Analyses of the development of liver cancer and cirrhosis by using cytoglobin-deficient mice

2011 Fiscal Year Final Research Report

• Project/Area Number: 21390232
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Osaka City University
• Principal Investigator: KAWADA Norifumi 大阪市立大学, 大学院・医学研究科, 教授 (30271191)
• Co-Investigator(Kenkyū-buntansha): MORITA Takashi 大阪市立大学, 大学院・医学研究科, 教授 (70150349) ; TAMORI Akihiro 大阪市立大学, 大学院・医学研究科, 准教授 (30291595) ; ENOMOTO Masaru 大阪市立大学, 大学院・医学研究科, 准教授 (20423874)
• Project Period (FY): 2009 – 2011
• Keywords: サイトグロビン / 肝硬変 / 肝癌 / 線維芽細胞 / 動物モデル

Research Abstract

To clarify the molecular function of cytoglobin(Cygb) in vivo, we generated Cygb-deficient mice. Administration of diethylnitrosamine(25 ppm) induced the development of liver tumors(liver cancer and hemangioma) in all of the Cygb-deficient mice, which were accompanied by the accumulation of collagen and the increased mRNA expression of α-fetoprotein, interleukin-1β, and transforming growth factor-β・in the liver. Based on these findings, we concluded that Cygb-deficiency triggers dysregulation of oxidative stress and accelerates tumorigenesis of the liver. Cygb is a novel tumor-suppressor.

Research Products

• [Journal Article] Antifibrotic role of macrophage migration inhibitory factor : discovery of an unexpected function. Thuy le TT (2012)
  • Author(s): Kawada N.
  • Journal Title: Hepatology Volume: 55 Pages: 1295-7
• [Journal Article] Inflammation and fibrogenesis in steatohepatitis (2012)
  • Author(s): Fujii H, Kawada N.
  • Journal Title: J Gastroenterol Volume: 47 Pages: 215-25
• [Journal Article] N-Acetylglucosaminyltransferase V regulates TGF-βresponse in hepatic stellate cells and the progression of steatohepatitis (2012)
  • Author(s): Kamada Y, Mori K, Matsumoto H, Kiso S, Yoshida Y, Shinzaki S, Hiramatsu N, Ishii M, Moriwaki K, Kawada N, Takehara T, Miyoshi E.
  • Journal Title: Glycobiology Volume: 22 Pages: 778-87
• [Journal Article] MicroRNA-221/222 upregulation indicates the activation of stellate cells and the progression of liver fibrosis. (2012)
  • Author(s): Ogawa T, Enomoto M, Fujii H, Sekiya Y, Yoshizato K, Ikeda K, Kawada N.
  • Journal Title: Gut Volume: (in press)
• [Journal Article] Fascin, a novel marker of human hepatic stellate cells, may regulate their proliferation, migration, and collagen gene expression through the FAK-PI3K-Akt pathway (2012)
  • Author(s): Uyama N, Iimuro Y, Kawada N, Reynaert H, Suzumura K, Hirano T, Kuroda N, Fujimoto J.
  • Journal Title: Lab Invest Volume: 92 Pages: 57-71
• [Journal Article] Down-regulation of cyclin E1 expression by microRNA-195 accounts for interferon-β-induced inhibition of hepatic stellate cell proliferation (2011)
  • Author(s): Sekiya Y, Ogawa T, Iizuka M, Yoshizato K, Ikeda K, Kawada N.
  • Journal Title: J Cell Physiol Volume: 226 Pages: 2535-42
• [Journal Article] Promotion of liver and lung tumorigenesis in DEN-treated cytoglobin-deficient mice. Thuy le TT (2011)
  • Author(s): Morita T, Yoshida K, Wakasa K, Iizuka M, Ogawa T, Mori M, Sekiya Y, Momen S, Motoyama H, Ikeda K, Yoshizato K, Kawada N.
  • Journal Title: Am J Pathol Volume: 179 Pages: 1050-60
• [Journal Article] Cytoglobin expression of rectal subepithelial myofibroblasts : significant alterations of cytoglobin+stromal cells in long-standing ulcerative colitis (2011)
  • Author(s): Okayasu I, Mikami T, Yoshida T, Hana K, Yokozawa M, Sada M, Fujiwara M, Kawada N.
  • Journal Title: Histol Histopathol Volume: 26 Pages: 679-88
• [Journal Article] Evolution of hepatic fibrosis research (2011)
  • Author(s): Kawada N.
  • Journal Title: Hepatol Res Volume: 41 Pages: 199-208
• [Journal Article] Cytoglobin, a novel member of the globin family, protects kidney fibroblasts against oxidative stress under ischemic conditions (2011)
  • Author(s): Nishi H, Inagi R, Kawada N, Yoshizato K, Mimura I, Fujita T, Nangaku M.
  • Journal Title: Am J Pathol Volume: 178 Pages: 128-39
• [Journal Article] A human-type nonalcoholic steatohepatitis model with advanced fibrosis in rabbits (2010)
  • Author(s): Ogawa T, Fujii H, Yoshizato K, Kawada N
  • Journal Title: Am J Pathol Volume: 177 Pages: 153-65
• [Journal Article] Inhibition of pancreatic stellate cell activation by halofuginone prevents pancreatic xenograft tumor development (2010)
  • Author(s): Spector I, Honig H, Kawada N, Nagler A, Genin O, Pines M.
  • Journal Title: Pancreas Volume: 39 Pages: 1008-15
• [Presentation] Cytoglobin as a novel tumor suppressor in the liver (2011)
  • Author(s): Kawada N
  • Organizer: Le TT. AASLD
  • Place of Presentation: サンフランシスコ、USA
  • Year and Date: 2011-11-04
• [Presentation] Promotion of liver and lung tumorgenesis in DEN-treated cytoglobin-deficient mice (2011)
  • Organizer: 16^<th> International Symposium on Cells of the Heatic Sinusoid
  • Place of Presentation: イタリア、フロレンス
  • Year and Date: 2011-09-23
• [Remarks]
  • URL: http://www.med.osaka-cu.ac.jp/syoukaki/hepatology/index.html
• [Patent(Industrial Property Rights)] サイトグロビン遺伝子ノックアウト非ヒト癌モデル動物 (2010)
  • Inventor(s): 河田則文
  • Industrial Property Rights Holder: 河田則文
  • Industrial Property Number: 特願、2010-052244
  • Filing Date: 2010-03-09