1994 Fiscal Year Annual Research Report

HGF2ファミリーによる形態形成、器官再生、がん特性の分子細胞生物学的研究

Research Project

Project/Area Number	06283216
Research Category	Grant-in-Aid for Scientific Research on Priority Areas
Research Institution	Osaka University
Principal Investigator	中村敏一大阪大学, 医学部, 教授 (00049397)
Co-Investigator(Kenkyū-buntansha)	根本康夫大阪大学, 医学部, 助手 (30250088) 原英二大阪大学, 医学部, 助手 (80263268) 松本邦夫大阪大学, 医学部, 講師 (90201780)
Keywords	HGF / c-met / c-sea / Ron / インジュリン / HLP
Research Abstract	本年度の主な研究成果は以下の3つに要約できる。 1)HLP-MSPのレセプターはレセプター型チロシンキナーゼRonである:c-met/HGFレセプターのファミリーにはc-seaとRonの3種類が現在まで明らかになっているが、c-seaもRonもそのリガンドが不明であった。最近、RonのリガンドがHGF-like Protein(HLP)であることを明らかにした。HLPは1993年に私達と米国のLeonardらのグループによりマクロファージ活性因子(MSP)と同一物質であることが明らかにされたHGFファミリーである。 2)HGFによる癌細胞の浸潤誘導と癌-宿主相互作用:癌細胞の悪性度は宿主間質との相互作用により大きく影響されることが古くから知られている。胆嚢癌は極めて浸潤・転移能の高い癌であるが、胆嚢癌細胞をコラーゲン上に培養してもゲル内に浸潤しない。ところが線維芽細胞とのco-culture系ではゲル内に浸潤し、線維芽細胞が何らかのinvasion factorを分泌していることが示唆された。最近この線維芽細胞由来の浸潤因子がHGFであることを明らかにした。一方、胆嚢癌細胞を含む種々の癌細胞はHGF誘導因子(インジュリン)を産生しており、胆嚢癌細胞由来のインジュリンはIL-1βであることが明らかになった。したがって胆嚢癌細胞はHGF誘導因子を産生し、宿主間質の線維芽細胞にHGF産生を促し、このHGFに依存して浸潤すると考えられる。 3)HGFとそのレセプターの共発現による細胞がん化:マウス肝上皮細胞(MLE-10)はHGFレセプターのc-metを発現するHGF標的細胞である。この細胞にcytomegalovirusのプロモーターにつないだラットHGFcDNA発現プラスミドを導入しHGFを強制発現させると、MLE-10細胞はがん化し、in vitroではsoft agar中でコロニーを作り、in vivoではヌードマウス移植下に肝腫瘤を形成した。HGFとそのレセプターの共発現によるオートクリンループの形成は細胞をがん化(carcinogenesis)させうることが明らかになった。事実、胃がんや乳がん、肺がん、肝がんなどの多くの上皮細胞癌の中にHGFとそのレセプターが共発現し、オートクリンループを形成しているものがみられる。

Research Products

(49 results)

All Other

All Publications (49 results)

[Publications] H.Nakamura: "Molecular clonig of Xenopus HGFcDNA and its expression studies Xenopus early embryogenesis." Mech.Develop.49. 123-131 (1994)
[Publications] C.deJuan: "Hepatocyle growth factor up-regulates met expression in rat fetal hepatocytes in primary culture." Biochem.Biophys.Res.Commun.204. 1364-1370 (1994)
[Publications] T.Mitaka: "Effect of mitogens and co-mitogens on the formation of small-cell colonies in primary cultures of rat hepatocytes." J.Cell.Physiol.157. 461-468 (1994)
[Publications] H.Okazaki: "Prtial purification and characterization of “Injurin-like factor"whichstimulates production of hepatocyte growth factor." Biochem.Biophys.Acta. 1220. 291-298 (1994)
[Publications] K.Takaishi: "Involvement of rho p21 small GTP-binding protein and its regulatory protein in the HGF-induced cell motility." Oncogene. 9. 273-279 (1994)
[Publications] K.Ohashi.: "Cloning of novel receptor tyrosine kinase,Sky,predominantly expressedin brain." Oncogene. 9. 699-705 (1994)
[Publications] K.Mizuno: "Purification and chracterization of hepatocyte growh factor(HGF)-converting enzyme:Activatin of Pro HGF." Biochem.Biophys.Res.Commun.198. 1161-1169 (1994)
[Publications] K.Mizuno: "Hairpin loop and second kringledomain are essential sites for heparin-binding and biological activity of hepatocyte growth factor." J.Biol.Chem.269. 1131-1136 (1994)
[Publications] Y.Tanoue: "A specific inhibitor for hepatocyte growth factor(HGF)-Converting enzyme synthesis adn effects on the mitogenic activity of pro-HGF." Peptide Chemistry Protein Research Fundation,Osaka. 201-204 (1994)
[Publications] S.Bellusci: "Creation of HGF/SF autocrine loop in carcinoma cells induces invasiveproperties associated with increased tumorigenicity." Oncogene. 9. 1091-1099 (1994)
[Publications] T.Kobayashi: "Hepatocyte growth factor elevates the activity levels of glycolopid sulfotransferase in renal cell carcinoma cell." Eur.J.Biochem.219. 407-413 (1994)
[Publications] G.Shiota: "Hepatocyte growth factor in transgenic mice:Effects on hepatocyte growth,liver regeneration and gene expression." Hepatology. 19. 962-972 (1994)
[Publications] G.Shiota: "Hepatocyte growth factor regulates transforming growth factor alpha inHepG2 hepatic cells." Biochem.Biophys.Res.Commun.200. 1099-1104 (1994)
[Publications] K.Kawaida: "Hepatocyte growth factor prevent acute renal failure and accelerate renal regeneration." Proc.Nalt.Acad.Sci.USA. 91. 4357-4361 (1994)
[Publications] J.J.Couper: "High glucose and hyprrosmolality stimulate hepatocyte growth factor secrection from cultured human mesangial cells." Diabetologia. 37. 533-535 (1994)
[Publications] J.W.S.Fang: "Hepatocyte proliferation as an indicator of outcome in acute alcoholic hepatitis." Lancet. 343. 820-823 (1994)
[Publications] M.Lyon: "The interaction of hepatocyte growth factor with heparan sulphate:Elucidation of the major heparan sulphatestructural determinants." J.Biol.Chem.269. 11216-11223 (1994)
[Publications] O.Amano: "Expression and localization of hepatocyte growth factor in rat submandibular gland." Growth Factors. 10. 145-151 (1994)
[Publications] O.F.P.Santos: "Involvement of Hepatocyte growth factor in kidney development." Develop.Biol.163. 525-529 (1994)
[Publications] K.Mizuno: "Identification of a human cDNA encoding anovel protein kinase with two repeats of the LIM/double zinc finger motif in the molecule." Oncogene. 9. 1605-1612 (1994)
[Publications] S.Dremier: "Mitogenic,dedifferentiating,and scattering effects of hepatocyte growth factor on dog thyroid cells." Endocrinology. 135. 135-140 (1994)
[Publications] H.Chang: "Blood hepatocyte growth factor levels in chronic renal failure patients." Nephron. 67. 498 (1994)
[Publications] J.Wojta: "Hepatocyte growth factor stimulates expression of plasminogen activator inhibitor type 1and tissue factor in HepG2 cells in culture." Blood. 84. 151-157 (1994)
[Publications] Y.Itakura: "Autocrine stimulation of motility in SBC-5 human lung carcinoma cells by a two-kringle variant of HGF." Cancer Lett.83. 235-243 (1994)
[Publications] K.Ohashi: "Molecular cloning of a chicken lung cDNA encoding a novel protein kinase with N-terminal two LIM/double zinc finger motifs." J.Biochem.116. 636-642 (1994)
[Publications] H.Shinozuka: "Roles of growth factors and of tumor necrosis factor-α on liver cell proliferation induced in rats by lead nitrate." Lab.Invest.71. 35-41 (1994)
[Publications] Y.Kato: "Heparin-hepatocyte growth factor(HGF)complex with low plasma clearance and retained hepatocyte proliferating activity." Hepatology. 20. 417-424 (1994)
[Publications] M.Suzuki: "Cloned cells develop renal cortical collecting tubules." Nephron. 68. 118-124 (1994)
[Publications] N.Rahimi: "Roles of hepatocyte growth factor in breast cancer:A novel mitogenic factor secreted by adipocytes." DNA and Cell Biol.13. 1189-1197 (1994)
[Publications] G.Shiota: "Inhibition effect of hepatocytegrowth factor against FaO hepatocellular carcinoma cells may be associated with changes of intracellular signalling pathways mediated by protein kinase." Res.Commun.Chem.Pathol.Pharmacol.85. 271-278 (1994)
[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.(in press). (1995)
[Publications] T.Takabayashi: "Hepatocyte growth factor/scatter factor has mitogenic,motogenic and morphogenetic activities on chondrocytes." J.Cell Biol.(in press). (1995)
[Publications] K.Matsumoto: "Hepatocyte growth factor as a potent survival factor for rat pheochromocytoma PC12 cells." Exp.Cell Res.(in press). (1995)
[Publications] G.Shiota: "Serum hepatocyte growth factor in acute hepatic failure in comparison to acute hepatitis." Res.Commun.Mole.Pathol.Pharmacol.85. 157-162 (1994)
[Publications] G.Shiota: "Assessment of in vitro growth potential of hepatocyte expressing hepatocyte growth factor in an autocrine fasion." Res.Commun.Mole.Pathol.Pharmacol.85. 151-156 (1994)
[Publications] M.Joannidis: "Regional expression of hepatocyte growth factor/c-met in experimentalrenal hypertrophy and hyperplasia." Am.J.Physiol.267. F231-F236 (1994)
[Publications] R.J.Mason: "Hepatocyte growth factor is a growth for rat alveolar typeII cells." Am.J.Respir.Cell Mol.Biol.11. 561-567 (1994)
[Publications] K.Matsumoto: "Hepatocyte growth factor/scatter factor induces tyrosin phosphonlation of focal adhesion kinsase(p125FAK)and promotes migration and invasion by oral squamous cell carcinoma cells." J.Biol.Chem.269. 31807-31813 (1994)
[Publications] A.Koj: "Hepatocyte growth factor and retinoic acid exert opposite effects on synthesis of class 1 and class 2 acutephase proteins in rat hepatoma cells." Int.J.Biochem.(in press). (1995)
[Publications] F.Myokai: "Expression of the hepatocyte growth factor gene during development ofthe chicken limb." Develop.dynamics. (in press). (1995)
[Publications] T.Sato: "Hepatocyte growth factor(HGF)isinvolved in the formation of osteoclast-like cells mediated by clonal stromal cells(MC3T3-C1/PA6)." J.Cell.physiol.(in press). (1995)
[Publications] J.V.Soriano: "Hepatocyte growth factor stimulates extensive develoment of branchingduct-like structures by cloned mammary gland epithelial cell." J.Cell Sci.(in press). (1995)
[Publications] M.J.Gomez-Lechon: "Effect of hepatocyte growth factor(h-rHGF)on the growth and metubolism of human hepatocytes in primary culture." Hepatology. (in press). (1995)
[Publications] W.G.Jiang: "Anti-motility and anti-invasiveness properties of invasion inhibitingfactor(11F-2)on human colon cancer cells." Surg.Res.Commun.(in press). (1995)
[Publications] S.Saito: "Hepatocyte growth factor promotes the growth of cytotrophoblasts by the paracrine system." J.Biochem.(in press). (1995)
[Publications] T.Nakamura: "Hepatocyte growth factor as mitogen,motogen and morphosgen,and its roles in organ regeneration." Princeton Scientific Pub lishing Co.Inc., 19 (1994)
[Publications] K.Matsumoto: "Structure,pleiotropic actions,and organotrophic roles of hepatocyte growth factor." Springer Verlag, 21 (1994)
[Publications] K.Matsumoto: "Pleiotropic roles of HGF in mitogenesis,morphogenesis and organ regeneration." Gann Monograph No.42:Growth Factors;Cell Growth,Morphogenesis and Transformation, 21 (1994)
[Publications] K.Matsumoto: "Hepatotrophic and renotrophic activities of HGF in vivo:Possible application of HGF for hepatic and renal diseases." Springer Verlag, 14 (1994)

1994 Fiscal Year Annual Research Report

HGF2ファミリーによる形態形成、器官再生、がん特性の分子細胞生物学的研究

Principal Investigator

中村 敏一 大阪大学, 医学部, 教授 (00049397)

Research Products

[Publications] H.Nakamura: "Molecular clonig of Xenopus HGFcDNA and its expression studies Xenopus early embryogenesis." Mech.Develop.49. 123-131 (1994)

[Publications] C.deJuan: "Hepatocyle growth factor up-regulates met expression in rat fetal hepatocytes in primary culture." Biochem.Biophys.Res.Commun.204. 1364-1370 (1994)

[Publications] T.Mitaka: "Effect of mitogens and co-mitogens on the formation of small-cell colonies in primary cultures of rat hepatocytes." J.Cell.Physiol.157. 461-468 (1994)

[Publications] H.Okazaki: "Prtial purification and characterization of “Injurin-like factor"whichstimulates production of hepatocyte growth factor." Biochem.Biophys.Acta. 1220. 291-298 (1994)

[Publications] K.Takaishi: "Involvement of rho p21 small GTP-binding protein and its regulatory protein in the HGF-induced cell motility." Oncogene. 9. 273-279 (1994)

[Publications] K.Ohashi.: "Cloning of novel receptor tyrosine kinase,Sky,predominantly expressedin brain." Oncogene. 9. 699-705 (1994)

[Publications] K.Mizuno: "Purification and chracterization of hepatocyte growh factor(HGF)-converting enzyme:Activatin of Pro HGF." Biochem.Biophys.Res.Commun.198. 1161-1169 (1994)

[Publications] K.Mizuno: "Hairpin loop and second kringledomain are essential sites for heparin-binding and biological activity of hepatocyte growth factor." J.Biol.Chem.269. 1131-1136 (1994)

[Publications] Y.Tanoue: "A specific inhibitor for hepatocyte growth factor(HGF)-Converting enzyme synthesis adn effects on the mitogenic activity of pro-HGF." Peptide Chemistry Protein Research Fundation,Osaka. 201-204 (1994)

[Publications] S.Bellusci: "Creation of HGF/SF autocrine loop in carcinoma cells induces invasiveproperties associated with increased tumorigenicity." Oncogene. 9. 1091-1099 (1994)

[Publications] T.Kobayashi: "Hepatocyte growth factor elevates the activity levels of glycolopid sulfotransferase in renal cell carcinoma cell." Eur.J.Biochem.219. 407-413 (1994)

[Publications] G.Shiota: "Hepatocyte growth factor in transgenic mice:Effects on hepatocyte growth,liver regeneration and gene expression." Hepatology. 19. 962-972 (1994)

[Publications] G.Shiota: "Hepatocyte growth factor regulates transforming growth factor alpha inHepG2 hepatic cells." Biochem.Biophys.Res.Commun.200. 1099-1104 (1994)

[Publications] K.Kawaida: "Hepatocyte growth factor prevent acute renal failure and accelerate renal regeneration." Proc.Nalt.Acad.Sci.USA. 91. 4357-4361 (1994)

[Publications] J.J.Couper: "High glucose and hyprrosmolality stimulate hepatocyte growth factor secrection from cultured human mesangial cells." Diabetologia. 37. 533-535 (1994)

[Publications] J.W.S.Fang: "Hepatocyte proliferation as an indicator of outcome in acute alcoholic hepatitis." Lancet. 343. 820-823 (1994)

[Publications] M.Lyon: "The interaction of hepatocyte growth factor with heparan sulphate:Elucidation of the major heparan sulphatestructural determinants." J.Biol.Chem.269. 11216-11223 (1994)

[Publications] O.Amano: "Expression and localization of hepatocyte growth factor in rat submandibular gland." Growth Factors. 10. 145-151 (1994)

[Publications] O.F.P.Santos: "Involvement of Hepatocyte growth factor in kidney development." Develop.Biol.163. 525-529 (1994)

[Publications] K.Mizuno: "Identification of a human cDNA encoding anovel protein kinase with two repeats of the LIM/double zinc finger motif in the molecule." Oncogene. 9. 1605-1612 (1994)

[Publications] S.Dremier: "Mitogenic,dedifferentiating,and scattering effects of hepatocyte growth factor on dog thyroid cells." Endocrinology. 135. 135-140 (1994)

[Publications] H.Chang: "Blood hepatocyte growth factor levels in chronic renal failure patients." Nephron. 67. 498 (1994)

[Publications] J.Wojta: "Hepatocyte growth factor stimulates expression of plasminogen activator inhibitor type 1and tissue factor in HepG2 cells in culture." Blood. 84. 151-157 (1994)

[Publications] Y.Itakura: "Autocrine stimulation of motility in SBC-5 human lung carcinoma cells by a two-kringle variant of HGF." Cancer Lett.83. 235-243 (1994)

[Publications] K.Ohashi: "Molecular cloning of a chicken lung cDNA encoding a novel protein kinase with N-terminal two LIM/double zinc finger motifs." J.Biochem.116. 636-642 (1994)

[Publications] H.Shinozuka: "Roles of growth factors and of tumor necrosis factor-α on liver cell proliferation induced in rats by lead nitrate." Lab.Invest.71. 35-41 (1994)

[Publications] Y.Kato: "Heparin-hepatocyte growth factor(HGF)complex with low plasma clearance and retained hepatocyte proliferating activity." Hepatology. 20. 417-424 (1994)

[Publications] M.Suzuki: "Cloned cells develop renal cortical collecting tubules." Nephron. 68. 118-124 (1994)

[Publications] N.Rahimi: "Roles of hepatocyte growth factor in breast cancer:A novel mitogenic factor secreted by adipocytes." DNA and Cell Biol.13. 1189-1197 (1994)

[Publications] G.Shiota: "Inhibition effect of hepatocytegrowth factor against FaO hepatocellular carcinoma cells may be associated with changes of intracellular signalling pathways mediated by protein kinase." Res.Commun.Chem.Pathol.Pharmacol.85. 271-278 (1994)

[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.(in press). (1995)

[Publications] T.Takabayashi: "Hepatocyte growth factor/scatter factor has mitogenic,motogenic and morphogenetic activities on chondrocytes." J.Cell Biol.(in press). (1995)

[Publications] K.Matsumoto: "Hepatocyte growth factor as a potent survival factor for rat pheochromocytoma PC12 cells." Exp.Cell Res.(in press). (1995)

[Publications] G.Shiota: "Serum hepatocyte growth factor in acute hepatic failure in comparison to acute hepatitis." Res.Commun.Mole.Pathol.Pharmacol.85. 157-162 (1994)

[Publications] G.Shiota: "Assessment of in vitro growth potential of hepatocyte expressing hepatocyte growth factor in an autocrine fasion." Res.Commun.Mole.Pathol.Pharmacol.85. 151-156 (1994)

[Publications] M.Joannidis: "Regional expression of hepatocyte growth factor/c-met in experimentalrenal hypertrophy and hyperplasia." Am.J.Physiol.267. F231-F236 (1994)

[Publications] R.J.Mason: "Hepatocyte growth factor is a growth for rat alveolar typeII cells." Am.J.Respir.Cell Mol.Biol.11. 561-567 (1994)

[Publications] K.Matsumoto: "Hepatocyte growth factor/scatter factor induces tyrosin phosphonlation of focal adhesion kinsase(p125FAK)and promotes migration and invasion by oral squamous cell carcinoma cells." J.Biol.Chem.269. 31807-31813 (1994)

[Publications] A.Koj: "Hepatocyte growth factor and retinoic acid exert opposite effects on synthesis of class 1 and class 2 acutephase proteins in rat hepatoma cells." Int.J.Biochem.(in press). (1995)

[Publications] F.Myokai: "Expression of the hepatocyte growth factor gene during development ofthe chicken limb." Develop.dynamics. (in press). (1995)

[Publications] T.Sato: "Hepatocyte growth factor(HGF)isinvolved in the formation of osteoclast-like cells mediated by clonal stromal cells(MC3T3-C1/PA6)." J.Cell.physiol.(in press). (1995)

[Publications] J.V.Soriano: "Hepatocyte growth factor stimulates extensive develoment of branchingduct-like structures by cloned mammary gland epithelial cell." J.Cell Sci.(in press). (1995)

[Publications] M.J.Gomez-Lechon: "Effect of hepatocyte growth factor(h-rHGF)on the growth and metubolism of human hepatocytes in primary culture." Hepatology. (in press). (1995)

[Publications] W.G.Jiang: "Anti-motility and anti-invasiveness properties of invasion inhibitingfactor(11F-2)on human colon cancer cells." Surg.Res.Commun.(in press). (1995)

[Publications] S.Saito: "Hepatocyte growth factor promotes the growth of cytotrophoblasts by the paracrine system." J.Biochem.(in press). (1995)

[Publications] T.Nakamura: "Hepatocyte growth factor as mitogen,motogen and morphosgen,and its roles in organ regeneration." Princeton Scientific Pub lishing Co.Inc., 19 (1994)

[Publications] K.Matsumoto: "Structure,pleiotropic actions,and organotrophic roles of hepatocyte growth factor." Springer Verlag, 21 (1994)

[Publications] K.Matsumoto: "Pleiotropic roles of HGF in mitogenesis,morphogenesis and organ regeneration." Gann Monograph No.42:Growth Factors;Cell Growth,Morphogenesis and Transformation, 21 (1994)

[Publications] K.Matsumoto: "Hepatotrophic and renotrophic activities of HGF in vivo:Possible application of HGF for hepatic and renal diseases." Springer Verlag, 14 (1994)

中村敏一大阪大学, 医学部, 教授 (00049397)