KAWAGUCHI Makiko

写真a

Affiliation

Faculty of Medicine School of Medicine Oncopathology and morphopathology

Title

Assistant Professor

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Degree 【 display / non-display

  • 博士(医学) ( 2010.3   宮崎大学 )

Research Areas 【 display / non-display

  • Life Science / Experimental pathology

 

Papers 【 display / non-display

  • Protease-activated receptor-2 accelerates intestinal tumor formation through activation of nuclear factor-κB signaling and tumor angiogenesis in Apc<sup>Min/+</sup> mice Reviewed

    Kawaguchi M., Yamamoto K., Kataoka H., Izumi A., Yamashita F., Kiwaki T., Nishida T., Camerer E., Fukushima T.

    Cancer Science   111 ( 4 )   1193 - 1202   2020.4

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    Authorship:Lead author   Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Cancer Science  

    © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. Hepatocyte growth factor activator inhibitor-1 (HAI-1), encoded by the SPINT1 gene, is a membrane-bound protease inhibitor expressed on the surface of epithelial cells. Hepatocyte growth factor activator inhibitor-1 regulates type II transmembrane serine proteases that activate protease-activated receptor-2 (PAR-2). We previously reported that deletion of Spint1 in ApcMin/+ mice resulted in accelerated formation of intestinal tumors, possibly through enhanced nuclear factor-κB signaling. In this study, we examined the role of PAR-2 in accelerating tumor formation in the ApcMin/+ model in the presence or absence of Spint1. We observed that knockout of the F2rl1 gene, encoding PAR-2, not only eliminated the enhanced formation of intestinal tumors caused by Spint1 deletion, but also reduced tumor formation in the presence of Spint1. Exacerbation of anemia and weight loss associated with HAI-1 deficiency was also normalized by compound deficiency of PAR-2. Mechanistically, signaling triggered by deregulated protease activities increased nuclear translocation of RelA/p65, vascular endothelial growth factor expression, and vascular density in ApcMin/+-induced intestinal tumors. These results suggest that serine proteases promote intestinal carcinogenesis through activation of PAR-2, and that HAI-1 plays a critical tumor suppressor role as an inhibitor of matriptase, kallikreins, and other PAR-2 activating proteases.

    DOI: 10.1111/cas.14335

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  • Hepatocyte growth factor activator inhibitor-2 stabilizes Epcam and maintains epithelial organization in the intestine Reviewed

    Kawaguchi M., Yamamoto K., Takeda N., Fukushima T., Yamashita F., Sato K., Kitamura K., Hippo Y., Janetka J., Kataoka H.

    Communications biology   2   11   2019.1

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1038/s42003-018-0255-8

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  • Matriptase-2 regulates iron homeostasis primarily by setting the basal levels of hepatic hepcidin expression through a nonproteolytic mechanism Reviewed

    Enns C.A., Weiskopf T., Zhang R.H., Wu J., Jue S., Kawaguchi M., Kataoka H., Zhang A.S.

    Journal of Biological Chemistry   299 ( 10 )   105238   2023.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Journal of Biological Chemistry  

    Matriptase-2 (MT2), encoded by TMPRSS6, is a membrane-anchored serine protease. It plays a key role in iron homeostasis by suppressing the iron-regulatory hormone, hepcidin. Lack of functional MT2 results in an inappropriately high hepcidin and iron-refractory iron-deficiency anemia. Mt2 cleaves multiple components of the hepcidin-induction pathway in vitro. It is inhibited by the membrane-anchored serine protease inhibitor, Hai-2. Earlier in vivo studies show that Mt2 can suppress hepcidin expression independently of its proteolytic activity. In this study, our data indicate that hepatic Mt2 was a limiting factor in suppressing hepcidin. Studies in Tmprss6−/− mice revealed that increases in dietary iron to ∼0.5% were sufficient to overcome the high hepcidin barrier and to correct iron-deficiency anemia. Interestingly, the increased iron in Tmprss6−/− mice was able to further upregulate hepcidin expression to a similar magnitude as in wild-type mice. These results suggest that a lack of Mt2 does not impact the iron induction of hepcidin. Additional studies of wild-type Mt2 and the proteolytic-dead form, fMt2S762A, indicated that the function of Mt2 is to lower the basal levels of hepcidin expression in a manner that primarily relies on its nonproteolytic role. This idea is supported by the studies in mice with the hepatocyte-specific ablation of Hai-2, which showed a marginal impact on iron homeostasis and no significant effects on iron regulation of hepcidin. Together, these observations suggest that the function of Mt2 is to set the basal levels of hepcidin expression and that this process is primarily accomplished through a nonproteolytic mechanism.

    DOI: 10.1016/j.jbc.2023.105238

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  • Early-onset tufting enteropathy in HAI-2-deficient mice is independent of matriptase-mediated cleavage of EpCAM Reviewed

    Szabo R., Kawaguchi M., Kataoka H., Bugge T.H.

    Development (Cambridge)   150 ( 17 )   2023.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Development (Cambridge)  

    Congenital tufting enteropathy (CTE) is a life-threatening intestinal disorder resulting from loss-of-function mutations in EPCAM and SPINT2. Mice deficient in Spint2, encoding the protease inhibitor HAI-2, develop CTE-like intestinal failure associated with a progressive loss of the EpCAM protein, which is caused by unchecked activity of the serine protease matriptase (ST14). Here, we show that loss of HAI-2 leads to increased proteolytic processing of EpCAM. Elimination of the reported matriptase cleavage site strongly suppressed proteolytic processing of EpCAM in vitro and in vivo. Unexpectedly, expression of cleavage-resistant EpCAM failed to prevent intestinal failure and postnatal lethality in Spint2- deficient mice. In addition, genetic inactivation of intestinal matriptase (St14) counteracted the effect of Spint2 deficiency in mice expressing cleavage-resistant EpCAM, indicating that matriptase does not drive intestinal dysfunction by excessive proteolysis of EpCAM. Interestingly, mice expressing cleavageresistant EpCAM developed late-onset intestinal defects and exhibited a shortened lifespan even in the presence of HAI-2, suggesting that EpCAM cleavage is indispensable for EpCAM function. Our findings provide new insights into the role of EpCAM and the etiology of the enteropathies driven by Spint2 deficiency.

    DOI: 10.1242/dev.201801

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  • Adrenomedullin alleviates mucosal injury in experimental colitis and increases claudin-4 expression in the colonic epithelium. Reviewed

    Kawaguchi M, Kataoka H, Kiwaki T, Weiting L, Nagata S, Kitamura K, Fukushima T

    FEBS open bio   13 ( 4 )   713 - 723   2023.4

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1002/2211-5463.13577

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  • Hepatocyte growth factor activator (HGFA): Pathophysiological functions in vivo

    Kataoka H., Kawaguchi M.

    FEBS Journal   277 ( 10 )   2230 - 2237   2010.5

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (bulletin of university, research institution)   Publisher:FEBS Journal  

    Hepatocyte growth factor activator (HGFA) is a serine protease initially identified as a potent activator of hepatocyte growth factor/scatter factor. Hepatocyte growth factor/scatter factor is known to be critically involved in tissue morphogenesis, regeneration, and tumor progression, via its receptor, MET. In vivo, HGFA also activates macrophage-stimulating protein, which has roles in macrophage recruitment and inflammatory processes, cellular survival and wound healing through its receptor, RON. Therefore, the pericellular activity of HGFA might be an important factor regulating the activities of these multifunctional cytokines in vivo. HGFA is secreted mainly by the liver, circulates in the plasma as a zymogen (pro-HGFA), and is activated in response to tissue injury, including tumor growth. In addition, local production of pro-HGFA by epithelial, stromal or tumor cells has been reported. Although the generation of HGFA-knockout mice revealed that the role played by HGFA in normal development and physiological settings can be compensated for by other protease systems, HGFA has important roles in regeneration and initial macrophage recruitment in injured tissue in vivo. Insufficient activity of HGFA results in impaired regeneration of severely damaged mucosal epithelium, and may contribute to the progression of fibrotic lung diseases. On the other hand, deregulated excess activity of HGFA may be involved in the progression of some types of cancer. © 2010 FEBS.

    DOI: 10.1111/j.1742-4658.2010.07640.x

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  • Activation of MET receptor tyrosine kinase in ulcer surface epithelial cells undergoing restitution

    Nagai M., Takahashi N., Miyazawa K., Kawaguchi M., Chijiiwa K., Kataoka H.

    Pathology International   58 ( 7 )   462 - 464   2008.7

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (bulletin of university, research institution)   Publisher:Pathology International  

    DOI: 10.1111/j.1440-1827.2008.02255.x

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Presentations 【 display / non-display

  • Loss of matriptase leads to colorectal carcinogenesis at an early stage

    Kawaguchi M, Kiwaki T, Yamashita F, Yamamoto K, Fukushima T, Kataoka H

    第80回日本癌学会学術総会  日本癌学会

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    Event date: 2021.9.30 - 2021.10.2

    Language:Japanese   Presentation type:Poster presentation  

  • Matriptase欠損マウスは早期に浸潤性大腸癌を発生する

    川口 真紀子、Liang Weiting、山下 文希、木脇 拓道、福島 剛、片岡 寛章

    第26回 日本病態プロテアーゼ学会学術集会  日本病態プロテアーゼ学会

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    Event date: 2021.8.27

    Language:Japanese   Presentation type:Symposium, workshop panel (public)  

  • HAI-2 (SPINT2 ) はEpCAM/Claudin-7複合体を安定化し、腸上皮完全性を維持する

    川口真紀子、山本晃士、山下文希、福島剛、片岡寛章

    第109回 日本病理学会総会  日本病理学会

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    Event date: 2020.7.1 - 2020.7.31

    Language:Japanese   Presentation type:Poster presentation  

  • HAI-1 deficient ApcMin+mice increased tumor formation through promoting tumor angiogenesis by PAR-2 signaling

    Kawaguchi M, Yamamoto K, Fukushima T, Kataoka H

    第78回日本癌学会学術総会 

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    Event date: 2019.9.26 - 2019.9.28

    Language:Japanese   Presentation type:Poster presentation  

  • Protease-activated receptor 2 promotes intestinal tumorigenesis through activation of NF-kB signaling and tumor angiogenesis in ApcMin/+mice International conference

    Kawaguchi M, Yamamoto K, Kiwaki T, FukushimaT, Camerer E, Kataoka H

    ASBMB Special Symposia Series; Serine Proteases in Pericellular Proteolysis and Signaling 

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    Event date: 2019.9.12 - 2019.9.15

    Language:Japanese   Presentation type:Poster presentation  

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Grant-in-Aid for Scientific Research 【 display / non-display

  • 大腸発癌におけるマトリプターゼ発現の意義に関する研究

    Grant number: 22K07154  2022.04 - 2025.03

    独立行政法人日本学術振興会  科学研究費補助金  基盤研究(C)

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    Authorship:Principal investigator 

  • 腸管発癌におけるセリンプロテアーゼ活性制御の意義に関する研究

    2015.04 - 2018.03

    科学研究費補助金  基盤研究(C)

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    Authorship:Principal investigator 

    Hepatocyte growth factor activator inhibitor type 1 (HAI-1) は全身の様々な上皮組織に発現する細胞膜結合型セリンプロテアーゼインヒビターである。申請者は、HAI-1の遺伝子改変マウスを用いた解析を通してHAI-1による標的酵素活性調節が上皮細胞完全性維持に必須であることを報告してきた。さらに、HAI-1欠損マウスでは腸管発癌が亢進することを明らかにした。しかし、その明確な分子機序は不明である。本研究の目的は、HAI-1欠損に伴い腫瘍形成が亢進する分子機序を解明することである。具体的には、原因となるHAI-1の標的酵素及びその基質を同定し、HAI-1欠損による標的酵素活性異常が細胞周囲にどのような変化をもたらし、発癌の亢進に結びついているのかを解明することである。

  • 表皮における細胞膜結合型セリンプロテアーゼ活性制御の意義に関する研究

    2013.04 - 2014.03

    科学研究費補助金  基盤研究(B)

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    HAI-1 KOマウスは胎盤形成不全のため致死となることから、胎盤機能をレスキューしたマウスを作製し、解析を行った。まず、HAI-1 KOマウスと野生型マウスの皮膚組織を、透過電子顕微鏡を用いて超微形態学的に解析し、HAI-1 KOマウスの皮膚組織はデスモソームの数が減少し、トノフィラメント収束不全が生じていることを明らかにした。さらに、ヒト不死化表皮細胞株HaCaTを用いてレンチウィルスによるHAI-1の安定的ノックダウンを行い、HAI-1の表皮における機能について、詳細な解析を行った。HAI-1ノックダウン(KD)細胞を3次元培養したところ、HAI-1 KOマウスの皮膚組織と同様にデスモソームの数が減少しており、この異常はp38阻害剤添加によって回避された。さらにp38活性化はPAR2を介して生じることを明らかにした。PAR2はHAI-1の標的酵素であるmatriptaseの基質であり、HAI-1発現抑制に伴うmatriptase活性制御破綻がPAR2を介したp38活性化を引き起こし、表皮細胞の形態形成や細胞間接着性の異常を来たしている可能性を示した。

  • 腸上皮における細胞膜結合型セリンプロテアーゼインヒビターの生理的意義に関する研究

    2011.04 - 2012.03

    科学研究費補助金  若手研究(B)

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    HAI-1 KOマウスは胎生致死であり、生体における機能は全く分かっていなかったが、HAI-1遺伝子をLoxPではさんだHAI-1 floxed マウスを作製し、cre-loxPシステムを用いたHAI-1コンディショナルKOマウスを世界に先駆け作製した。本研究では、HAI-1が強く発現する腸管上皮特異的にHAI-1を欠失するマウスを作製し、HAI-1が腸上皮の完全性維持に必須であることを明らかにした。また、腸管上皮特異的HAI-1 KOマウスは腸上皮のバリア機能が低下しており、炎症に対する感受性が亢進していることを明らかにした。

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