-dependent protective immunity (2012)
  • Author(s): Zeissig S, Murata K, Sweet L, Publicover J, Hu Z, Kaser A, Bosse E, Hussain MM, Balschun K, Rocken C, Arlt A, Gunther R, Hampe J, Schreiber S, Baron JL, Moody DB, Liang TJ, Blumberg RS.
  • Journal Title: Nat Med Volume: 18 Issue: 7 Pages: 1060-1068
  • DOI: 10.1038/nm.2811
• [Journal Article] Factors responsible for the discrepancy between IL28B polymorphism prediction and the viral response to peginterferon plus ribavirin therapy in Japanese chronic hepatitis C patients (2012)
  • Author(s): Saito H, Ito K, Sugiyama M, Matsui T, Aoki Y, Imamura M, Murata K, Masaki N, Nomura H, Adachi H, Hige S, Enomoto N, Sakamoto N, Kurosaki M, Mizokami M, Watanabe S
  • Journal Title: Hepatol Res Volume: 42(10) Issue: 10 Pages: 958-65
  • DOI: 10.1111/j.1872-034x.2012.01013.x
  • Peer Reviewed
• [Journal Article] Development of specific and quantitative real-time detection PCR and immunoassays for λ3-interferon (2012)
  • Author(s): Sugiyama M, Kimura T, Naito S, Mukaide M, Shinauchi T, Ueno M, Ito K, Murata K, Mizokami M
  • Journal Title: Hepatol Res Volume: 42(11) Issue: 11 Pages: 1089-99
  • DOI: 10.1111/j.1872-034x.2012.01032.x
  • Peer Reviewed
• [Journal Article] LecT-Hepa, a glyco-marker derived from multiple lectins, as a predictor of liver fibrosis in chronic hepatitis C patients (2012)
  • Author(s): Ito K, Kuno A, Ikehara Y, Sugiyama M, Saito H, Aoki Y, Matsui T, Imamura M, Korenaga M, Murata K, Masaki N, Tanaka Y, Hige S, Izumi N, Kurosaki M, Nishiguchi S, Sakamoto M, Kage M, Narimatsu H, Mizokami M
  • Journal Title: Hepatology Volume: 56 Issue: 4 Pages: 1448-56
  • DOI: 10.1002/hep.25815
  • Peer Reviewed
• [Journal Article] LecT-Hepa, a glyco-marker derived from multiple lectins, as a predictor of liver fibrosis in chronic hepatitis C patients. (2012)
  • Author(s): Ito K, Kuno A, Ikehara Y, Sugiyama M, Saito H, Aoki Y, Matsui T, Imamura M, Korenaga M, Murata K, et al
  • Journal Title: Hepatology Volume: in press
  • Peer Reviewed
• [Journal Article] Factors responsible for the discrepancy between IL28B polymorphism prediction and the viral response to peginterferon plus ribavirin therapy in Japanese chronic hepatitis C patients. (2012)
  • Author(s): Saito H, Ito K, Sugiyama M, Matsui T, Aoki Y, Imamura M, Murata K, Masaki N, Nomura H, Adachi H, Hige S, Enomoto N, Sakamoto N, Kurosaki M, Mizokami M, Watanabe S.
  • Journal Title: Hepatol Res Volume: in press
  • Peer Reviewed
• [Journal Article] The rs8099917 polymorphism, when determined by a suitable genotyping method, is a better predictor for response to pegylated alpha interferon/ribavirin therapy in Japanese patients than other single nucleotide polymorphisms associated with interleukin-28B (2011)
  • Author(s): Ito K, Higami K, Masaki N, Sugiyama M, Mukaide M, Saito H, Aoki Y, Sato Y, Imamura M, Murata K, Nomura H, Hige S, Adachi H, Hino K, Yatsuhashi H, Orito E, Kani S, Tanaka Y, Mizokami M
  • Journal Title: J Clin Microbiol Volume: 49 Issue: 5 Pages: 1853-60
  • DOI: 10.1128/jcm.02139-10
• [Journal Article] Phenotype-dependent production of des-γ-carboxy prothrombin in hepatocellular carcinoma (2011)
  • Author(s): Suzuki H
  • Journal Title: J Gastroentero Volume: 46 Issue: 10 Pages: 1219-1229
  • DOI: 10.1007/s00535-011-0432-8
  • Peer Reviewed
• [Journal Article] Easy-to-use phylogenetic analysis system for hepatitis B virus infection (2011)
  • Author(s): Sugiyama M, Inui A, Shin-IT, Komatsu H, Mukaide M, Masaki N, Murata K, Ito K, Nakanishi M, Fujisawa T, Mizokami M
  • Journal Title: Hepatol Res Volume: 41(10) Issue: 10 Pages: 936-945
  • DOI: 10.1111/j.1872-034x.2011.00859.x
  • NAID: 10031144168
  • Peer Reviewed
• [Journal Article] Prevalence of amino acid mutation in hepatitis C virus core region among Japanese volunteer blood donors (2011)
  • Author(s): Furui Y, Mizokami M, et al
  • Journal Title: Journal of Medical Virology Volume: 83 Issue: 11 Pages: 1924-1929
  • DOI: 10.1002/jmv.22216
  • Peer Reviewed
• [Journal Article] Phenotype-dependent production of des-gamma carboxy prothrombin in hepatocellular carcinoma (2011)
  • Author(s): Suzuki H, Murata K, Gotoh T, Kusano M, Okano H, Oyamada T, Yasuda Y, Imamura M, Kudo M, Mizokami M, Sakamoto A
  • Journal Title: J Gastroenterol Volume: 46 Pages: 1219-1229
  • Peer Reviewed
• [Journal Article] Th rs8099917 polymorphism, determined by a suitable genotyping method, is a better predictor for response to pegylated interferon-/ribavirin therapy in Japanese patients than other SNPs associated with IL28B (2011)
  • Author(s): Ito K, Higami K, Masaki N, Sugiyama M, Mukaide M, Saito H, Aoki Y, Sato Y, Imamura M, Murata K, Nomura H, Hige S, Adachi H, Hino K, Yatsuhashi H, Orito E, Kani S, Tanaka Y, Mizokami M
  • Journal Title: J Clin Microbiol Volume: 49 Pages: 1853-1860
  • Peer Reviewed
• [Journal Article] Easy-to-use phylogenetic analysis system for hepatitis B virus infection (2011)
  • Author(s): Sugiyama M, Inui A, Shin-I T, Komatsu H, Mukaide M, Masaki N, Murata K, Ito K, Nakanishi M, Fujisawa T, Mizokami M
  • Journal Title: Hepatol Res Volume: 41 Pages: 936-945
  • Peer Reviewed
• [Presentation] B型急性肝炎におけるnatural killer T (NKT)細胞活性化機序 (2013)
  • Author(s): 村田一素、T. Jake Liang、溝上雅史
  • Organizer: 日本肝臓学会
  • Place of Presentation: 東京
• [Presentation] Ex vivo induction of IFN-lambda3 by a TLR7 agonist determines response to Peg-IFN/RBV therapy in chronic hepatitis C patients (2013)
  • Author(s): Murata K, Sugiyama M, Kimura T, Yoshio S, Kanto T, Asano M, Aoki Y, Takeda T, Korenaga M, Imamura M, Masaki N, Mizokami M
  • Organizer: The 19th Annual Meeting of the Korean Association for the Study of the Liver
  • Place of Presentation: Seoul
• [Presentation] Pre-treatment levels of serum IFN-lambda3 more accurately predict sustained virological response by pegylated interferon/ribavirin therapy than IL28B genotyping in chronic hepatitis C patients (2013)
  • Author(s): Aoki Y, Murata K,, Sugiyama M, Kimura T, Takeda T, Yoshio S, Yamagiwa Y, Korenaga M, Imamura M, Kanto T, Masaki N, Mizokami M
  • Organizer: The 64th annual meeting of the American association for the study of liver diseases
  • Place of Presentation: Washington DC
• [Presentation] IL28B遺伝子多型による治療効果予測不一致に寄与する宿主因子の検討 (2012)
  • Author(s): 村田一素、杉山真也、溝上雅史
  • Organizer: 第16回日本肝臓学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2012-10-10
• [Presentation] PIVKA-IIは、脈管侵襲のバイオマーカーになりうるか? (2012)
  • Author(s): 村田一素
  • Organizer: 第16回日本肝臓学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2012-10-10
• [Presentation] 肝癌におけるPIVKA-II産生機序とその臨床的意義 (2012)
  • Author(s): 村田一素
  • Organizer: 第29回犬山シンポジウム
  • Place of Presentation: 岐阜
  • Year and Date: 2012-08-02
• [Presentation] ソラフェニブ治療でなぜPIVKA-IIが上昇するのか? (2012)
  • Author(s): 村田一素
  • Organizer: 第6回日本肝がん分子標的治療研究会
  • Place of Presentation: 神奈川
  • Year and Date: 2012-06-16
• [Presentation] PIVKA-IIの産生機序とその臨床的意義 (2012)
  • Author(s): 村田一素
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 金沢
  • Year and Date: 2012-06-07
• [Presentation] Interferon-λ3 determines response to pegylated interferon/ribavirin therapy in chronic hepatitis C (2012)
  • Author(s): Murata K, Sugiyama M, Kimura T, Yoshio S, Kanto T, Aoki Y, Hiramine S, Matsui T, Korenaga M, Imumura M, Masaki N, Mizokami M.
  • Organizer: The 63^<th> annual meeting of the American association for the study of liver diseases
  • Place of Presentation: Boston
• [Presentation] Different amount of IFN-l3 determines the outcome of Peg-IFN/RBV therapy in HCV patients (2012)
  • Author(s): Murata K, Sugiyama M, Kimura T, Yoshio S, Kanto T, Asano M, Aoki Y, Takeda T, Korenaga M, Imamura M, Masaki N, Mizokami M.
  • Organizer: The 10^<th> JSH Single Topic Conference"Hepatitis C : Best Practice Based on Science
  • Place of Presentation: Tokyo
• [Presentation] PIVKA-IIの産生機序とその臨床的意義 (2012)
  • Author(s): 村田一素
  • Organizer: 第48回 日本肝臓学会総会 ランチョンセミナー
  • Place of Presentation: 金沢
  • Invited
• [Presentation] ソラフェニブ治療でなぜPIVKA-IIが上昇するのか？ (2012)
  • Author(s): 村田一素
  • Organizer: 第6回 日本肝がん分子標的治療研究会
  • Place of Presentation: 箱根
  • Invited
• [Presentation] 肝癌におけるPIVKA-II産生機序とその臨床的意義 (2012)
  • Author(s): 村田一素
  • Organizer: 第29回 犬山シンポジウムサテライトシンポジウム
  • Place of Presentation: 犬山
  • Invited
• [Presentation] PIVKA-IIの産生機序とその臨床的意義 (2011)
  • Author(s): 村田一素
  • Organizer: 第47回日本肝癌研究会
  • Place of Presentation: 静岡
  • Year and Date: 2011-07-29
• [Presentation] PIVKA-IIの産生機序とその臨床的意義 (2011)
  • Author(s): 村田一素
  • Organizer: 日本肝癌研究会(招待講演)
  • Place of Presentation: 静岡
• [Presentation] Induction of interleukin-28B by ex vivo stimulation of peripheral blood mononuclear cells predicts the efficacy of pegylated interferon-alpha/ribavirin therapy in chronic hepatitis C (2011)
  • Author(s): Murata K, Sato Y, Kirikae I, Ogami T, Saito H, Aoki Y, Matsui T, Ito K, Imamura M, Masaki N, Mizokami M
  • Organizer: AASLD
  • Place of Presentation: サンフランシスコ
• [Book] ウイルス肝炎・肝癌の病態と治療 (2013)
  • Author(s): 村田一素
  • Total Pages: 208
  • Publisher: 株式会社メディカルトリビューン
• [Book] 肝細胞がんのVascular Invasion（In vitroの系からみたPIVKA-IIと脈管侵襲） (2013)
  • Author(s): 村田一素
  • Publisher: アークメディア
• [Book] 伊豆肝臓カンファレンス（PIVKA-IIは、脈管侵襲のバイオマーカーになりうるか？） (2013)
  • Author(s): 村田一素
  • Publisher: アークメディア