初期発生ならびに器官形成過程におけるHGFならびにそのファミリー分子の機能

1995 Fiscal Year Annual Research Report

• Project/Area Number: 07044201
• Research Institution: Osaka University
• Principal Investigator: 松本 邦夫 大阪大学, 医学部, 講師 (90201780)
• Co-Investigator(Kenkyū-buntansha): MONTESANO Ro University of Geneva, Faculty of Medicine, 教授 ; 根本 康夫 大阪大学, 医学部, 助手 (30250088) ; 小清水 右一 大阪大学, 医学部, 助手 ; 中村 敏一 大阪大学, 医学部, 教授 (00049397)
• Keywords: HGF / Met / HLP / Ron / 上皮-間葉相互作用 / 形態形成 / 器官形成

Research Abstract

アフリカツメガエルならびにニワトリのHGFとc-metのcDNAクローニングを行ない、胚発生過程における遺伝子発現パターンを解析したところ、主に腹側内蔵臓器と骨格系の形成過程において発現していることが明らかになった。さらにc-metのドミナントネガティブ体をアフリカツメガエル胚に導入し、HGFのシグナルをブロックすると、肝臓や腎臓などの内蔵臓器と骨格の形態形成に異常をきたした。これらの結果からHGFは肝臓や腎臓などの内蔵臓器の形態形成ならびに胚の骨格形成に重要な役割を担うと考えられる。また、上皮細胞と間葉細胞の特異的相互作用によりその器官形成が進行することが知られている肺および歯の発生におけるHGFの機能について解析を行った。in situ hybridizationによる解析の結果、ラット胎児肺においては活発に枝分れを繰り返す気管支上皮組織においてc-Met/HGFレセプターが発現し、HGFはその周辺の間葉組織で産生されていることが明らかになった。さらに器官培養系においてリコンビナントHGFは胎児肺原基の枝分れした管腔形成“branching morphogenesis"を促進する一方、HGFのアンチセンスオリゴDNAを添加して内因性HGFの産生を抑制すると肺原基の発生は著しく阻害された。また、歯胚形成過程においてもHGFの発現は歯胚間葉組織にc-Met/HGFレセプターは上皮組織に局在した。歯胚の発生、形態形成におけるHGFの機能を明らかにするため、HGFのアンチセンスDNAを歯胚器官培養系に添加したところ、著しい形態形成の異常が観察された。また乳腺上皮組織に由来する培養細胞株に対しても、HGFはコラーゲンゲル内で枝分れした管腔構造を誘導し、HGFは様々な上皮系細胞形態形成因子であることが明らかになった。

Research Products

• [Publications] N.Nakayama: "Differing distribution of hepatocyle growth factor-positive cells in the liver of LEC rats with acute hepatitis,chronic hepatitis and hepatoma." Jap.J.Cancer Res.86. 5-9 (1995)
• [Publications] H.Nakamura: "Molecular cloning of Xenopus HGF cDNA,nad its expression studied in Xenopus early embryogenesis." Mech.Develop.49. 121-131 (1995)
• [Publications] G.Shiota: "Serum hepatocyte growth factor level : its clinical implication." Hepatology. 21. 106-112 (1995)
• [Publications] W.G.Jiang: "Inhibition of motility and invasion by invasion inhibiting factor-2 (11F-2) on human colon cancer cells." Surg.Res.Commun.17. 67-78 (1995)
• [Publications] K.Matsumoto: "Novel function of prostaglandins as inducer of gene expression of hepatocyte growth factor." J.Biochem.117. 458-464 (1995)
• [Publications] F.Myokai: "Expression of the hepatocyte growth factor gene during development of the chicken limb." Develop.dynamics. 202. 80-90 (1995)
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• [Publications] M.J.Gomez-Lechon: "Effect of hepatocyte growth factor (h-rHGF) on the growth and metabolism of human hepatocytes in primary culture." Hepatology. 21. 1248-1254 (1995)
• [Publications] S.Saito: "Hepatocyte growth factor promotes the growth of cytotrophoblasts by the paracrine system." J.Biochem.117. 671-676 (1995)
• [Publications] M.Takahashi: "Hepatocyte growth factor is the most potent endogenous stimulant of rabbit gastric epithelial cell proliferation and migration in primary culture." J.Clin.Invest.95. 1994-2003 (1995)
• [Publications] T.Takabayashi: "Hepatocyte growth factor/scatter factor has mitogenic,motogenic and morphogenetic activities on chondrocytes." J.Cell Biol.129. 1411-1419 (1995)
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• [Publications] S.Seslar: "Tumor-stroma interactions and stromal cell density regulate hepatocyte growth factor protein levels : A role for transforming growth factor-β activation." Endocrinology. 136. 1945-1953 (1995)
• [Publications] A.Yamada: "Rapid and sensitive enzyme-linked immunosorbent assay for measurement of HGF in rat and human tissues." Biomed.Res.16. 105-114 (1995)
• [Publications] E.J.G.Barros: "Differential tubulogenic and branching morphogenetic activities of growth factors : Implications for epithelial tissue development." Proc.Natl.Acad.Sci.USA. 92. 4412-4416 (1995)
• [Publications] H.Shimura: "Induction of invasive growth in a gallbladder cancer cell line by hepatocyte growth factor in vitro." Jap.J.Cancer Res.86. 662-669 (1995)
• [Publications] K.Ohashi: "Molecular cloning,characterization and in situe localization in the brain of rat sky receptor tyrosine kinase." J.Biochem.117. 1267-1275 (1995)
• [Publications] T.Adachi: "Roles of prostaglandin production and MAP kinase activation in hepatocyte growth factor-mediated rat hepatocyte proliferation." Hepatology. 21. 1668-1674 (1995)
• [Publications] M.Yaono: "Hepatocyte growth factor enhancement of GST-P positive hepatic foci development in rats treated with diethylnitrosamine and N-ethyl-N-hydroxy ethylnitrosamine." Jap.J.Cancer Res.86. 718-723 (1995)
• [Publications] Y.Matsuda: "Inhibition of HGF/SF-induced membrane ruffling and cell motility by transient elevation of cytosolic free Ca^<2+>." Exp.Cell Res.220. 424-433 (1995)
• [Publications] W.G.Jiang: "Hepatocyte growth factor prevents liver cirrhosis caused by dimethylnitrosamine in rats." J.Biochem.118. 643-649 (1995)
• [Publications] S.Honda: "Localization and functional coupling of HGF and c-Met/HGF receptor in rat brain : implication as neurotrophic factor." Mole.Brain Res.32. 197-210 (1995)
• [Publications] M.R.Vila: "Hepatocyte growth factor is a potent mitogen for normal human pancreas cells in vitro." Lab.Invest.73. 409-418 (1995)
• [Publications] P.Gines: "Tyrosine kinase growth factor receptors but not seven-membrane-spanning or phorbol esters activate mitogen-activated protein kinase in rat hepatocytes." Hepatology. 22. 1296-1303 (1995)
• [Publications] M.Hu: "Human peri-tumoral and lung fibroblasts produce paracrine motility factors for recently established human sarcoma cell strains." Intn.J.Cancer. 62. 585-592 (1995)
• [Publications] Y.Nakamura: "Expression of local hepatocyte growth factor system in vascular tissue." Biochem.Biophys.Res.Commun.215. 483-488 (1995)
• [Publications] M.Takahashi: "Hepatocyte growth factor stimulates wound repair of the rabbit esophageal epithelial cells in primary culture." Biochem.Biophys.Res.Commun.216. 298-305 (1995)
• [Publications] W.G.Jiang: "Induction of tyrosine phosphorylation and translocation of ezrin by hepatocyte growth factor/scatter factor (HGF/SF)." Biochem.Biophys.Res.Commun.217. 1062-1069 (1995)
• [Publications] T.Kaido: "Continous HGF supply from spleen transplanted HGF-expressing fibroblasts prevents CCl_4-induced acute liver injury in rats." Biochem.Biophys.Res.Commun.218. 1-5 (1996)
• [Publications] K.Matsumoto: "Acute Renal Failure : Emerging New Concepts and Therapeutic Strategies." Churchill Livingstone, 24 (1995)
• [Publications] H.Amaike: "Takahashi Memorial Forum,Tokyo,5-November 1994,Excepta Medica International Congress Series 1086" Elsevier Science B.V.Amsterdam., 14 (1995)
• [Publications] K.Matsumoto: "Acute Renal Failure : Emerging New Concepts and Therapeutic Strategies." Churchill Livingstone, 24 (1995)
• [Publications] 坂倉照 予: "細胞外マトリックス" 羊土社, 13 (1995)
• [Publications] 中村敏一: "用語ライブラリー:発生・神経" 羊土社, 163 (1996)
• [Publications] 中村敏一 監訳: "細胞増殖因子(I.A.McKay and I.M.Leigh編)" メディカル・サイエンス インターナショナル, 232 (1995)
• [Publications] U.Koshimizu: "Liver and Environmental Xenobiotics" Narosa-Elsevier Verlag (in press), (1996)