Analysis of mechanism of serine protease activation by membrane-type matrix metalloproteinase

• Project/Area Number: 25460382
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Kanazawa University
• Principal Investigator: Sato Hiroshi 金沢大学, がん進展制御研究所, 教授 (00115239)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: がん転移 / マトリックスメタロプロテアーゼ / MT1-MMP / HAI-1 / セリンプロテアーゼ / MMP-9 / マトリプターゼ

Outline of Final Research Achievements

Membrane-Type Matrix Metalloproteinase (MT1-MMP) was shown to cleave and inactivate membrane-type serine protease inhibitor HAI-1(Hepatocyte Growth Factor Inhibitor-1), which subsequently induced activation of matriptase. Activated matriptase induced further activation of serine protease cascade, which was named “Protease Storm”. Protease storm caused Epithelial-Mesenchymal Transition (EMT) in cancer cells. These results indicate that MT1-MMP contributes to malignant transformation of cancer cells by triggering protease activation cascade.

Research Products

• [Journal Article] Tip60 regulates MT1-MMP transcription and invasion of glioblastoma cells through NF-κB pathway (2016)
  • Author(s): Takino T, Nakada M, Li Z, Yoshimoto T, Domoto T, Sato H.
  • Journal Title: Clinical & Experimental Metastasis Volume: ３３ Issue: 1 Pages: 45-52
  • DOI: 10.1007/s10585-015-9756-8
  • NAID: 120005680038
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] NECAB3 Promotes Activation of Hypoxia-inducible factor-1 during Normoxia and Enhances Tumourigenicity of Cancer Cells (2016)
  • Author(s): 1.Nakaoka HJ, Hara T, Yoshino S, Kanamori A, Matsui Y, Shimamura T, Sato H, Murakami Y, Seiki M, Sakamoto T
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 22784-22784
  • DOI: 10.1038/srep22784
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Suppressing TGFβ signaling in regenerating epithelia in an inflammatory microenvironment is sufficient to cause invasive intestinal cancer. (2015)
  • Author(s): Oshima H, Nakayama M, Han TS, Naoi K, Ju X, Maeda Y, Robine S, Tsuchiya K, Sato T, Sato H, Taketo MM, Oshima M.
  • Journal Title: Cancer Res. Volume: 75 Issue: 4 Pages: 766-776
  • DOI: 10.1158/0008-5472.can-14-2036
  • NAID: 120005593962
  • Peer Reviewed / Open Access
• [Journal Article] Glycogen synthase kinase 3β sustains invasion of glioblastoma via the focal adhesion kinase, Rac1 and c-Jun N-terminal kinase-mediated pathway. (2015)
  • Author(s): Chikano Y, Domoto T, Furuta T, Sabit H, Kitano-Tamura A, Ilya V. Pyko, Takino T, Sai Y, Hayashi Y, Sato H, Miyamoto K, Nakada M, MinamotoT.
  • Journal Title: Molecular Cancer Therapeutics Volume: 14 Issue: 2 Pages: 564-574
  • DOI: 10.1158/1535-7163.mct-14-0479
  • Peer Reviewed / Open Access
• [Journal Article] Membrane-type 1 matrix metalloproteinase regulates fibronectin assembly and N-cadherin adhesion. (2014)
  • Author(s): Takino T, Yoshimoto T, Nakada M, Li Z, Domoto T, Kawashiri S, Sato H.
  • Journal Title: Biochem Biophys Res Commun. Volume: ４５０ Issue: 2 Pages: 1016-1020
  • DOI: 10.1016/j.bbrc.2014.06.100
  • NAID: 120005478703
  • Peer Reviewed
• [Journal Article] Vinculin negatively regulates transcription of MT1-MMP through MEK/ERK pathway. (2014)
  • Author(s): Yoshimoto T, Takino T, Li Z, Domoto T, Sato H
  • Journal Title: Biochem Biophys Res Commun. Volume: 455 Issue: 3-4 Pages: 251-255
  • DOI: 10.1016/j.bbrc.2014.10.154
  • NAID: 120005537877
  • Peer Reviewed
• [Journal Article] Characterizing invading glioma cells based on IDH1-R132H and Ki-67 immunofluorescence. (2014)
  • Author(s): Sabit H, Nakada M, Furuta T, Watanabe T, Hayashi Y, Sato H, Kato Y, Hamada JI.
  • Journal Title: Brain Tumor Pathol Volume: 未定 Issue: 4 Pages: 3-3
  • DOI: 10.1007/s10014-013-0172-y
  • Peer Reviewed
• [Journal Article] MT1-MMP prevents growth inhibition by three dimensional fibronectin matrix. (2013)
  • Author(s): 1. Takino T, Guo L, Domoto T, Sato H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 30 Pages: 175-179
  • NAID: 120005302290
  • Peer Reviewed
• [Presentation] 炎症反応とTGFｂシグナル抑制による大腸がん浸潤誘導 (2015)
  • Author(s): 大島浩子、中山瑞穂、佐藤博、武藤誠、大島正伸
  • Organizer: 日本癌学会
  • Place of Presentation: 愛知県名古屋市 名古屋国際会議場
  • Year and Date: 2015-10-08
• [Presentation] GSK3ｂはFAK/JNK経路を介するMMPｓの発現亢進によって膠芽腫細胞の浸潤を推進する (2015)
  • Author(s): 堂本貴寛、古田拓也、滝野隆久、佐藤博、中田光俊、源利成
  • Organizer: 日本癌学会
  • Place of Presentation: 愛知県名古屋市 名古屋国際会議場
  • Year and Date: 2015-10-08
• [Presentation] VinculinはMEK/ERK経路を介したMT1-MMPの転写を不に制御する (2015)
  • Author(s): 吉本泰祐、滝野隆久、堂本貴寛、川尻秀一、佐藤博
  • Organizer: 日本癌学会
  • Place of Presentation: 愛知県名古屋市 名古屋国際会議場
  • Year and Date: 2015-10-08
• [Presentation] Tip60はNF-ｋB経路を介して膠芽腫のMT1-MMP発現と浸潤を制御する (2015)
  • Author(s): 滝野隆久、中田光俊、堂本貴寛、佐藤博
  • Organizer: 日本癌学会
  • Place of Presentation: 愛知県名古屋市 名古屋国際会議場
  • Year and Date: 2015-10-08
• [Presentation] VinculinはMEK/ERK経路を介したMT1-MMPの転写を不に制御する (2015)
  • Author(s): 吉本泰祐、滝野隆久、堂本貴寛、川尻秀一、佐藤博
  • Organizer: 日本がん転移学会
  • Place of Presentation: 大阪府大阪市 シティプラザ大阪
  • Year and Date: 2015-07-23
• [Presentation] GSK3ｂはFAK-Raｃ１－JNK経路を介して膠芽腫細胞の浸潤を推進する (2015)
  • Author(s): 堂本貴寛、滝野隆久、佐藤博、源利成
  • Organizer: 日本がん転移学会
  • Place of Presentation: 大阪府大阪市 シティプラザ大阪
  • Year and Date: 2015-07-23
• [Presentation] MT1-MMPによる細胞接着斑を介したフィブロネクチンマトリックス形成制御 (2014)
  • Author(s): 滝野隆久、吉本泰祐、佐藤博
  • Organizer: 第７３回日本癌学会学術総会
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] TX-2137をリード化合物としたAkt選択的抗転移低酸素サイトトキシンTX-２２８２の開発 (2014)
  • Author(s): 芝一休、遠藤良夫、佐藤博、宇都義浩
  • Organizer: 第７３回日本癌学会学術総会
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 慢性炎症とTGFｂシグナル抑制による消化管腫瘍の浸潤誘導 (2014)
  • Author(s): 大島浩子、中山瑞穂、佐藤博、武藤誠、大島正伸
  • Organizer: 第７３回日本癌学会学術総会
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] MT1-MMPによるフィブロネクチン重合とN-カドヘリン接着の制御 (2014)
  • Author(s): 吉本泰祐、滝野隆久、川尻修一、佐藤博
  • Organizer: 第２３回日本がん転移学会学術総会
  • Place of Presentation: 金沢（金沢市文化ホール）
  • Year and Date: 2014-07-10 – 2014-07-11
• [Presentation] MT1-MMPによる細胞接着ネットワークの制御 (2013)
  • Author(s): 滝野 隆久，堂本 貴寛，佐藤 博
  • Organizer: 第21回日本がん転移学会総会
  • Place of Presentation: 松本
• [Presentation] MT1-MMPによるＮ－カドヘリン接着制御 (2013)
  • Author(s): 滝野 隆久，堂本 貴寛，佐藤 博
  • Organizer: 第７２回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Book] 実験医学 (2015)
  • Author(s): 佐藤 博
  • Total Pages: 4
  • Publisher: 羊土社
• [Book] がん微小環境と標的治療 (2015)
  • Author(s): 滝野隆久、 佐藤博
  • Total Pages: 207
  • Publisher: 羊土社
• [Remarks] 金沢大学がん進展制御研究所
  • URL: http://www.kanazawa-u.ac.jp/~ganken/
• [Remarks] 金沢大学がん進展制御研究所
  • URL: http://www.kanazawa-u.ac.jp/~ganken/