Cell migration induced by alternation of extracellular matrix microenvironment

2010 Fiscal Year Final Research Report

• Project/Area Number: 20590306
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Kanazawa University
• Principal Investigator: TAKINO Takahisa Kanazawa University, がん研究所, 准教授 (40322119)
• Project Period (FY): 2008 – 2010
• Keywords: 細胞運動 / 浸潤 / ECM / MMP

Research Abstract

Membrane-type 1 matrix metalloproteinase (MT1-MMP) is essential for tumor invasion and growth. We show here that MT1-MMP induces extracellular signal-regulated kinase (ERK) activation in cancer cells cultured in collagen gel, which is indispensable for their proliferation. Inhibition of MT1-MMP by MMP inhibitor or small interfering RNA suppressed activation of focal adhesion kinase (FAK) and ERK in MT1-MMP-expressing cancer cells, which resulted in up-regulation of p21^<WAF1> and suppression of cell growth in collagen gel. Cell proliferation was also abrogated by the inhibitor against ERK pathway without affecting FAK phosphorylation. MT1-MMP and integrin α_vβ_3 were shown to be involved in c-Src activation, which induced FAK and ERK activation in collagen gel. These MT1-MMP-mediated signal transductions were paxillin dependent, as knockdown of paxillin reduced cell growth and ERK activation, and co-expression of MT1-MMP with paxillin induced ERK activation. The results suggest that MT1-MMP contributes to proliferation of cancer cells in the extracellular matrix by activating ERK through c-Src and paxillin.

Research Products

• [Journal Article] MT1-MMP promotes cell growth and ERK activation through c-Src and paxillin in three-dimentional collagen matrix. (2010)
  • Author(s): Takino, T., Tsuge, H., Ozawa, T., Sato, H.
  • Journal Title: Biochemical and Biophysical Research Communications 396 Pages: 1042-1047
  • Peer Reviewed
• [Journal Article] Coordinate action of membrane-type matrix metalloproteinase-1 (MT1-MMP) and MMP-2 enhances pericellular proteolysis and invasion. (2010)
  • Author(s): Sato, H., Takino, T.
  • Journal Title: Cancer Science 101 Pages: 843-847
  • Peer Reviewed
• [Journal Article] GI24 enhances tumor invasiveness by regulating cell surface membrane-type 1 matrix metalloproteinase. (2010)
  • Author(s): Sakr, M., Takino, T., Domoto, T., Nakano, H., Wong, R., Sasaki, M., Nakanuma, Y., Sato, H.
  • Journal Title: Cancer Science 101 Pages: 2368-2374
  • Peer Reviewed
• [Journal Article] Activation of matrix metalloproteinase-2 (MMP-2) by membrane type 1 matrix metalloproteinase through an artificial receptor for proMMP-2 generates active MMP-2. (2008)
  • Author(s): Nishida, Y., Miyamori, H., Thompson, E.W., Takino, T., Endo, Y., Sato, H.
  • Journal Title: Cancer Research 68 Pages: 9096-9104
  • Peer Reviewed
• [Journal Article] The scaffold protein c-Jun NH_2-terminal kinase-associated leucine zipper protein regulates cell migration through interaction with the G protein G (alpha 13). (2008)
  • Author(s): Gantulga, D., Tuvshintugs, B., Endo, Y., Takino, T., Sato, H., Murakami, S., Yoshioka, K.
  • Journal Title: Journal of Biochemistry 144 Pages: 693-700
  • Peer Reviewed
• [Presentation] MT1-MMPは3次元コラーゲンゲル内でc-Src1とPaxillinを介してERK活性化と細胞増殖を亢進する (2010)
  • Author(s): 滝野隆久、堂本貴寛、佐藤博
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪国際会議場(大阪府)
  • Year and Date: 2010-09-22
• [Presentation] MT1-MMPによる浸潤性細胞増殖誘導 (2009)
  • Author(s): 滝野隆久、佐藤博
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2009-10-03
• [Presentation] MT1-MMPによる浸潤性増殖誘導 (2008)
  • Author(s): 滝野隆久、佐藤博
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸国際会議場(兵庫県)
  • Year and Date: 2008-10-22
• [Presentation] MT1-MMPによる浸潤性増殖誘導 (2008)
  • Author(s): 滝野隆久、小澤晃正、西田有希、佐藤博
  • Organizer: 第17回日本がん転移学会学術集会
  • Place of Presentation: 鹿児島サンロイヤルホテル(鹿児島県)
  • Year and Date: 2008-07-24