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

• Project/Area Number: 15K08311
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: University 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: ¥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.

Research Products

• [Int'l Joint Research] INSERM(France)
• [Int'l Joint Research] INSERM(France)
• [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
  • 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
  • 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
  • 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
  • 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 signaling (2015)
  • 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
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Ghrelin administration suppresses inflammation-associated colorectal carcinogenesis in mice (2015)
  • 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
  • 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
• [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
• [Presentation] Accelerated tumor formation induced by Hai-1 deficiency in the ApcMin/+ model is prevented by concomitant deficiency of Par-2 (2017)
  • Author(s): Kawaguchi M, Yamamoto K, FukushimaT, Camerer E, Kataoka H
  • Organizer: ASBMB Special Symposia Series; Membrane-Anchored Serine Proteases
  • Int'l Joint Research
• [Presentation] Excess activation of PAR-2 increased frequency of tumor formation in HAI-1 deficient ApcMin+ mice (2017)
  • Author(s): Kawaguchi M, Yamamoto K, Fukushima T, Kataoka H
  • Organizer: 第76回日本癌学会学術総会
• [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
• [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
• [Presentation] Loss of HAI-1 upregulates MMP-9 expression and induces degradation of epidermal basement membrane (2016)
  • 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
• [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
• [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
• [Presentation] HGF activator inhibitors (HAIs) may have fundamental roles in biology of colon adenocarcinoma cells (2015)
  • 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
• [Presentation] Protease-activated receptor-2 is not involved in the susceptibility to DSS-induced colitis associated with HAI-1deficiency (2015)
  • 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
  • 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