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Roles of HAI-1, a membrane-anchored serine protease inhibitor, in intestinal carcinogenesis through regulating pericellular proteolysis

Research Project

Project/Area Number 15K08311
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pathological medical chemistry
Research InstitutionUniversity of Miyazaki

Principal Investigator

Kawaguchi Makiko  宮崎大学, 医学部, 助教 (90405598)

Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsセリンプロテアーゼ / セリンプロテアーゼインヒビター / 腸管発癌 / HAI-1 / PAR-2
Outline of Final Research Achievements

Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is a membrane-bound serine protease inhibitor expressed on epithelial and carcinoma cell surface. We have previously reported that HAI-1 KO mice showed significantly accelerated tumor formation in the intestine. This study aimed to analyze the roles for HAI-1 in intestinal carcinogenesis. To examine whether PAR-2 signaling is responsible for increased tumor formation observed with Hai-1 deficiency in the ApcMin+ model, we generated HAI-1,PAR-2 double KO mice. We observed that concomitant knockout of PAR-2 reduced the formation of intestinal tumors. Moreover, loss of PAR-2 alleviate the activation of NF-kB in the HAI-1 KO intestine. These results suggested that insufficient Hai-1 function induced PAR-2 activation. Excess activation of PAR-2 induces the activation of NF-kB signaling, which may be responsible for increased intestinal tumorigenesis.

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (20 results)

All 2018 2017 2016 2015 Other

All Int'l Joint Research (2 results) Journal Article (6 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 6 results,  Open Access: 4 results,  Acknowledgement Compliant: 3 results) Presentation (12 results) (of which Int'l Joint Research: 2 results)

  • [Int'l Joint Research] INSERM(France)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] INSERM(France)

    • Related Report
      2016 Research-status Report
  • [Journal Article] Hepatocyte growth factor activator inhibitor type-2 (HAI-2)/SPINT2 contributes to invasive growth of oral squamous cell carcinoma cells.2018

    • Author(s)
      Yamamoto K, Kawaguchi M, ShimomuraT, Izumi A, Konari K, Honda A, Lin CY, Johnson MD, Yamashita Y, FukushimaT and Kataoka K.
    • Journal Title

      Oncotarget.

      Volume: 9 Issue: 14 Pages: 11691-11706

    • DOI

      10.18632/oncotarget.24450

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Prognostic significance of hepatocyte growth factor activator inhibitor type 1 (HAI-1)/SPINT1 immunoreactivity in pancreatic ductal adenocarcinoma.2017

    • Author(s)
      Sakugawa C, Haruyama Y, Tanaka H, Fukushima T, Kawaguchi M, Kataoka H
    • Journal Title

      BMC Res Notes

      Volume: 10:674 Issue: 1 Pages: 1-7

    • DOI

      10.1186/s13104-017-3014-x

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Deregulated matriptase activity in oral squamous cell carcinoma promotes the infiltration of cancer‐associated fibroblasts by paracrine activation of protease‐activated receptor 2.2017

    • Author(s)
      Kanemaru A, Yamamoto K, Kawaguchi M, Fukushima T, Lin C-Y, Johnson MD, Camerer E, Kataoka H.
    • Journal Title

      International Journal of Cancer

      Volume: 140 Issue: 1 Pages: 130-141

    • DOI

      10.1002/ijc.30426

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Inhibition of nuclear factor-κB signaling suppresses Spint1-deletion-induced tumor susceptibility in the ApcMin/+ model.2016

    • Author(s)
      Kawaguchi M, Yamamoto K, Kanemaru A, Tanaka H, Umezawa K, Fukushima T, Kataoka H.
    • Journal Title

      Oncotarget

      Volume: 7 Issue: 42 Pages: 68614-68622

    • DOI

      10.18632/oncotarget.11863

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Hepatocyte growth factor activator inhibitor type 1 maintains the assembly of keratin into desmosomes in keratinocytes by regulating protease-activated receptor 2-dependent p38 signaling2015

    • Author(s)
      Kawaguchi M, Kanemaru A, Sawaguchi A, Yamamoto K, Baba T, Lin C-Y, Johnson MD, Fukushima T, Kataoka H
    • Journal Title

      Am. J. Pathol.

      Volume: 185 Issue: 6 Pages: 1610-1623

    • DOI

      10.1016/j.ajpath.2015.02.009

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Ghrelin administration suppresses inflammation-associated colorectal carcinogenesis in mice2015

    • Author(s)
      Kawaguchi M, Kanemaru A, Fukushima T, Yamamoto K, Tanaka H, Haruyama Y, Itoh H, Matsumoto N, Kangawa K, Nakazato M, Kataoka H
    • Journal Title

      Cancer Sci.

      Volume: 106 Issue: 9 Pages: 1130-1136

    • DOI

      10.1111/cas.12725

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 表皮及び毛髪の形態形成の諸段階におけるHAI-1発現の意義に関する検討2017

    • Author(s)
      川口真紀子、山本晃士、福島剛、片岡寛章
    • Organizer
      第106回日本病理学会総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] HAI-1欠損はPAR-2シグナル活性化を介して腸管発癌を亢進させる2017

    • Author(s)
      川口真紀子、山本晃士、福島剛、片岡寛章
    • Organizer
      第22回日本病態プロテアーゼ学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Accelerated tumor formation induced by Hai-1 deficiency in the ApcMin/+ model is prevented by concomitant deficiency of Par-22017

    • Author(s)
      Kawaguchi M, Yamamoto K, FukushimaT, Camerer E, Kataoka H
    • Organizer
      ASBMB Special Symposia Series; Membrane-Anchored Serine Proteases
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Excess activation of PAR-2 increased frequency of tumor formation in HAI-1 deficient ApcMin+ mice2017

    • Author(s)
      Kawaguchi M, Yamamoto K, Fukushima T, Kataoka H
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] HAI-1 は proteasxe activated receptor-2 (PAR-2) を介して表皮及び毛髪の形態形成を維持する2017

    • Author(s)
      川口真紀子、山本晃士、福島剛、片岡寛章
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] PAR-2活性化は軽度のDSS誘発大腸炎におけるHAI-1欠損マウスの感受性亢進に関与する2016

    • Author(s)
      川口真紀子、山本晃士、福島剛、片岡寛章
    • Organizer
      第39回日本分子生物学会年会
    • Place of Presentation
      横浜市
    • Year and Date
      2016-11-30
    • Related Report
      2016 Research-status Report
  • [Presentation] Loss of HAI-1 upregulates MMP-9 expression and induces degradation of epidermal basement membrane2016

    • Author(s)
      Kawaguchi M, Fukushima T, Kataoka H
    • Organizer
      第75回日本癌学会学術総会
    • Place of Presentation
      横浜市
    • Year and Date
      2016-10-06
    • Related Report
      2016 Research-status Report
  • [Presentation] HAI-1欠損はPAR-2活性化を介して炎症に対する感受性を亢進させる2016

    • Author(s)
      川口真紀子、山本晃士、福島剛、片岡寛章
    • Organizer
      第21回日本病態プロテアーゼ学会
    • Place of Presentation
      豊中市
    • Year and Date
      2016-08-05
    • Related Report
      2016 Research-status Report
  • [Presentation] HAI-1欠損はnuclear factor-κB経路の活性化を介して腸管発癌を亢進させる2016

    • Author(s)
      川口真紀子、山本晃士、福島剛、片岡寛章
    • Organizer
      第34回日本ヒト細胞学会学術集会
    • Place of Presentation
      奈良市
    • Year and Date
      2016-07-16
    • Related Report
      2016 Research-status Report
  • [Presentation] HGF activator inhibitors (HAIs) may have fundamental roles in biology of colon adenocarcinoma cells2015

    • Author(s)
      Kawaguchi M, Fukushima T, Kataoka H
    • Organizer
      第74回 日本癌学会学術集会
    • Place of Presentation
      名古屋市
    • Year and Date
      2015-10-08
    • Related Report
      2015 Research-status Report
  • [Presentation] Protease-activated receptor-2 is not involved in the susceptibility to DSS-induced colitis associated with HAI-1deficiency2015

    • Author(s)
      Kawaguchi M, Kanemaru A, Yamamoto K, Fukushima T, Camerer E, Kataoka H
    • Organizer
      ASBMB Special Symposia Series; Membrane-Anchored Serine Proteases
    • Place of Presentation
      Potomac, MD, USA
    • Year and Date
      2015-09-17
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] HAI-1による標的プロテアーゼ活性調節を介したがん悪性形質の制御2015

    • Author(s)
      川口真紀子、 福島剛、金丸愛、山本晃士、田中弘之、片岡 寛章
    • Organizer
      第33回 日本ヒト細胞学会学術集会
    • Place of Presentation
      宮崎市
    • Year and Date
      2015-08-22
    • Related Report
      2015 Research-status Report

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Published: 2015-04-16   Modified: 2019-03-29  

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