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1998 Fiscal Year Final Research Report Summary

Molecular and cellular biological analyzes of morphogenesis modulated by HGF

Research Project

Project/Area Number 08408027
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional biochemistry
Research InstitutionOsaka University

Principal Investigator

NAKAMURA Toshikazu  Osaka University, Department of Oncology, Professor, 医学部, 教授 (00049397)

Co-Investigator(Kenkyū-buntansha) FUNAKOSHI Hiroshi  Osaka University, Dept of Oncology, Assisitant Prof., 医学部, 助手 (40273685)
KOSHIMIZU Uichi  Osaka University, Dept of Oncology, Assistant Prof., 医学部, 助手 (50281126)
MIYAMOTO Kazumasa  Osaka University, Dept of Oncology, Assistant Prof., 医学部, 助手 (60273679)
Project Period (FY) 1996 – 1998
KeywordsHGF / fatty liver / cirrhosis / chronic renal failure / cardiac infarction / gene therapy / brain ischemia / transgenic mice
Research Abstract

1. Rats fed ethanol-containing diets for 37 days showed remarkable increase in hepatic lipids and lipid droplet accumulation in the hepatocytes, indicating the onset of alcholic fatty liver. Administration of hepatocyte growth factor (HGF) for the last seven days of ethanol treatment markedly decreased hepatic lipids to the level lower than that seen before HGF treatment.
2. In a rat model of lethal liver cirrhosis produced by dimethylnitrosamine administrations, repeated transfections of the human HGF gene into skeletal muscles induced ahigh plasmalevel of human as well as endogeneous rat HGF, and tyrosine phosphorylation of the c-Met/HGR receptor. Transduction with the HGF gene also inhibited fibrogenesis and hepatocyte appoptosis, and produced the complete resolution of fibrosis in the cirrhotic liver, thereby improving the survival rate of rats with this severe illness.
3. The mice, a spontaneous mouse model for chronic renal disease (ICGN strain), progressively developed glomerular … More sclerotic injury, tubular atrophy and renal disfunction until they were 17 wk of age. Administration of HGF for 4-wk-periods(from weeks 14-17) prevented the progression of renal dysfunction and fibrosis in a spontaneous mouse model for chronic renal disease (ICGN strain).
4. HGF was produced in cardiomyocytes and cardiac endothelial cells in culture, and in viable border zone of reperfused myocardiac infarction. Administration of HGF and HGF gene markedly decreased infarct area and apoptotic cradiac cell death in rat postreperfusion myocardial injury, compared with saline treatment.
5. HGF prevented cerebral corteical neuronal cell induced by glutamate.
6. Continuous intra-ventricular administration of HGF by mini-pump attenuated delayed neuronal cell death of cerebral cortex in acute brain ischemic model.
7. We have previously demonstrated a four-kringle-containing fragment of HGF, HGF/NK4 inhibits invasion of tumors in vivo, as well as in vitro, and HGF/NK4 also competitively inhibited the binding of HGF to Met/HGF receptor on GB-d1 human gallbladder carcinoma cells, increased apoptosis of implanted GE-d1 apoptotic cell death and inhibited this tumor growth in vivo. In addition to the antagonistic activity against HGF, HGF/NK4 inhibited angiogenesis induced by FGF, VEGF and HGF in vitro and in vivo, and decreased growth size and angiogenesis of tumors, such as Luwis lung cancer cells, suggesting bipotential role of HGF for tumor grwoth and invasion. Less

  • Research Products

    (77 results)

All Other

All Publications (77 results)

  • [Publications] M.T.Donato et al.: "Human hepatocyle growth factor down regulated the expression of cytochrome P450 isozymes in human hepatocytes in primaoy culture." J.Pharmacl Exp.Therap.284. 760-767 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y.Yo et al.: "Actions of hepatocyte growth factor as a local modulator in the kidney : Potential role in pathogenesis of renal disease." Kindney Intern.53. 50-58 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] D.Schuppan et al.: "Collagens in the liver extracellular matrix hepatocyle growth factor." Gastroenterology.114. 139-152 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M.Lyon et al.: "Hepatocyte growth factor/scatter factor binds with high affinity to dermatan sulphate." J.Biol.Chem.273. 271-278 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] H.Li et al.: "Hepatocyte growht factor stimuolates invasion of gallbadder carcinoma cell lines in vitro." Clin.Exp.Metastasis.16. 74-82 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] S.Nakamura et al.: "A Novel vascular modulator, hepatocyte growth factor (HGF), as a potentlal index of the severity of hypertention." Biochem.Biophys.Res.Commun.242. 238-243 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K.Liu et al.: "Protamine enhances the proliferative activity of hepatocyte growth factor in rats." Am.J.Physiol.274. G21-G28 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] R.Gal-Levi et al.: "Hepatocyte growth factor plays a dual role in regulating skeletal muscle satellite cell proliferation and differentiation." Biochem.Biophys.Acta.1402. 39-51 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] T.Miyazawa et al.: "Protection of hippocampal neurons from ischemia-induced delayed neuronal death by hepatocyte growth factor : A novel neurotrophic factor." J.Celebral Blood Flow Metabolism.18. 345-348 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] H.Ohmichi et al.: "Hepatocyte growth factor (HGF) acts as a mesenchynal-derived morphogenic factor during fetal lung develpment." Development.125. 1315-1324 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] S.Mizuno et al.: "Hepatocyte growth factor prevents renal fibrosis and dysfunction in a mouse model of chronic renal-disease." J.Clin.Invest.101. 1827-1834 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] S.Yi et al.: "Paracrine effects of hepatocyte growth factor/scatter factor on non-small cell lung carcinoma cell lines." Brit.J.Cancer.77. 2162-2170 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K.Kosai et al.: "Hepatocyte growth factor abrogates Fas-induced lethal liver apoptosis in mice." Biochem.Biophys.Res.Commun.244. 683-690 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M.Suzuki et al.: "Stimulation by histamine of TPA-dependent hepatocyte growth factor production in promyelotic leukemia HL-60 cells." Biosci.Biotechnol.Biochem.62. 1399-1402 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] S.Tanimura et al.: "Activation of the 41-/43 kDa mitogen-activated protein kinase signaling pathway is required for hepatocyte growth factor-induced scattering." Oncogene. 17. 57-65 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] T.Motoi et al.: "Coexpression of hepatocyte growth factor and c-met proto-oncogene product in synovialsarcoma." Pathology Intern.48. 769-775 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K.Matsumoto et al.: "Cooperative interaction between α-chain and β-chain of HGF on c-Met receptor confers ligand-induced receptor tyrosine phosphorylation." J.Biol.Chem.273. 22913-22920 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K.Date et al.: "Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor." Oncogene. 17. 3045-3054 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y.Yo et al.: "Potential role of hepatocyte growth factor in the maintenance of renal structure : Anti-apoptotic action of HGF on epithelial cells." Kidney Intern.54. 1128-1138 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K-X.Liu et al.: "Ligand-induced down-regulation of receptor-mediated clearance of hepatocyte growth factor in rats." Am.J.Physiol.274. G21-G28 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] N.Nakano et al.: "Negative regulation of local hepatocyte growth factor (HGF) expression by angiotensin II and transforming growth factor-β in blood vessels." Hypertension. 32. 444-451 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] H.Takahashi et al.: "A novel transcript encoding truncated LIM-kinase 2 is specifically expressed in male germ cells undergaing meiosis." Biochem.Biophys.Res.Commun.249. 138-145 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] R.Paciucci et al.: "Activation of the UPA/UPA-R system and redistribution of E-cadherin are associated with HGF-induced motility of pancreas tumor cells." Am.J.Pathol.153. 201-212 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] A.Jikko et al.: "The role of hepatocyte growth factor in growth plate cartilage." J.Bone Miner.Metab.16. 170-177 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K.Sugahara et al.: "Elevation of serum human hepatocyte growth factor (HGF) level in patients with pneumonectomy during perioperative period." Intensive Care Med.24. 434-437 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] I.Weimar et al.: "Hepatocyte growth factor/scatter facotr (HGF/SF) affects proliferation and migration of myeloid leukemic cells." Leukemia. 12. 1195-1203 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] A.Bosch et al.: "Effects of keratinocyte and hepatocyte growth factor in vivo : Implications for retroviral-mediated gene transfer to liver." Human Gene Therapy. 9. 1747-1754 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] S.Nakamura et al.: "Hepatocyte growth factor as a potential index of complication in diabetes mellitus." J.Hypertension. 16. 2019-2026 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] T.Ueki et al.: "Hepatocyte growth factor gene therapy of liver cirrhosis in rats" Nature Medicine. 5. 226-230 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y.Liu et al.: "Upregulation of hepatocyte growth factor receptor : an amplification and targeting mechanism for hepatocyte growth factor action in acute renal failure." Kidney Intern.55. 442-453 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M.Tahara et al.: "Hepatocyte gowth factor leads to recovery from alcohol-induced fatty liver in rats." J.Clin.Invest.103. 313-320 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K.Matsumoto & T.Nakamura: "Hepatocyte growth factor and Met : Molecular dialogue for tissue organization and repair." Korean J.Biol.Sci.2. 1-8 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 中村敏一: "HGFの分子医学-病態生理・診断・治療-" メディカルレビュー社, 221 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K.Matsumoto & T.Nakamura: "The Proceedings of the Second International Symposium of Tissue Engineering for Therapeutic Use." Churchill Livingstone in press, (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M.T.Donato, et al.: "Human hepatocyte growth factor down regulated the expression of cytochrome P450 isozymes in human hepatocyted in primary culture" J.Pharmacl Exp.Therap.284. 760-767 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Y.Yo, et al.: "Actions of hepatocyte growth factor as alocal modulator in the kidney : Potential role in pathogenesis of renal disease." KIndney lntem.53. 50-58 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] D.Schuppan, et al.: "Collagens in the liver extracellular matrix hepatocyte growth factor." Gastroenterology. 114. 139-152 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] M.Lyon, et al.: "Hepatocyte growth factor/scatter factor binds with high affinity to dermatan sulphate." J.Biol.Chem.273. 271-278 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] H.Li, et al.: "Hepatocyte growth factor stimuolates invasion of gallbladder carcinoma cell lines in vitro." Clin.Exp.Metastasis.16. 74-82 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] S.Nakamura, et al.: "A Novel vascular modulator, hepatocyte growth factor (HGF), as a potential index of the severity of hypertention." Biochem.Biophys.Res.Commun.242. 238-243 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K.Liu, et al.: "Protamine enhances the proliferative activity of hepatocyte growth factor in rats." Am.J.Physiol.274. G21-G28 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] R.Gal-Levi, et al.: "Hepatocyte growht factor plays a dual role in regulating skeletal muxcke satellite cell proliferation and differentiation." Biochem.Biophys.Acta.1402. 39-51 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] T.Miyazawa, et al.: "Protection of hippocampal neurons from ischemia-induced delayd neuronal death by hepatocyte growth factor : A novel neurotrophic factor." J.Celebral Blood Flow Metabolism.18. 345-348 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] H.Ohmichi, et al.: "Hepatocyte growth factor (HGF) acts as a mesenchynal-derived morphogenic factor during fetallung develpment." Development. 125. 1315-1324 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] S.Mizuno, et al.: "Hepatocyte growth factor prevents renal fibrosis and dysfunction in a mouse model of chronio renal disease." J.Clin.Invest.101. 1827-1834 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] S.Yi, et al.: "Paracrineefects of hepatocyte growth factor/scatter factor on non-small cell lung carcinoma cell lines." Brit.J.Cancer.77. 2162-2170 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K.Kosai, et al.: "Hepatocyte growth factor abrogates Fas-induced lethal liver apoptosis in mice." Biochem.Biophys.Res.Commun.244. 683-690 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] M.Suzuki, et al.: "Stimulation by histamine of TPA-dependent hepatocyte growth factor production in promyelocytic leukemia HL-60 cells." Biosci.Biotechnol.Biochem.62. 1399-1402 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] S.Tanimura, et al.: "Activation of the 41-/43 kdDamitogen-activated protein kinase signaling pathway is required for hepatocyte growth factor-induced cell scattering." Oncogene.otechnol.Biochem.17. 57-65 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] T.Motoi, et al.: "Coexpression of hepatocyte growth factor and c-met proto-oncogene product in synovial sarcoma." Pathology Intem.48. 769-775 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K.Matsumoto, et al.: "Cooperative interaction betweenEphi-chain and E*-chain of HGF ON c-Met receptor confers ligand-induced receptor tyrosine phosphorylation and multiple biological responses." J.Biol.Chem.273. 22913-22920 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K.Date, et al.: "Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor." Oncogene. 17. 3045-3054 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Y.Yo, et al.: "Potential role of hepatocyte growth factor in the maintenance of renal structure : Anti-apoptotic action of HGF on epithelial cells." Kidney Intem.54. 1128-1138 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K-X.Liu, et al.: "Ligand-induced down-regulation of receptor-mediated clearance of hepatocyte growth factor in rats." Am.J.Physiol.274. G21-G28 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] N.Nakano, et al.: "Negative regulation of local hepatocyte growth factor (HGF) expression by angiotensin II and tranforming rowth factor-E* in blood vessels : Potential role of HGF in cardiovascular disease." Hypertension. 32. 444-451 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] H.Takahashi, et al.: "A novel transcript encoding truncated LIM-kinase 2 is specifically expressed in male germ cells undergaing meiosis." Biochem.Biophys.Res.Commun.249. 138-145 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] R.Paciucci, et al.: "Activation of the urokinase plasminogen activator/urokinase plasminogen activator receptor system and redistribution of E-cadherin are associated with hepatocyte growth factor-induced motility of pancreas tumor cells overexpressing Met." Am.J.Pathol.153. 201-212 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] A.Jikko, et al.: "The role of hepatocyte growth factor in growth plate cartilage." J.Bone Miner.Metab.16. 170-177 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K.Sugahara, et al.: "Elevation of serum human hepatocyte growth factor (HGF) level in patients with pneumonectomy during perioperative period." Intensive Care Med.24. 434-437 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] I.Weimar, et al.: "Hepatocyte growth factor/scattr facotr (HGF/SF) affects proliferation and migration of myeloid leukemic cells." Leukemia. 12. 1195-1203 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] A.Bosch, et al.: "Effects of keratinocyte and hepatocyte growth factor in vivo : Implications for retroviral-mediated gene transfer to liver." Human Gene Therapy. 9. 1747-1754 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] S.Nakamura, et al.: "Hepatocyte growth factor as a potential index of complication in diabetes mellitus." J.Hypertensions.16. 2019-2026 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] W.G.Jiang, et al.: "Hepatocyte growth factor/scatter factor, its molecular, cellular and clinical impacts in cancer." Crit.Rev.in Oncogenesis/Hematology. 9. (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K.Matsumoto and T.Nakamura: "Hepatocyte growth factor and Met : Molecular dialogue for tissue organization and repair." Korean J.Biol.Sci.2. 1-8 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] T.Ueki, et al.: "Hepatocyte growth factor gene therapy of liver cirrhosis in rats." Nature Medicine. 5. 226-230 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Y.Liu, et al.: "Upregulation of hepatocyte growth factor receptor : and amplification and targeting mechanism for hepato cyte growth factor action in acute renal failure." Kidney Intem.55. 442-453 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] M.Tahara, et al.: "Hepatocyte gowth factor leads to recovery from alcohol-induced fatty liver in rats." J.Clin.Invest.103. 313-320 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K.Liu, et al.: "Change in hepatic handling of hepatocyte growth factor during liver regeneration in rats." Am.J.Physiol.269(in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] F.Tamura, et al.: "FK506 promotes liver regeneration by suppressing natural killer cell activity." J.Gastroenterol.and Hepatol.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] A.Uchiyama, et al.: "Significance of locally -secreted hepatocyte growth factor after thoricic cancer surgery as a stimulator for postoperative cancer invasion." Jpn.J.Clin.Oncol.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] S.Takada, et al.: "Effect of hepatocyte growth factor on tacrolimus (FK506)-induced nephrotoxicity in spontaneously hypertensive rats." Transplant.Intem. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] H.Ueda, et al.: "Gene transfection of hepatocyte growth factor attenuates reperfusion injury in the heart." Annals.Thoracic Surg.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] J.Wojta, et al.: "Hepatocyte growth factor (HDF) increases expression of vascular endothelial growth factor (VEGF) and plasminogen activator inhibitor-1 (PAl-1) in human keratinocytes and the VEGF receptorflk-1 in human endothelial cells. Evidence for a paracrine loop in wound healing." Lab.Invest.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] R.Hashina, et al.: "Autocrine and paracrine motility factors and their involvement in invasiveness in a human oral carcinoma cell line." Brit.J.Cancer.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K.Kosai, et al.: "Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice." Hepatology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] N.Taniura-Matsumoto, et al.: "Prostaglandin production in mouse mammary carcinoma cells confers invasive growht potential by incing hepatocyte growth factor in fibroblasts." Brit.J.Cancer.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] K.Kitajima, et al.: "Expression of anovel type of classic cadherin in developing brain and limb bud of mouse fetus." Develop.Dyn.(in press).

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-12-08  

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