HGF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

1996 Fiscal Year Annual Research Report

• Project/Area Number: 06283216
• Research Institution: Osaka University
• Principal Investigator: 中村 敏一 大阪大学, 医学部, 教授 (00049397)
• Co-Investigator(Kenkyū-buntansha): 小清水 右一 大阪大学, 医学部, 助手 (50281126) ; 松本 邦夫 大阪大学, 医学部, 助教授 (90201780)
• Keywords: HGF / c-Met / 形態形成 / HGFアンタゴニスト / 劇症肝炎 / 慢性腎不全 / 浸潤・転移 / Fas

Research Abstract

1.JGFはα鎖、β鎖からなるヘテロダイマー分子であるが、HGFのc-Met/HGFレセプターへの特異的結合をα鎖が担う一方、c-Met/HGFレセプターのチロシンリン酸化ならびにHGFの生物活性発現にはβ鎖が必要であることを明らかにし、α鎖とβ鎖の協調的相互作用によってHGFの活性が最大に発揮されることを解明した。
2.肺の器官形成過程におけるHGFの機能を解析した結果、HGFは間葉に由来する因子として肺上皮組織の形態形成(管腔形成)を担う因子であることを明らかにした。
3.Fas活性化による大量肝細胞死が難治性疾患である劇症肝炎における大量肝細胞死を引き起こしているが、リコンビナントHGF投与はFas活性化による大量肝細胞死を強力に防止することを見い出した。HGFは劇症肝炎に対する有効な治療薬となるものと考えられる。
4.自然発症慢性腎不全モデルマウスを用いてHGFが慢性腎不全の発症を抑え、腎機能の改善作用をもつことを明らかにした。慢性腎不全の根本的治療法はなく、HGFは慢性腎不全に対する画期的な治療薬となることが期待される。
5.HGFならびにHGF誘導因子を介した局所的ながん細胞と間質細胞の相互作用が、がん-間質相互作用を介したがん細胞悪性化の分子機構の一つであることを明らかにした。このような観点から、HGFの作用をブロックするHGFアンタゴニストを調製し、このHGFアンタゴニストがin vitroでがん細胞の基底膜浸潤、コラーゲンゲル内浸潤をほぼ完全にブロックすることを明らかにした。HGFアンタゴニストはがん細胞の浸潤・転移をブロックする新しい薬剤となる可能性がある。

Research Products

• [Publications] N.Nishi: "Changes in gene expression of growth factors and their receptors during castration-induced involusion and androgen-induced regrowth of rat prostate" Prostate. 28. 139-152 (1996)
• [Publications] M.Hamanoue: "Neurotrophic effect of hepatocyte growth factor on CNS neurons in vivo" J.Neurosci.Res.43. 554-564 (1996)
• [Publications] T.Kaido: "Continous HGF supply from spleen ransplanted HGF-expressing fibroblasts prevents CCl_4-induced acute live r injury in rats" Biochem.Biophys.Res.Commun.218. 1-5 (1996)
• [Publications] M.Inui: "Enhanced gene expression of transforming growth factor-α and c-met in rat urinary bladder cancer" Urol.Res.24. 55-60 (1996)
• [Publications] H.Yamazaki: "Biphasic changes in serum hepatocyte growth factor after transcatheter arterial chemoembolization theraphy for hepatocellular carcinoma" Cytokine. 8. 178-182 (1996)
• [Publications] T.Imai: "Expression of hepatocyte growth factor and c-met mRNAs during rat chemically induced hepatocarcinogenesis in the Solt-Farber model" Carcinogenesis. 17. 19-24 (1996)
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• [Publications] S.Takada: "Serum HGF levels in acute renal rejection after living related renal transplantation" Transplant.Intern.9. 151-154 (1996)
• [Publications] M.Joaquin: "Hepatocyte growth factor and transforming growth factor beta regulates 6-phosph of ructo-2-kinase/fructose-2,6-bisphos-phatase geneexpression in rat hepatocyte primary cultures" Biochem.J.314. 235-240 (1996)
• [Publications] M.Takahashi: "Constitutive expression of hepatocyte growth factor may maintain the sheet construction of gastric epithelial cells through facilitating actin-myosin contractile system" Biochem.Biophys.Res.Commun.219. 40-46 (1996)
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• [Publications] P.Gines: "Inhibitory actions of cyclic adenosine monophosphate and pertussis toxin define two distinct epidermal growth factor-regulated pathways leading to activation of mitogen-activated protein kinase in rat hepatocytes" Hepatology. 23. 1167-1173 (1996)
• [Publications] K.Sugimoto: "Molecular cloning and characterization of a newly identified member of the cadherin family,PB-cadherin" J.Biol.Chem.271. 11548-11556 (1996)
• [Publications] S.Takada: "HGF prevent tacrolimus(FK506)-induced nephrotoxicity in SHR rats" Transplant.Proc.28. 1089-1090 (1996)
• [Publications] T.Adachi: "Mitogen-activated protein kinase activation in hepatocyte growth factor-stimulated rat hepatocytes:Involvement of protein tyrosine kinase and protein kinase C" Hepatology. 23. 1244-1253 (1996)
• [Publications] M.J.Gomez-Lechon: "Cell cycle progression proteins(cyclins),oncogene expression and signal transduction during the proliferative response of human hepatocytes to hepatocyte growth factor" Hepatology. 23. 1012-1019 (1996)
• [Publications] S.Hayashi: "Autocrine-paraqrine effects of over-expression of hepatocyte growth factor gene on growth of endothelial cells" Biochem.Biophys.Res.Commun.220. 539-545 (1996)
• [Publications] H.Amaike: "Human recombinant HGF prevents lethal side effects of cyclosporin A in mice" Cytokine. 8. 387-394 (1996)
• [Publications] R.J.Mason: "Hepatocyte growth factor is a mitogen for alveolar type ΙΙ cells in rat lavage fluid" Am.J.Physiol.271. L46-L53 (1996)
• [Publications] N.Nakayama: "Hepatocyte growth factor and c-met expression in Long-Evans Cinnamon rats with spontaneous hepatitis and hepatoma" Hepatology. 24. 596-602 (1996)
• [Publications] H.Ohmichi: "In vivo mitogenic action of hepatocyte growth factor on branchial epithelial cells:Pulmotrophic role of HGF in lung regeneration" Am.J.Physiol.270. L1031-L1039 (1996)
• [Publications] M.I.Guillen: "The hepatocyte growth factor regulates the synthesis of acute-phase proteins in human hepatocytes. Divergent effects on IL-6-stimulated genes" Hepatology. 23. 1345-1352 (1996)
• [Publications] K.Matsumoto: "Acquisition of invasive phenotype in gallblader cancer cells via looped interaction of stromal fibroblasts and cancer cells mediated by HGF" Jap.J.Cancer Res.87. 702-710 (1996)
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• [Publications] Y.Nakamura: "A vaschlar modulator,hepatocyte growth factor(HGF),is associated with systolic blood pressure" Hypertension. 28. 409-413 (1996)
• [Publications] E.Ichimura: "Over expression of c-met/HGF receptor in human non small cell lung cancinoma in vitro and in vivo its prognostic significance" Jap.J.Cancer Res.87. 1063-1069 (1996)
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• [Publications] Y.Nakamura: "Hepatocyte growth factor(HGF)is a novel member of endothelium-specific growth factors:additive stimulatory effect of HGF with basic fibroblast growth factor,but not vascular endothelial growth factor" J.Hypertens.14. 1067-1072 (1996)
• [Publications] T.Mizuguchi: "Recovery of mRNA expression of tryptophan 2,3-dioxygenase and serine dehydratase in long-term cultures of primary rat hepatocytes" J.Biochem.120. 511-517 (1996)
• [Publications] A.Uchiyama: "Interleukin 4 inhibits hepatocyte growth factor-induced invasion and migration of colon carcinoma" J.Cell.Biochem.62. 443-453 (1996)
• [Publications] M.Dalmau: "Nitric oxide inhibits DNA synthesis and induces activation of poly(ADP-ribose)polymerase in cultured rat hepatocytes" Exp.Cell Res.228. 14-18 (1996)
• [Publications] Z.G.Han: "Regulaition of motility,invasiveness and growth of lung cancer cells by hepatocyte growth factor/scatter factor" Surg.Res.Commun.18. 217-229 (1996)
• [Publications] W.G.Jiang: "Hepatocyte growth factor induces tyrosine phosphorylation of focal adhesion kinase(FAK)and paxillin and enhances cell matrix interaction" Oncology Reports. 3. 819-823 (1996)
• [Publications] S.Aoki: "Molecular cloning of Xenopus c-met/hepatocyte growth factor receptor and its regional expression during early development" J.Biochem.120. 961-968 (1996)
• [Publications] T.Iwazawa: "Primary human fibroblasts induce diverse tumor invasiveness-Involvement of HGF as an important paracrine factor" Jap.J.Cancer Res.87. 1134-1142 (1996)
• [Publications] S.Kasai: "Hepatocyte growth factor is a paracrine regulator of rat prostate epithelial growth" Biochem.Biophys.Res.Commun.228. 646-652 (1996)
• [Publications] M.Takahashi: "Hepatocyte growth factor as a key to modulate anti-ulcer action of prostaglandins in stomach" J.Clin.Invest.98. 2604-2611 (1996)
• [Publications] G.Shiota: "Inhibitory effect of hepatocyte growth factor on metastosis of hepatocellular carcinoma in transgenic mice" Res.Commun.Mole.Pahol.Pharmacol.91. 33-39 (1996)
• [Publications] T.Adachi: "Phospholipase D activation in hepatocyte growth factor-stimulated rat hepatocytes mediates the expression of c-jun and c-fos:Involvement of protein tyrosine kinase,protein kinase C ,and Ca^<2+>" Hepatology. 24. 1274-1281 (1996)
• [Publications] K.Liu: "Change in hepatic handling of hepatocyte growth factor during liver regeneration in rats" Am.J.Physiol.269(in press). (1996)
• [Publications] N.Torok: "Upregulation of molecular motor encoding genes during HGF-and EGF-induced cell motiliy" J.Biol.Chem.(in press). (1997)
• [Publications] S.Hiscox: "Expression of HGF/SF and its receptor cMET in human colon cancers" Cancer Investigations. (in press). (1997)
• [Publications] G.Shiota: "Coexpression of hepatocyte growth factor and its receptor(c-met oncogene) in HGL 4 glioblastoma cells" Lab.Invest. (in press). (1997)
• [Publications] K.Takai: "Hepatocyte growth factor is constitutively produced by human bone marrow stromal cells and promotes erythropoiesis" Biood. (in press). (1997)
• [Publications] R.Morishita: "Potential role of endothelium-specific growth factor hepatocyte growth factor,on endothelial damage in diabetes militus" Diabetes. (in press). (1997)
• [Publications] I.S.Weimar: "Hepatocyte growth factor/scatter factor (HGF/SF) promotes adhesion of lymphoma cells to extra-cellular matrix molecules via α_4β,and α_5β,integrens" Blood. (in press). (1997)
• [Publications] T.Sakai: "Hepatocyre growth factor in bronchoalveolar lavage fluid and cells in patients with in flammatory chest diseases of the lower respitatory tract:Defection by RIA and in situ hybridization" Am.J.Resp.Cell Mole Biol.(in press). (1996)
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• [Publications] T.Takahashi: "Xenopus LIM motif-containing protein kinase 1 XLIMK 1 is expressed mainly in embryonic neural tissues that develop sensoryorgans" Develop.Dyn.(in press). (1997)
• [Publications] K.Matsumoto: "Emerging multipotent aspects of hepatocyte growth factor" J.Biochem.119. 591-600 (1996)
• [Publications] K.Matsumoto: "HGF in lung morphogenesis and tumor invasion:roles as a mediator in epithelial-mesenchymal and tumor-stromal interactions" Cancer Chemother.and Pharmacol.38. S42-S47 (1996)
• [Publications] 立石紀子、中村敏一: "Hepatocyte Growth Factor,HGF" 動脈硬化. 23. 683-688 (1996)
• [Publications] 天池寿、中村敏一: "HGFによる器官再生とその臨床応用" 治療. 78. 126-128 (1996)
• [Publications] 小清水右一、中村敏一: "解明進む器官形成のメカニズム:生体の組織恒常性を維持する普遍性機能因子としてのHGF" 化学と生物. 35. 8-10 (1996)
• [Publications] U.Koshimizu: "Liver and Environmental Xenobiotics" Narosa-Elsevier Verlag, 10 (1997)
• [Publications] 松本邦夫、青木俊介、中村敏一: "骨形成・吸収シグナリングと骨疾患" 羊土社, 90-96 (1996)
• [Publications] 中村敏一: "バイオサイエンス用語ライブラリー" 羊土社, 232 (1996)
• [Publications] 松本邦夫: "バイオサイエンス用語ライブラリー" 羊土社, 28-31 (1996)
• [Publications] 松本邦夫: "発生・神経 バイオサイエンス用語ライブラリー" 羊土社, 82-83 (1996)
• [Publications] 松本邦夫: "発生・神経 バイオサイエンス用語ライブラリー" 羊土社, 98-99 (1996)
• [Publications] 小清水右一: "発生・神経 バイオサイエンス用語ライブラリー" 羊土社, 44-45 (1996)
• [Publications] 小清水右一: "発生・神経 バイオサイエンス用語ライブラリー" 羊土社, 60-61 (1996)
• [Publications] 小清水右一: "発生・神経 バイオサイエンス用語ライブラリー" 羊土社, 86-88 (1996)
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• [Publications] 小清水右一、中村敏一: "細胞増殖因子研究の最前線‘97-‘98 実験医学増刊" 羊土社(印刷中),
• [Publications] 松本邦夫、中村敏一: "細胞増殖因子研究の最前線‘97-‘98 実験医学増刊" 羊土社(印刷中),
• [Publications] 松本邦夫、中村敏一: "タンパク質の生化学的分析 分子生物学プロトコール改訂第2版" 南江堂(印刷中),