細胞外基質分解とがん細胞の浸潤制御機構

• Project/Area Number: 12215023
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: 清木 元治 東京大学, 医科学研究所, 教授 (10154634)
• Co-Investigator(Kenkyū-buntansha): 後藤 勇 東京大学, 医科学研究所, 助手 (40323638) ; 森 英俊 東京大学, 医科学研究所, 教務職員 (00323642) ; 木全 弘治 愛知医科大学, 分子医学研究所, 教授 (10022641) ; 宮崎 香 横浜市立大学, 木原生物学研究所, 教授 (70112068) ; 森本 幾夫 東京大学, 医科学研究所, 教授 (30119028)
• Project Period (FY): 2000 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥281,100,000 (Direct Cost: ¥281,100,000); Fiscal Year 2004: ¥54,000,000 (Direct Cost: ¥54,000,000); Fiscal Year 2003: ¥54,000,000 (Direct Cost: ¥54,000,000); Fiscal Year 2002: ¥62,100,000 (Direct Cost: ¥62,100,000); Fiscal Year 2001: ¥54,000,000 (Direct Cost: ¥54,000,000); Fiscal Year 2000: ¥57,000,000 (Direct Cost: ¥57,000,000)
• Keywords: がん / 浸潤・転移 / マトリックスメタロプロテアーゼ / MT1-MMP / MMP-2 / CD44 / ラミニン / 癌細胞 / 細胞外基質 / MTCBP-1 / ヒアルロン酸 / 膜型マトリックスメタロプロテアーゼ / 細胞運動 / 浸潤転移 / メタロプロテアーゼ / MMP-7 / CD82 / インテグリン

Research Abstract

膜型マトリックスメタロプロテアーゼ(MT1-MMP)は、細胞上で細胞外基質分子や接着分子を切断することにより、がん細胞の浸潤や増殖を制御するプロテアーゼである。今年度は、その基質であるCD44とラミニン5に着目してその作用を解析した。接着分子であるCD44はMT1-MMPと結合し、MT1-MMPの局在を制御すると同時にMT1-MMPによって切断される。今回、MT1-MMPによるCD44の切断部位を決定し、切断部位特異的な抗体を作成した。その結果、MT1-MMPがCD44の主たる切断酵素であるADAMとは異なる部位を切断すること、また、MT1-MMPによる切断が腫瘍部において亢進していることを明らかにした。
MT1-MMPはラミニン5に対しても切断活性を持つと同時に、ラミニン上での細胞運動を亢進させる。今回、ラミニン5のgamma2モノマー鎖はヘテロトリマーで存在する分子に比べて10倍の感受性でMT1-MMPによってプロセッシングされEGF様活性を持つ断片を生成することを明らかにした。CD44およびラミニン5のプロセッシングに関与すると報告されている他のプロテアーゼとの関係で、MT1-MMPが担当する部分の理解が深まった。

Research Products

• [Journal Article] Membrane-type matrix metalloproteinase-1 (MT1-MMP) is a processing enzyme for human laminin gamma 2 chain (2005)
  • Author(s): Koshikawa, N.他4名
  • Journal Title: J.Biol.Chem. 280 Pages: 88-93
• [Journal Article] Constitutive and induced CD44 shedding by ADAM-like proteases and membrane-type 1 matrix metalloproteinase (2004)
  • Author(s): Nakamura, H.他7名
  • Journal Title: Cancer Research 64 Pages: 876-882
• [Journal Article] Membrane type 1 matrix metalloproteinase regulates collagen-dependent mitogen-activated protein/extracellular signal-related kinase activation and cell migration (2004)
  • Author(s): Takino, T.他5名
  • Journal Title: Cancer Research 64 Pages: 1044-1049
• [Journal Article] Differences between scirrhous and non-scirrhous human gastric carcinomas from the aspect of proMMP-2 activation regulated by TIMP-3 (2004)
  • Author(s): Yokoyama, T.他7名
  • Journal Title: Clin Exp Metastasis 21 Pages: 223-233
• [Publications] 植田純子 他: "Sequence-specific silencing of MT1-MMP expression suppresses tumor cell migration and invasion : importance of MT1-MMP as a therapeutic target for invasive tumors"Oncogene. 22巻. 22:8716-22:8872 (2003)
• [Publications] 松木宏和 他: "Monoclonal antibodies with defined recognition sequences in the stem region of CD44 : detection of differential glycosylation of CD44 between tumor and stromal cells in tissue"Cancer Research. 63巻. 8278-8283 (2003)
• [Publications] 滝野隆博 他: "Tetraspanin CD63 promotes targeting and lysosomal proteolysis of membrane-type 1 matrix metalloproteinase"Biochem Biophys Res Commun.. 304巻. 160-166 (2003)
• [Publications] 清木元治: "Membrane-type 1 matrix metalloproteinase : a key enzyme for tumor invasion"Cancer Letters. 194巻. 1-11 (2003)
• [Publications] 清木元治 他: "Role of pericellular proteolysis by membrane-type 1 matrix metalloproteinase in cancer invasion and angiogenesis"Cancer Metastasis Review. 22巻. 129-143 (2003)
• [Publications] 滝野隆博 他: "Cleavage of metastasis suppressor gene product KiSS-1 protein/metastin by matrix metalloproteinases"Oncogene. 22巻. 4617-4626 (2003)
• [Publications] 森英俊 他: "CD44 directs membrane-type 1 matrix metalloproteinase to lamellipodia by associating with its hemopexin-like domain"EMBO J. 21. 3949-3959 (2002)
• [Publications] 清木元治: "The cell surface : the stage for matrix metalloproteinase regulation of migration"Curr Opin Cell Biol. 14. 624-632 (2002)
• [Publications] 木全弘治 他: "Abnormal accumulation of hyaluronan matrix diminishes contact-inhibition of cell growth and promotes cell migration"Proc. Natl. Acad. Sci. USA. 99. 3609-3614 (2002)
• [Publications] 木全弘治 他: "Annexin VI, a putative cell-surface receptor for chondroitin sulfate chains"J. Cell. Sci. 115. 3309-3318 (2002)
• [Publications] Uekita T, Itoh Y, Yana I, Ohno H, Seiki M.: "Cytoplasmic tail dependent internalization of membrane-type 1 matrix metalloproteinase (MT1-MMP) is important for its invasion-promoting activity"Journal of Cell Biology. 155. 1345-1356 (2001)
• [Publications] Kajita M, Itoh Y, Chiba T, Mori H, Okada A, Kinoh H, Seiki M.: "Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration"Journal Of Cell Biology. 153. 893-904 (2001)
• [Publications] Itoh Y, Takamura A, Ito N, Maru Y, Sato H, Suenaga N, Aoki T, Seiki M.: "Homophilic complex formation of MT1-MMP facilitates proMMP-2 activation on the cell surface and promotes tumor cell invasion"The EMBO Journal. 20. 4782-4793 (2001)
• [Publications] Cha HJ, Okada A, Kim KW, Sato H, Seiki M.: "Identification of cis-acting promoter elements that support expression of membrane-type 1 matrix metalloproteinase (MT1-MMP) in v-src transformed Madin-Darby Canine Kidney Cells"Clinical and Experimental Metastasis. 18. 675-681 (2001)
• [Publications] Kojima,S. et al.: "MT6-MMP is the second GPI-anchored MMP."FEBS Letter. 480. 142-146 (2000)
• [Publications] Nabeshana,K., et al.: "Front-cell-specific expression of MT1-MMP and gelatinase A during cohort migration of colon carcinoma cells induced by HGE"Cancer Research. 60. 3364-3369 (2000)
• [Publications] Kim,K.R., et al.: "Transformation of MDCK epithelial cells by EB virus LMPS induced expression of Ets1 and inrasive growth"Oncogene. 19. 1764-1771 (2000)
• [Publications] Yamanaka,H., et al.: "Expression and tissue localization of MT1,2 and 3-MMP in rheumatoid synovium"Laboratory Investigation. 80. 677-687 (2000)
• [Publications] Ikashima,H., et al.: "Internalization of CD26 by mannose 6-phaphate/in salia-like growth factor II receptor contributes to T cell activation"Proceeding of National Acadency of Science, USA. 97. 8439-8444 (2000)
• [Publications] Koshikawa,N., et al.: "Role of cell surface metalloproteinse MT1-MMP in epithelial cell migration over laminin-5"Journal of Cell Biology. 148. 615-624 (2000)