上皮・間葉相互作用によるがん悪性化の分子機構とその制御

• Project/Area Number: 12215082
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Osaka University
• Principal Investigator: 中村 敏一 大阪大学, 医学系研究科, 教授 (00049397)
• Co-Investigator(Kenkyū-buntansha): 松本 邦夫 大阪大学, 医学系研究科, 助教授 (90201780) ; 船越 洋 大阪大学, 医学系研究科, 助教授 (40273685) ; 水野 信哉 大阪大学, 医学系研究科, 助手 (10219644) ; 町出 充 大阪大学, 医学系研究科, 助手 (90346198) ; 小清水 右一 大阪大学, 医学系研究科, 助手 (50281126)
• Project Period (FY): 2000 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥102,000,000 (Direct Cost: ¥102,000,000); Fiscal Year 2004: ¥22,000,000 (Direct Cost: ¥22,000,000); Fiscal Year 2003: ¥21,000,000 (Direct Cost: ¥21,000,000); Fiscal Year 2002: ¥21,000,000 (Direct Cost: ¥21,000,000); Fiscal Year 2001: ¥21,000,000 (Direct Cost: ¥21,000,000); Fiscal Year 2000: ¥17,000,000 (Direct Cost: ¥17,000,000)
• Keywords: HGF / c-Met / NK4 / 血管新生阻害 / 線維症 / 筋線維芽細胞 / 上皮・間葉相互作用 / がん悪性化 / 制癌 / 浸潤 / 転移 / 腫瘍血管新生 / HGFアンタゴニスト / 血管新生 / 浸潤・転移 / クリングルドメイン / LIMキナーゼ / 細胞骨格

Research Abstract

平成16年度において以下の成果を得た。
1)細胞の癌化は正常組織での細胞増殖制御の破綻を背景としているため、正常細胞における増殖停止機構の解明は重要な意義を持つ。本研究では、健常肝より調製した初代培養肝細胞を用いて、肝細胞増殖因子、HGFの細胞増殖誘導作用が細胞接着を介して抑制される分子機構について解析し、細胞接着により発現誘導されるチロシンフォスファターゼによりHGF受容体であるc-Metチロシンキナーゼの活性化が抑制されることを明らかにした。
またヒト株化肺癌細胞を用いて、c-Metのjuxtamembrane領域にある985番目のセリン残基がリン酸化されているとHGFの存在下でもc-Met活性化が抑制されることを見出した。
2)癌の浸潤・転移を抑制するための機能分子としてデザインしたHGFアンタゴニスト、NK4は血管新生も阻害する2機能性分子である。NK4による制癌作用の解析を進めた結果、NK4は血管内皮細胞の管腔形成阻害、細胞外基質への接着を阻止するとともに内皮細胞のアポトーシスを促進することが明らかとなった。一方、胃癌モデルにおいてNK4遺伝子治療は抗癌剤との併用により相乗的な制癌作用を示すことを見出した。
3)肝硬変に代表される慢性臓器疾患では、実質細胞の脱落に伴い、間質線維症に至る。今回、肝硬変と肺線維症の動物モデルを用い、間質線維化の過程で中心的な役割を担う筋線維芽細胞にc-Metの発現が誘導されていることを見出した。さらにHGFが筋線維芽細胞に作用し、アポトーシス誘導と細胞外基質融解を介して線維化を解除する機序を明らかにした。

Research Products

• [Journal Article] Hetatocyte Growth Factor, its receptor, their potential value in cancer therapy. (2005)
  • Author(s): Jiang W.G.et al.
  • Journal Title: Crit Rev Oncol Hematol 53 Pages: 35-69
• [Journal Article] HGF reduces advancing lung fibrosis in mice : a potential role for MMP-dependent myofibroblast apoptosis. (2005)
  • Author(s): Mizuno S.et al.
  • Journal Title: FASEB-Journal (In press)
• [Journal Article] Growth inhibition and apoptosis inlLiver myofibroblasts promoted by hepatocyte growth factor leads to resolution from liver cirrhosis. (2005)
  • Author(s): Kim H.W.et al.
  • Journal Title: Am J Pathol (In press)
• [Journal Article] Hepatocyte growth factor prevents tissue fibrosis, remodeling and dysfunction in cardiomyopathic hamster hearts. (2005)
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  • Journal Title: Am J Physiol (In press)
• [Journal Article] Bi-directional regulation of c-Met Ser-985 phosphorylation via PKC and protein phosphatase 2A involves c-Met activation and cellular responsiveness to HGF. (2004)
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  • Journal Title: J Biol Chem 279 Pages: 26445-26452
• [Journal Article] NK4 in cancer biology and therapeutics. (2004)
  • Author(s): Matsumoto K., Nakamura T.
  • Journal Title: Gann Monograph on Cancer Research 52 Pages: 125-139
• [Journal Article] Hepatic gene expression of NK4, an HGF-antagonist/angiogenesis inhibitor suppresses liver metastasis and invasive growth of colon cancer in mice. (2004)
  • Author(s): Wen J.et al.
  • Journal Title: Cancer Gene Therapy 11 Pages: 419-430
• [Journal Article] Gene therapy of secretory leukoprotease inhibitor promoter-controlled replication competent adenovirus for non-small cell lung cancer (2004)
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  • Journal Title: Cancer Res 64 Pages: 4611-4620
• [Journal Article] Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. (2004)
  • Author(s): Ohuchida K.et al.
  • Journal Title: Cancer Res 64 Pages: 3215-3222
• [Journal Article] Suppression of tumor metastasis by NK4 plasmid DNA released from cationized gelatin. (2004)
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  • Journal Title: Gene Therapy 11 Pages: 1205-1214
• [Journal Article] Essential role of HGF (hepatocyte growth factor) in blood formation in Xenopus. (2004)
  • Author(s): Koibuchi K.et al.
  • Journal Title: Blood 103 Pages: 3320-33257
• [Journal Article] Suppression of chronic glomerular injuries and TGF-β 1 production by HGF contributes in attenuation of murine diabetic nephropathy. (2004)
  • Author(s): Mizuno S., Nakamura T.
  • Journal Title: Am J Physiol 286
• [Journal Article] Recombinant hepatocyte growth factor accelerates cutaneous wound heating in diabetic mouse model. (2004)
  • Author(s): Yoshida S.et al.
  • Journal Title: Growth Factors 22 Pages: 111-119
• [Journal Article] Intrathecal injection of HVJ-E containing HGF gene to cerebrospinal fluid can prevent and ameliorate hearing impairment in rats. (2004)
  • Author(s): Oshima K.et al.
  • Journal Title: FASEB-Journal 18 Pages: 212-214
• [Journal Article] The plasminogen activation system reduces fibrosis in the lung by a hepatocyte growth factor dependent mechanism. (2004)
  • Author(s): Hattori N.et al.
  • Journal Title: Am J Pathol 164 Pages: 1091-1098
• [Journal Article] In vivo evidence of angiogenesis induced by transcription factor, Ets-1 : Ets-1 is located upstream of angiogenesis cascade. (2004)
  • Author(s): Hashiya N.et al.
  • Journal Title: Circulation 109 Pages: 3035-3041
• [Journal Article] Hepatocyte growth factor induces tolerance in murine cardiac transplantation. (2004)
  • Author(s): Yarmaura K.et al.
  • Journal Title: Circulation 110 Pages: 1650-1657
• [Journal Article] Hepatocyte growth factor suppresses vascular medial hyperplasia and matrix accumulation in advanced pulmonary hypertension of rats. (2004)
  • Author(s): Ono M.et al.
  • Journal Title: Circulation 110 Pages: 2896-2902
• [Journal Article] Electroporation-mediated HGF gene transfer ameliorated cyclosporine nephrotoxicity. (2004)
  • Author(s): Mizui M.et al.
  • Journal Title: Kidney Intl 65 Pages: 2041-2053
• [Journal Article] Treatment of dilated cardiomyopathy with electroporation of hepatocyte growth factor gene into skeletal muscle. (2004)
  • Author(s): Komamura K.et al.
  • Journal Title: Hypertension 44 Pages: 1-7
• [Journal Article] Skeletal muscle targeting in vivo electroporation-mediated HGF gene therapy of bleomycin-induced pulmonary fibrosis in mice. (2004)
  • Author(s): Umeda Y.et al.
  • Journal Title: Lab Invest 84 Pages: 836-844
• [Journal Article] Multiple biological responses are induced by glycosylation-deficient hepatocyte growth factor.
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  • Journal Title: Biochem J (in press)
• [Book] Encyclopedia Endocrine Diseases (2004)
  • Author(s): Matsumoto K., Nakamura T.
  • Total Pages: 7
  • Publisher: Elsevier Inc
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• [Publications] S.Mizuno, T.Nakamura: "Suppression of mesangial TGF-β1 expression by HGF contributes to attenuate glomerulosclenosis and renal dysfunction in murine diabetic nephropathy."Am.J.Physiol.. 286. F134-F143 (2004)
• [Publications] J.Wen, et al.: "Hydrocortisone potentiates hepatocyte growth factor expression in vascular endothelial cells."Biomed.Res.. In press. (2004)
• [Publications] K.Oshima, et al.: "Intrathecal injection of HVJ-E containing HGF gene to cerebrospinal fluid can prevent and ameliorate hearing impairment in rats."FASEB J. 18. 212-214 (2004)
• [Publications] N.Hattori, et al.: "The plasminogen activation system reduces fibrosis in the lung by a hepatocyte growth factor-dependent mechanism."Am.J Pathol.. In press. (2004)
• [Publications] H.Takahashi, et al.: "LIM-kinase as a regulator of actin dynamics in spermatogenesis."Cytogenie and Genome Research. In press. (2004)
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• [Publications] H.Funakoshi, T.Nakamura: "Hepatocyte growth factor : from diagnosis to clinical applications."Clin.Chem Acta. 327. 1-23 (2003)
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• [Publications] M.Nakabayashi, et al.: "HGF/NK4 inhibited VEGF-induced angiogenesis in in vitro cultured endothelial cells and in vivo rabbit model."Diabetologia. 46. 115-123 (2003)
• [Publications] T.Manabe, et al.: "Cell-based protein delivery system for pancreatic cancer therapy : NK4 gene-transduced oral mucosal epithelial cell sheet."Clin Cancer Res.. 9. 3158-3166 (2003)
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• [Publications] 橋ガ迫敦子, 他: "血液・免疫・腫瘍"メディカルレビュー社. 8 (2003)
• [Publications] 中村敏一: "日本医師会雑誌"日本医師会. 5 (2003)
• [Publications] 田村隆彦, 他: "Biotherapy"癌と化学療法社. 8 (2003)
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• [Publications] 松本邦夫, 中村敏一: "日本内科学雑誌"日本内科学学会. 5 (2003)
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• [Publications] K.Bessho, et al.: "Counteractive effects of HGF on PDGF-mediated mesangial cell proliferation in a rat model of glomerulonephritis"Am.J.Physiol.. (In press). (2003)
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• [Publications] W.Sun: "Overexpression of HGF retards disease progression and prolongs life span in a transgenic mouse model of ALS"J.Neurosci.. 22. 6537-6548 (2002)
• [Publications] Y.Sakamaki, et al.: "Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during ostpneumonectomy compenbatory lung growth in mice"Am.J.Respir.Cell Mol.Biol.. 26. 525-533 (2002)
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• [Publications] H.Funakoshi, et al.: "Identification of Gas 6, a putative ligand for Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons"J.Neursci.Res.. 68. 150-160 (2002)
• [Publications] T.Sumi, et al.: "Mitosis-dependent phosphorylation and activation of LIM-kinase 1"Biochem.Biophys.Res.Commun.. 290. 1315-1320 (2002)
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• [Publications] W.Sun, et al.: "Localization and functional role of hepatocyte growth factor (HGF) and its receptor c-Met in the rat developing cerebral cortex"Mol.Brain Res.. 103. 36-48 (2002)
• [Publications] H.Shibuki, et al.: "Expression and neuroprotective effect of hepatocyte growth factor in retinal ischemic-reperfusion injury"Invest.Ophthalmol.Vis.Sci.. 43. 528-536 (2002)
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• [Publications] M.Saimura, et al.: "Intraperitoneal injection of adenovirus-mediated NK4 gene suppresses peritoneal dissemination of pancreatic cancer cell line AsPC-1 in nude mice"Cancer Gene Therapy. 9. 799-806 (2002)
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• [Publications] 水野信哉, 他: "臨床免疫2003"科学論評社(印刷中). (2003)
• [Publications] 福田一弘, 他: "遺伝子医学別"メディカルドゥ(印刷中). (2003)
• [Publications] 水野信哉, 他: "再生医学・再生医療"東京化学同人. 12 (2002)
• [Publications] 水野信哉, 他: "Annual Review 腎臓"中外医学社. 11 (2002)
• [Publications] 別所一彦, 他: "遺伝子医学"メディカルドウ. 7 (2002)
• [Publications] 別所一彦, 他: "実験医学増刊"羊土社. 9 (2002)
• [Publications] 角 智行, 他: "生化学"日本生化学学会. 6 (2002)
• [Publications] 松本邦夫, 他: "日経サイエンス"日本経済新聞社. 12 (2002)
• [Publications] 坂巻靖, 他: "The Lung Perspective"メディカルレビュー社. 8 (2002)
• [Publications] 久場敬司, 他: "実験医学増刊"羊土社. 8 (2002)
• [Publications] T.Sumi, et al.: "Cofilin phosphorylation and actin cytoskeletal dynamics regulated by Rho-and Cdc42-activated LIM-kinase2"J.Cell Biol.. 147. 1519-1532 (1999)
• [Publications] T.Ueki, et al.: "Hepatocyte growth factor gene therapy of liver cirrhosis in rats"Nature Medicine. 5. 226-230 (1999)
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• [Publications] R.Hasina, et al.: "Autocrine and paracrine motility factors and their involvement in invasiveness in a human oral carcinoma cell line"Brit.J.Cancer. 80. 1708-1717 (1999)
• [Publications] N.Taniura-Matsumoto, et al.: "Prostaglandin production in mouse mammary carcinoma cells confers invasive growth potential by inducing hepatocyte growth factor in fibroblasts"Brit.J.Cancer. 81. 194-202 (1999)
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• [Publications] K.Kuba, et al.: "HGF/NK4, a four-kringle fragment of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice"Cancer Res.. 60. 6737-6743 (2000)
• [Publications] T.Nakamura, et al.: "Myocardial protection from infarction by endogenous and exogenous hepatocyte growth factor"J.Clin.Invest.. 106. 1511-1519 (2000)
• [Publications] S.Mizuno, et al.: "Reciprocal balance of hepatocyte growth factor and transforming growth factor-beta1 In renal fibrosis in mice"Kidney Intern.. 57. 937-948 (2000)
• [Publications] T.Yamada, et al.: "Enhanced expression of hepatocyte growth factor by pulmonary ischemia reperfusion injury in the rat"Am.J.Resp. Crit Care Med.. 162. 707-715 (2000)
• [Publications] S.Hiscox, et al.: "Inhibition of HGF-induced breast cancer cell matility and invasion by the HGF variant NK4"Breast Cancer Res. & Treat.. 59. 245-254 (2000)
• [Publications] K.Beppu, et al.: "Elevation of serum hepatocyte growth factor concentration in patients with gastric cancer is mediated by production by tumor tissue"Anticancer Res.. 20. 1263-1268 (2000)
• [Publications] T.Sumi, et al.: "Specific activation of LIM-kinase 2 via threonine-505 phosphoiylation by ROCK under the control of Rho"J.Biol.Chem.. 276. 670-676 (2001)
• [Publications] T.Sumi, et al.: "Activation of LIM-kinases by Myotonic dystrophy kinase-related Cdc 42-binding kinase-alpha"J.Biol.Chem.. 276. 23092-23096 (2001)
• [Publications] S.Mizuno, et al.: "Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy"Kidney Intern.. 59. 1304-1314 (2001)
• [Publications] K.Matsumoto, T.Nakamura: "Hepatocyte growth factor renotropic role and potential therapeutics for renal diseases"Kidney Intern.. 59. 2023-2038 (2001)
• [Publications] K.Matsumoto, et al.: "Hepatocyte growth factor in renal regeneration, renal disease, and potential therapeutics"Current Opinion in Nephrogy and Hypertension. 8. 395-402 (2001)
• [Publications] T.Kuroiwa, et al.: "Hepatocyte growth factor ameliorates acute graft-verus-host disease and promotes hematopoietic function"J.Clin.Invest.. 107. 1365-1373 (2001)
• [Publications] N.Maehara, et al.: "NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells"Br.J.Cancer. 84. 864-873 (2001)
• [Publications] H.Azuma, et al.: "Hepatocyte growth factor prevents development of chronic allograft nephropathy in an experimental rat transplant model"J.Am.Soc.Nephrol.. 12. 1280-1292 (2001)
• [Publications] T.Nakamura: "Molecular cloning and characterization of Kremen, a novel Kringle-containing transmembrane protein"Biochem.Biophys.Acta. 93513. 1-10 (2001)
• [Publications] D.Tomioka, et al.: "Inhibition of growth, invasion and metastasis of human panereatic carcinoma cells by NK4 in an orthotopic mouse model"Cancer Res.. 61. 7518-7524 (2001)
• [Publications] Y.Taniyama, et al.: "Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hind limb ischemia models : Preclinical study for treatment of peripheral arterial disease"Gene Therapy. 8. 181-189 (2001)
• [Publications] K.Hayashi, et al.: "Gene therapy for preventing neuronal death using hepatocyte growth factor in vivo gene transfer of HGF to subarachiroid space prevents delayed neuronal death in gerbil hipopocampal CA1 neurons"Gene Therapy. 8. 1263-1268 (2001)
• [Publications] H.Takahashi, et al.: "Impaired spematogenic ability of testicular germ cells in mice dificient in the LIM-kinase 2 gene"Develop.Biol.. 241. 259-272 (2002)
• [Publications] T.Sumi, et al.: "Mitosis-Dependent Phosphorylation and Activation of LIM-Kinase 1"Biochem.Biophys.Res.Commun.. 290. 1315-1320 (2002)
• [Publications] H.Funakoshi, et al.: "Identification of Gas 6, a putative ligand for Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons"J.Neursci.Res.. (In press). (2002)
• [Publications] Y.Taniyama, et al.: "Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat diabetic hind limb ischemia model : Molecular mechanisms of delayed angiogenesis in diabetes"Circulation. 104. 2344-2350 (2002)
• [Publications] H.Shibuki, et al.: "Expression and neuroprotective effect of hepatocyte growth factor in retinal ischemic-reperfusion injury"Invest.Ophthalmol.Vis.Sci.. 43. 528-536 (2002)
• [Publications] Y.Sakamaki, et al.: "Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postpneumonectomy compensatory lung growth in mice"Am.J.Respir.Cell Mol.Biol.. (In press). (2002)
• [Publications] 松本邦夫: "HGFによる再生医学の実践-肝臓と腎臓を中心として"実験医学. 18. 424-430 (1999)
• [Publications] 松本邦夫, 他: "HGFの分子内断片NK4による血管新生阻害と制癌"Molecular Medicine. 37. 276-282 (2000)
• [Publications] 松本邦夫, 他: "二面性癌悪化性阻止分子HGF/NK4による新しい癌治療"治療. 82. 1642-1644 (2000)
• [Publications] 船越洋, 他: "HGFの神経系における機能と神経疾患治療への展望"神経研究の進歩. 44. 414-422 (2000)
• [Publications] 松本邦夫, 他: "浸潤・転移ならびに血管新生阻害作用を有するHGFの分子内断片NK4による癌悪性化阻止"生物物理化学. 44. 119-124 (2000)
• [Publications] 小清水右一, 他: "HGFと形態形成"現代治療. 32. 1931-1938 (2000)
• [Publications] 久場啓司, 他: "NK4による癌の浸潤・転移抑制と腫瘍血管新生阻害"分子がん治療. 1. 46-55 (2000)
• [Publications] 前原直樹, 他: "新規浸潤・転移/血管新生阻止因子NK4(malignostatin)による癌治療"Cancer Frontier. 2. 61-68 (2000)
• [Publications] 仲村輝也, 他: "HGF(肝細胞増殖因子)-臓器再生・保護機能と再生治療への応用-"救急医学. 24. 1604-1610 (2000)
• [Publications] 松本邦夫, 他: "NK4(malignostatin)による癌悪性化防止:浸潤・転移・血管新生阻止による新しい制癌戦略"最新医学. 55. 1960-1968 (2000)
• [Publications] 富岡大策, 他: "HGFを介した腫瘍血管新生とNK4による制癌"医学のあゆみ. 194. 792-798 (2000)
• [Publications] 松本邦夫, 他: ""肝細胞の培養法"「細胞生物学実験法I」"広川書店. 20 (1999)
• [Publications] K.Matsumoto, et al.: "Hepatocyte growth factor and Met in tumour invasion-metastasis : from mechanisms to cancer prevention. In "Cancer Metastasis : Molecular & Cellular Mechanisms and Clinical Interventions""Kluwer Academic Publishers. 50 (2000)
• [Publications] K.Matsumoto, et al.: "HGF-c-Met receptor pathway in tumor invasion-metastasis and potential cancer treatment with NK4. In "Growth Factors and Their Receptors in Cancer Metastasis""Kluwer Academic Publishers. 35 (2001)
• [Publications] K.Matsumoto, et al.: "分担: HGF-c-Met receptor pathway in tumor invasion-metastasis and potential cancer treatment with NK4 書名: Growth Factors and Their Receptors in Cancer Metastasis"Kluwer Academic Publisher. 35 (2001)
• [Publications] 水野信哉, 中村敏一: "先端医療シリーズ7・泌尿器科:診断と治療の最前線"先端医療技術研究所. 11 (2000)
• [Publications] 水野信哉, 中村敏一: "Annual Review 腎臓2000"中外医学社. 8 (2000)
• [Publications] S.Hiscox: "Inhibition of HGF/SF-induced breast cancer cell matility and invasion by the HGF/SF variant, NK4."Breast Cancer Res.& Treat.. 59. 245-254 (2000)
• [Publications] M.Nakano: "Hepatocyte growth factor is essential for amelioration of hyperglycemia in strepto zotocin-induced diabetic mice receiving a marginal mass of intrahepnic islet grafts."Transplantation. 69. 214-221 (2000)
• [Publications] S.Mizuno: "Reciprocal balance of hepatocyte growth factor and transforming growth factor-β1 in renal fibrosis in mice"Kidney Intern.. 57. 937-948 (2000)
• [Publications] K.Beppu: "Elevation of serum hepatocyte growth factor concentration in patients with gastric cancer is mediated by production by tumor tissue."Anticancer Res.. 20. 1263-1268 (2000)
• [Publications] M.Aoki: "Angiogenesis induced by hepatocyte growth factor in non-infarcted myocardium and infarcted myocardium : up-regalation of essential transcription factor for angiogenesis, ets."Gene Therapy. 7. 417-427 (2000)
• [Publications] T.Yamada: "Enhanced expression of hepatocyte growth factor by pulmonary ischemia reperfusion injury in the rat."Am.J.Resp.Crit Care Med.. 162. 707-715 (2000)
• [Publications] Y.Taniyama: "Potential contribution of a novel anti-fibrotic factor, hepatocyte growth factor, to prevention of myocardial fibrosis by angiotensin II blockade in cardiomyopathic hamster."Circulation. 102. 246-252 (2000)
• [Publications] T.Kunisada: "Keratinocyte expression of transgenic hepatocyte growth factor (HGF) affects melanocyte development, leading to dermal melanocytosis."Mech.Dev.. 94. 67-78 (2000)
• [Publications] S.Radaeva: "Unique epithelial cell production of hepatocyte growth factor/scatter factor by putative precancerous intestinal metaplasias and associated "intestinal-type" of biliary cancer chemically-induced in rat liver."Hepatology. 31. 1257-1265 (2000)
• [Publications] J.-M.Otte: "Functional expression of HGF and its receptor in human colorectol Cancer."Digestion. 61. 237-246 (2000)
• [Publications] O.Muto: "HGF/SF-induced spreading of MDCK cells corelates with disappearance of barmotin/7H6, a tight junction-associated protein, from the cell membrane."Cell Biol.Intern.. 24. 439-446 (2000)
• [Publications] T.Kikuchi: "Secretory leukoprotease inhibitor augments hepatocyte growth factor production in human lung fibroblasts."Am.J.Respir.Cell Mol.Biol.. 23. 364-370 (2000)
• [Publications] K.Hayashi: "In vivo transfer of human hepatocyte growth factor gene accelerates re-endothelization and inhibition neointimal formation after balloon injury in rat model."Gene Therapy. 7. 1664-1671 (2000)
• [Publications] H.Nakagami: "Anti-apoptotic action of hepatocyte growth factor through mitogen-activated protein kinase on human aortic endothelial cells."J.Hypertension. 18. 1411-1420 (2000)
• [Publications] T.Nakamura: "Myocardial protection from infarction by endogenous and exogenous hepatocyte growth factor."J.Clin.Invest.. 106. 1511-1519 (2000)
• [Publications] K.Kuba: "HGF/NK4, a four-kringle fragment of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice."Cancer Res.. 60. 6737-6743 (2000)
• [Publications] K.Kuba: "Kringle 1-4 of hepatocyte growth factor inhibits proliferation and migration of human microvascular endothelial cells."Biocem.Biophys.Res.Commun.. 279. 846-852 (2000)
• [Publications] W.Sun: "A sensitive quantification method for evaluating the lebel of hepatocyte growth factor and c-met/HGF receptor mRNAs in the nervous system using competitive RT-PCR."Brain Res.Protoc.. 5. 190-7 (2000)
• [Publications] G.H.Lai: "Unique epithelial cell production of hepatocyte growth factor/scatter factor by putative precancerous intestinal metaplasias and associated"intestinal-type"biliary cancer chemically induced in rat liver."Hepatology. 31. 1257-1265 (2000)
• [Publications] G.Shiota: "In vivo transfer of hepatocyte growth factor gene accelerates proliferation of hepatic oval cells in a 2-acetylaminofluorene/partial hepatectomy model in rats."FEBS Lett.. 470. 325-330 (2000)
• [Publications] K.Matsumoto: "Hepatocyte growth factor and met in tumor invasion-metastasis : Mechanisms related to cancer prevention. In "Cancer metastasis, molecular and cellular biology and clinical aspects""Academic Publishers. 143-193 (2000)
• [Publications] K.Matsumoto: "Hepatocyte growth factor in renal regeneration, renal disease, and potential therapeutics."Hypertension. 9. 395-402 (2000)
• [Publications] T.Takahashi: "Functional involvement of LIM-kinase in Xenopus oocyte maturation."Develop.Biol.. 229. 554-567 (2001)
• [Publications] T.Sumi: "Specific activation of LIM-kinase 2 via threonine-505 phosphorylation by ROCK under the control of Rho."J.Biol.Chem.. 276. 670-676 (2001)
• [Publications] F.Tamura: "FK506 promotes liver regeneration by suppressing natural killer cell activity.".Gastroenterol.and Hepatol.. (in press). (2001)
• [Publications] A.Uchiyama: "Significance of locally-secreted hepatocyte growth factor after thoracic cancer surgery as a stimulator for postoperative cancer invasion."Jpn.J.Clin.Oncol.. (in press). (2001)
• [Publications] H.Azuma: "Hepatocyte growth factor prevents development of chronic allograft nephropathy in an experimental rat transplant model."J.Am.Soc.Nephrol.. (in press). (2001)
• [Publications] S.Mizuno: "Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy."Kidney Intern.. (in press). (2001)
• [Publications] K.Nakamura: "Molecular cloning and functional characterization of human scavenger receptor with c-type lectin (SRCL), a novel member of scavenger receptor family."Biochem.Biophys.Res.Commun.. (in press). (2001)
• [Publications] N.Maehara: "NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells."Br.J.Cancer. (in press). (2001)
• [Publications] T.Nakamura: "Molecular cloning and characterization of Kremen, a novel Kringle-containing transmembrane protein."Biochem.Biophys.Acta. (in press). (2001)
• [Publications] N.Tsuzuki: "Hepatocyte growth fector reduces the infarct volume after transient focal cerebral ischemia."Neurol.Res.. (in press). (2001)
• [Publications] K.Matsumoto: "Hepatocyte growth factor : renotropic role and potential therapeutics for renal diseases."Kidney Intern.. (in press). (2001)
• [Publications] K.Matsumoto: "Cancer Metastasis: Molecular & Cellular Mechanisms and Clinical Interventions"Kluwer Academic Publisher. 50 (2000)
• [Publications] K.Matsumoto: "Growth Factors and Their Receptors in Cancer Metastasis"Kluwer Academic Publisher (in press). (2001)