Updated on 2025/07/01

写真a

 
Kawaguchi Makiko
 
Organization
Graduate School of Medicine Program for Nursing and Health Sciences Professor
Title
Professor

Degree

  • 博士（医学） ( 2010.3   宮崎大学 )

Research Areas

  • Life Science / Experimental pathology

Education

  • University of Miyazaki   Graduate School, Division of Medical Sciences

    - 2010.3

    　 More details

    Country： Japan

Research History

  • Ehime University   Graduate School of Medicine Nurse Course   Professor

    2025.4

  • University of Miyazaki   Faculty of Madicine School of Madicine Pathology course tumor and reproduction condition study field   Assistant Professor

    2015.4 - 2025.3

Professional Memberships

  • 日本癌学会

  • 日本ヒト細胞学会

  • 日本病態プロテアーゼ学会

Qualification acquired

  • Health Nurse

  • General Nurse

Papers

  • Loss of tumor cell surface hepatocyte growth factor activator inhibitor-1 predicts worse prognosis in esophageal squamous cell carcinoma. International journal

    Yoshiko Umekita, Takumi Kiwaki, Makiko Kawaguchi, Koji Yamamoto, Makoto Ikenoue, Shinsuke Takeno, Tsuyoshi Fukushima, Yuichiro Sato, Hiroaki Kataoka

    Pathology, research and practice   266   155809 - 155809   2025.1

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    Language：English   Publishing type：Research paper (scientific journal)  

    Hepatocyte growth factor activator inhibitor-1 (HAI-1) is an epithelial type-1 transmembrane protease inhibitor that regulates the pericellular activities of hepatocyte growth factor activator and type-2 transmembrane serine proteases. It is strongly expressed in the stratified squamous epithelium and functions on the cell surface. We previously reported that the cell surface immunoreactivity of HAI-1 was reduced at the invasion front of oral squamous cell carcinoma. In this study, we investigate the relationship between cell surface HAI-1 (csHAI-1) and prognosis of esophageal squamous cell carcinoma (ESCC) after surgery. The effect of HAI-1 knockdown on cultured ESCC cells was also analyzed in vitro. HAI-1 exhibited distinct cell surface immunoreactivity in normal esophageal epithelium. In contrast, alterations in HAI-1 immunoreactivity were frequent in cancer cells, which exhibited aberrant intracytoplasmic localization and decreased cell surface immunoreactivity. The preservation of csHAI-1 immunoreactivity was a sign of a well-differentiated phenotype of ESCC cells. The decreased csHAI-1 was associated with shorter overall survival (OS) and disease-free survival (DFS) in the patients. In 55 cases of early (T1) ESCC cases, decreased csHAI-1 also predicted poor OS and DFS. The loss of HAI-1 enhanced migration and invasion of ESCC cells in vitro. These results suggest that the decreased cell surface immunoreactivity of HAI-1 is associated with a less differentiated phenotype and worse prognosis in ESCC. The cell surface-localized HAI-1 may serve as a promising marker for predicting recurrence and prognosis of ESCC.

    DOI： 10.1016/j.prp.2025.155809

    PubMed

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

    Caroline A Enns, Tyler Weiskopf, Richard H Zhang, Jeffrey Wu, Shall Jue, Makiko Kawaguchi, Hiroaki Kataoka, An-Sheng Zhang

    The Journal of biological chemistry   299 ( 10 )   105238 - 105238   2023.10

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    Language：English   Publishing type：Research paper (scientific journal)  

    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

    PubMed

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

    Roman Szabo, Makiko Kawaguchi, Hiroaki Kataoka, Thomas H Bugge

    Development (Cambridge, England)   150 ( 17 )   2023.9

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    Language：English   Publishing type：Research paper (scientific journal)  

    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 cleavage-resistant 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

    PubMed

  • LRP11は肺腺癌の予後不良と関連する(Low-density lipoprotein receptor related protein 11(LRP11) contributes to poor prognosis in lung adenocarcinoma)

    木脇 拓道, 川口 真紀子, 片岡 寛章, 福島 剛

    日本癌学会総会記事   82回   1397 - 1397   2023.9

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    Language：English   Publisher：(一社)日本癌学会  

  • HAI-1機能不全はケラチノサイトのMMP-9発現を誘導する(Insufficiency of HAI-1 upregulates MMP-9 expression and induces degradation of epidermal basement membrane)

    川口 真紀子, 木脇 拓道, 福島 剛

    日本癌学会総会記事   82回   1341 - 1341   2023.9

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    Language：English   Publisher：(一社)日本癌学会  

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

    Makiko Kawaguchi, Hiroaki Kataoka, Takumi Kiwaki, Liang Weiting, Sayaka Nagata, Kazuo Kitamura, Tsuyoshi Fukushima

    FEBS open bio   13 ( 4 )   713 - 723   2023.4

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    Language：English   Publishing type：Research paper (scientific journal)  

    Adrenomedullin (AM) is a peptide with pleiotropic physiological functions that attenuates intestinal mucosal inflammation. However, the mechanism underpinning mucosal protection by AM is not fully understood, and its effect on intestinal epithelial cells remains unclear. Here, we investigated the effects of AM on junctional molecules in primary-cultured murine intestinal epithelial cells and discovered that AM upregulates claudin-4 expression. In a mouse model of dextran sulfate sodium-induced colitis, AM administration also enhanced claudin-4 expression and accelerated mucosal regeneration. Furthermore, AM reversed TNFα-mediated downregulation of claudin-4 and loss of cell-cell adhesion of the HCT116 human intestinal epithelial cell line in vitro. These results indicate that AM may enhance intestinal epithelial integrity by upregulating claudin-4 expression.

    DOI： 10.1002/2211-5463.13577

    PubMed

  • 全身転移をきたした脳腫瘍の一剖検例

    福島 剛, 齋藤 清貴, 堀之内 翔一, 川口 真紀子, 木脇 拓道

    日本病理学会会誌   112 ( 1 )   315 - 315   2023.3

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    Language：Japanese   Publisher：(一社)日本病理学会  

  • Blueberry Leaf Extract Prevents Lacrimal Hyposecretion in Sjögren's Syndrome-like Model of Non-obese Diabetic Mice. International journal

    Kenjirou Ogawa, Karin Urata, Saki Maeda, Yuta Ohno, Keitaro Satoh, Yoshiyuki Yamada, Yosuke Suzuki, Yasuko Koga, Kazuhiro Sugamoto, Makiko Kawaguchi, Hisato Kunitake, Kazuo Nishiyama, Y O Goto, Takayuki Nakayama, Masao Yamasaki

    In vivo (Athens, Greece)   37 ( 1 )   149 - 162   2023

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    Language：English   Publishing type：Research paper (scientific journal)  

    BACKGROUND/AIM: This study evaluated the effect of blueberry leaf hot water extract (BLEx) on Sjögren's syndrome (SS)-like lacrimal hyposecretion in male non-obese diabetic (NOD) mice. MATERIALS AND METHODS: NOD or BALB/c mice were fed 1% BLEx or control (AIN-93G) for 2 weeks from the age of 4 to 6 weeks. Pilocarpine-induced tear volume was measured using a phenol red-impregnated thread. The lacrimal glands were evaluated histologically by H&E staining. The IL-1β and TNF-α levels in the lacrimal gland tissue were measured by ELISA. The mRNA expression levels of secretion-related proteins were measured by real-time PCR. LC3 I/II and arginase 1 expression levels were measured by western blot. RESULTS: After feeding with BLEx, pilocarpine-induced tear secretion in NOD mice was increased. In contrast, the mRNA expression levels of the cholinergic muscarinic M3 receptor, aquaporin 5, and ion channels related to lacrimal secretion were not changed by BLEx administration. In addition, the protein expression of arginase 1, which was recently reported to be involved in tear hyposecretion in NOD mice, was also not improved by BLEx administration. Although infiltration in the lacrimal gland of NOD mice was not decreased, the levels of TNF-α and the autophagy-related protein LC3 were significantly suppressed by BLEx treatment. CONCLUSION: BLEx treatment may ameliorate lacrimal hyposecretion in NOD mice by delaying the progression of autoimmune disease by suppressing autophagy in lacrimal glands.

    DOI： 10.21873/invivo.13064

    PubMed

  • MGMTメチル化以外の膠芽腫の抗がん剤耐性機序(Mechanism of chemoresistance to temozolomide besides MGMT status in glioblastoma cells)

    福島 剛, 川口 真紀子, 木脇 拓道, 片岡 寛章

    日本癌学会総会記事   81回   P - 2303   2022.9

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    Language：English   Publisher：(一社)日本癌学会  

  • マトリプターゼ欠損は大腸発癌を誘発し、Claudin-7の局在異常をもたらす(Loss of matriptase leads to colorectal carcinogenesis and causes abnormal localization of Claudin-7 in tumor cells)

    川口 真紀子, 木脇 拓道, 福島 剛, 片岡 寛章

    日本癌学会総会記事   81回   P - 2088   2022.9

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    Language：English   Publisher：(一社)日本癌学会  

  • Insufficiency of hepatocyte growth factor activator inhibitor‐1 confers lymphatic invasion of tongue carcinoma cells

    Aya Izumi, Koji Yamamoto, Makiko Kawaguchi, Fumiki Yamashita, Tsuyoshi Fukushima, Takumi Kiwaki, Hiroyuki Tanaka, Yoshihiro Yamashita, Hiroaki Kataoka

    Cancer Science   113 ( 6 )   2179 - 2193   2022.6

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    Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    DOI： 10.1111/cas.15346

  • Role of the polycystic kidney disease domain in matriptase chaperone activity and localization of hepatocyte growth factor activator inhibitor‐1

    Fumiki Yamashita, Takashi Kaieda, Takeshi Shimomura, Makiko Kawaguchi, Chen‐Yong Lin, Michael D Johnson, Hiroyuki Tanaka, Takumi Kiwaki, Tsuyoshi Fukushima, Hiroaki Kataoka

    The FEBS Journal   289 ( 12 )   3422 - 3439   2022.6

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    Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    DOI： 10.1111/febs.16348

  • マトリプターゼ欠損は早期に大腸発癌を誘発する

    川口 真紀子, 木脇 拓道, 山下 文希, 山本 晃士, 福島 剛, 片岡 寛章

    日本癌学会総会記事   80回   [P10 - 6]   2021.9

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    Language：English   Publisher：(一社)日本癌学会  

  • Decreased prostasin expression is associated with aggressiveness of oral squamous cell carcinoma.

    Koji Yamamoto, Fumiki Yamashita, Makiko Kawaguchi, Aya Izumi, Takumi Kiwaki, Hiroaki Kataoka, Takeshi Kaneuji, Yoshihiro Yamashita, Tsuyoshi Fukushima

    Human cell   34 ( 5 )   1434 - 1445   2021.9

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    Language：Japanese   Publishing type：Research paper (scientific journal)  

    Prostasin is a glycosylphosphatidylinositol-anchored serine protease widely expressed in epithelial cells, with crucial epidermal barrier functions. Evidence has suggested prostasin may have served as a tumor suppressor in various cancers, but its role in oral squamous cell carcinoma (OSCC) remains unclear. Thus, herein, we conducted an immunohistochemical prostasin study in 119 resected OSCC cases. Prostasin expression was decreased in 63% (75/119) of cases. OSCC with decreased prostasin immunoreactivity (low prostasin cases) tended to show a higher histological grade (p = 0.0088) and a more infiltrative cancer cell morphology (p = 0.0024). We then explored the role of prostasin in the OSCC cell lines: SAS and HSC-4. SAS did not express detectable prostasin levels, whereas HSC-4 expressed low but distinct levels. Prostasin overexpression suppressed the proliferation and migration of both OSCC lines in vitro. Conversely, prostasin silencing significantly enhanced growth rates of HSC-4. Finally, we analyzed the impact of prostasin expression on the prognosis of patients with OSCC; decreased expression tended to correlate with shorter overall survival (p = 0.0291) after resection. This trend was supported by our analyses using a public database (Kaplan-Meier plotter) of head and neck squamous cell carcinomas. In conclusion, we showed decreased prostasin expression was associated with aggressive features and a poorer prognosis of OSCC.

    DOI： 10.1007/s13577-021-00575-3

    PubMed

  • 膠芽腫と小細胞癌の鑑別に苦慮した一剖検例

    福島 剛, 山本 晃士, 齋藤 清貴, 堀之内 翔一, 木脇 拓道, 川口 真紀子, 田中 弘之, 片岡 寛章

    日本病理学会会誌   110 ( 1 )   261 - 261   2021.3

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    Language：Japanese   Publisher：(一社)日本病理学会  

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

    Makiko Kawaguchi, Koji Yamamoto, Hiroaki Kataoka, Aya Izumi, Fumiki Yamashita, Takumi Kiwaki, Takahiro Nishida, Eric Camerer, Tsuyoshi Fukushima

    Cancer Science   111 ( 4 )   1193 - 1202   2020.4

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    Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    DOI： 10.1111/cas.14335

    Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.14335

  • 腸上皮の完全性維持における細胞膜結合セリンプロテアーゼ制御の重要性 Invited

    山本晃士, 川口真紀子, 片岡寛章

    BIO Clinica   34 ( 13 )   100 - 104   2019.11

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    Language：Japanese   Publishing type：Research paper (scientific journal)  

  • A Nucleoside Derivative 5-Vinyluridine (VrU) for Imaging RNA in Cells and Animals Reviewed

    Hong Shan Liu, Takumi Ishizuka, Makiko Kawaguchi, Ryuichi Nishii, Hiroaki Kataoka, Yan Xu

    Bioconjugate Chemistry   2019.11

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    Publisher：American Chemical Society ({ACS})  

    DOI： 10.1021/acs.bioconjchem.9b00643

  • 腸上皮の正常性維持に不可欠な細胞膜結合セリンプロテアーゼ制御機構 Invited

    山本晃士, 川口真紀子, 片岡寛章

    メディカルサイエンスダイジェスト   45 ( 10 )   44 - 47   2019.9

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    Language：Japanese   Publishing type：Research paper (scientific journal)  

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

    Makiko Kawaguchi, Koji Yamamoto, Naoki Takeda, Tsuyoshi Fukushima, Fumiki Yamashita, Katsuaki Sato, Kenichiro Kitamura, Yoshitaka Hippo, James W. Janetka, Hiroaki Kataoka

    Communications Biology   2 ( 1 )   11   2019.1

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

    DOI： 10.1038/s42003-018-0255-8

    PubMed

    Other Link： http://www.nature.com/articles/s42003-018-0255-8

  • Aberrant methylation and silencing of the SPINT2 gene in high-grade gliomas. International journal

    Tsuyoshi Fukushima, Makiko Kawaguchi, Koji Yamamoto, Fumiki Yamashita, Aya Izumi, Takashi Kaieda, Yuka Takezaki, Hiroshi Itoh, Hideo Takeshima, Hiroaki Kataoka

    Cancer science   109 ( 9 )   2970 - 2979   2018.7

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    Language：Japanese   Publishing type：Research paper (scientific journal)  

    Hepatocyte growth factor activator inhibitor type 2 (HAI-2), encoded by the SPINT2 gene, is a membrane-anchored protein that inhibits proteases involved in the activation of hepatocyte growth factor (HGF), a ligand of MET receptor. Epigenetic silencing of the SPINT2 gene has been reported in a human glioblastoma cell line (U87) and glioblastoma-derived cancer stem cells. However, the incidence of SPINT2 methylation in tumor tissues obtained from glioma patients is unknown. In this study, we analyzed the methylation status of the SPINT2 gene of eight human glioblastoma cell lines and surgically resected glioma tissues of different grades (II, III, and IV) by bisulfite sequence analysis and methylation-specific PCR. Most glioblastoma lines (7/8) showed methylation of the SPINT2 gene with a significantly reduced level of SPINT2mRNA compared to cultured astrocytes and normal brain tissues. However, all glioblastoma lines expressed mRNA for HGF activator (HGFAC), a target protease of HAI-2/SPINT2. Forced expression of SPINT2 reduced MET phosphorylation of U87 glioblastoma cells both in vitro and in intracranial xenografts in nude mice. Methylation-specific PCR analysis of the resected glioma tissues indicated notable methylation of the SPINT2 gene in 33.3% (2/6), 71.4% (10/14), and 74.3% (26/35) of grade II, III, and IV gliomas, respectively. Analysis of RNA sequencing data in a public database indicated an increased HGFAC/SPINT2 expression ratio in high-grade compared to low-grade gliomas (P = .01). In summary, aberrant methylation of the SPINT2 gene is frequently observed in high-grade gliomas and might confer MET signaling in the glioma cells.

    DOI： 10.1111/cas.13732

    PubMed

  • Hepatocyte growth factor activator inhibitors (HAI-1 and HAI-2): Emerging key players in epithelial integrity and cancer

    Hiroaki Kataoka, Makiko Kawaguchi, Tsuyoshi Fukushima, Takeshi Shimomura

    Pathology International   68 ( 3 )   145 - 158   2018.3

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

    DOI： 10.1111/pin.12647

    Scopus

    PubMed

  • Hepatocyte growth factor activator inhibitor type-2 (HAI- 2)/SPINT2 contributes to invasive growth of oral squamous cell carcinoma cells

    Koji Yamamoto, Makiko Kawaguchi, Takeshi Shimomura, Aya Izumi, Kazuomi Konari, Arata Honda, Chen-Yong Lin, Michael D. Johnson, Yoshihiro Yamashita, Tsuyoshi Fukushima, Hiroaki Kataoka

    Oncotarget   9 ( 14 )   11691 - 11706   2018.2

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Impact Journals LLC  

    DOI： 10.18632/oncotarget.24450

    Scopus

    PubMed

  • An Outbreak of Skin Infection due to Community Acquired-MRSA that Occurred among the Women Who Gave Birth in a Maternity Clinic and their Families Reviewed

    Tajiri Akihiko, Shimauchi Chieko, Katahira Katsuyuki, Gotoh Yasuhiro, Shigeta Mari, Kawaguchi Makiko, Tateyama Sunao, Ogura Yoshitoshi, Hayashi Tetsuya

    The Japanese Journal of Dermatology   128 ( 3 )   413 - 424   2018

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    Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Dermatological Association  

    <p>We report an outbreak of skin infection due to community-acquired methicillin-resistant <i>Staphylococcus aureus</i> (CA-MRSA), among the women who gave birth in a maternity clinic and their families. The number of patients who visited our clinic with deep infections of the skin, such as furuncle and carbuncle, suddenly increased in 2001. Many of the patients were epidemiologically linked to a maternity clinic, so we performed bacteriological examinations of isolated strains and investigated MRSA carriage in the staff and hospitalized patients at the maternity clinic. The results indicated an outbreak due to Panton-Valentine leukocidin-positive CA-MRSA and the maternity clinic as the most likely source of infection. Although relatively fewer numbers of CA-MRSA outbreaks have been reported in Japan, we need to implement adequate hospital infection control to prevent the occurrence of this type of CA-MRSA outbreaks.</p>

    DOI： 10.14924/dermatol.128.413

  • Prognostic significance of hepatocyte growth factor activator inhibitor type 1 (HAI-1) immunoreactivity in pancreatic ductal adenocarcinoma

    Chihiro Sakugawa, Yukihiro Haruyama, Hiroyuki Tanaka, Tsuyoshi Fukushima, Makiko Kawaguchi, Hiroaki Kataoka

    BMC Research Notes   10 ( 1 )   674   2017.12

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central Ltd.  

    DOI： 10.1186/s13104-017-3014-x

    Scopus

    PubMed

  • HAI-2 stabilizes, inhibits and regulates SEA-cleavage-dependent secretory transport of matriptase

    Annika W. Nonboe, Oliver Krigslund, Christoffer Soendergaard, Signe Skovbjerg, Stine Friis, Martin N. Andersen, Vincent Ellis, Makiko Kawaguchi, Hiroaki Kataoka, Thomas H. Bugge, Lotte K. Vogel

    TRAFFIC   18 ( 6 )   378 - 391   2017.6

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1111/tra.12482

    Web of Science

    PubMed

  • Deregulated matriptase activity in oral squamous cell carcinoma promotes the infiltration of cancer-associated fibroblasts by paracrine activation of protease-activated receptor 2

    Ai Kanemaru, Koji Yamamoto, Makiko Kawaguchi, Tsuyoshi Fukushima, Chen-Yong Lin, Michael D. Johnson, Eric Camerer, Hiroaki Kataoka

    INTERNATIONAL JOURNAL OF CANCER   140 ( 1 )   130 - 141   2017.1

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1002/ijc.30426

    Web of Science

    PubMed

  • Inhibition of nuclear factor-kappa B signaling suppresses Spint1-deletion- induced tumor susceptibility in the Apc(Min/+) model

    Makiko Kawaguchi, Koji Yamamoto, Ai Kanemaru, Hiroyuki Tanaka, Kazuo Umezawa, Tsuyoshi Fukushima, Hiroaki Kataoka

    ONCOTARGET   7 ( 42 )   68614 - 68622   2016.10

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.18632/oncotarget.11863

    Web of Science

  • Ghrelin administration suppresses inflammation-associated colorectal carcinogenesis in mice Reviewed

    Makiko Kawaguchi, Ai Kanemaru, Tsuyoshi Fukushima, Koji Yamamoto, Hiroyuki Tanaka, Yukihiro Haruyama, Hiroshi Itoh, Nobuhiro Matsumoto, Kenji Kangawa, Masamitsu Nakazato, Hiroaki Kataoka

    CANCER SCIENCE   106 ( 9 )   1130 - 1136   2015.9

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1111/cas.12725

    Web of Science

  • 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 Reviewed

    Makiko Kawaguchi, Ai Kanemaru, Akira Sawaguchi, Koji Yamamoto, Takashi Baba, Chen-Yong Lin, Michael D. Johnson, Tsuyoshi Fukushima, Hiroaki Kataoka

    AMERICAN JOURNAL OF PATHOLOGY   185 ( 6 )   1610 - 1623   2015.6

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.ajpath.2015.02.009

    Web of Science

  • Mechanisms of Hepatocyte Growth Factor Activation in Cancer Tissues

    Makiko Kawaguchi, Hiroaki Kataoka

    CANCERS   6 ( 4 )   1890 - 1904   2014.12

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.3390/cancers6041890

    Web of Science

    PubMed

  • Aberrant expression of monocarboxylate transporter 4 in tumour cells predicts an unfavourable outcome in patients with hepatocellular carcinoma Akinobu Ohno

    Akinobu Ohno, Kenji Yorita, Yukihiro Haruyama, Kazuhiro Kondo, Atsuhiko Kato, Toshihiko Ohtomo, Makiko Kawaguchi, Kousuke Marutuska, Kazuo Chijiiwa, Hiroaki Kataoka

    LIVER INTERNATIONAL   34 ( 6 )   942 - 952   2014.7

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1111/liv.12466

    Web of Science

    PubMed

  • Loss of hepatocyte growth factor activator inhibitor type 1 participates in metastatic spreading of human pancreatic cancer cells in a mouse orthotopic transplantation model Reviewed

    Jingjia Ye, Makiko Kawaguchi, Yukihiro Haruyama, Ai Kanemaru, Tsuyoshi Fukushima, Koji Yamamoto, Chen-Yong Lin, Hiroaki Kataoka

    CANCER SCIENCE   105 ( 1 )   44 - 51   2014.1

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1111/cas.12306

    Web of Science

  • Hepatocyte Growth Factor Activator Inhibitor Type 1 Is a Suppressor of Intestinal Tumorigenesis

    Shinri Hoshiko, Makiko Kawaguchi, Tsuyoshi Fukushima, Yukihiro Haruyama, Kenji Yorita, Hiroyuki Tanaka, Motoharu Seiki, Haruhiko Inatsu, Kazuo Kitamura, Hiroaki Kataoka

    CANCER RESEARCH   73 ( 8 )   2659 - 2670   2013.4

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1158/0008-5472.CAN-12-3337

    Web of Science

    PubMed

  • Loss of membrane-bound serine protease inhibitor HAI-1 induces oral squamous cell carcinoma cells' invasiveness

    Takashi Baba, Makiko Kawaguchi, Tsuyoshi Fukushima, Yuko Sato, Hiroshi Orikawa, Kenji Yorita, Hiroyuki Tanaka, Chen-Yong Lin, Sumio Sakoda, Hiroaki Kataoka

    JOURNAL OF PATHOLOGY   228 ( 2 )   181 - 192   2012.10

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1002/path.3993

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    PubMed

  • Activation of macrophage-stimulating protein by human airway trypsin-like protease

    Hiroshi Orikawa, Makiko Kawaguchi, Takashi Baba, Kenji Yorita, Sumio Sakoda, Hiroaki Kataoka

    FEBS LETTERS   586 ( 3 )   217 - 221   2012.2

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.febslet.2012.01.009

    Web of Science

    PubMed

  • Antitumor effect of dehydroxymethylepoxyquinomicin, a small molecule inhibitor of nuclear factor-kappa B, on glioblastoma

    Tsuyoshi Fukushima, Makiko Kawaguchi, Kenji Yorita, Hiroyuki Tanaka, Hideo Takeshima, Kazuo Umezawa, Hiroaki Kataoka

    NEURO-ONCOLOGY   14 ( 1 )   19 - 28   2012.1

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1093/neuonc/nor168

    Web of Science

    PubMed

  • Regulation of pericellular proteolysis by hepatocyte growth factor activator inhibitor type 1 (HAI-1) in trophoblast cells

    Kazuyo Kohama, Makiko Kawaguchi, Tsuyoshi Fukushima, Chen-Yong Lin, Hiroaki Kataoka

    Human Cell   25 ( 4 )   100 - 110   2012

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1007/s13577-012-0055-2

    Scopus

    PubMed

  • Membrane-Bound Serine Protease Inhibitor HAI-1 Is Required for Maintenance of Intestinal Epithelial Integrity

    Makiko Kawaguchi, Naoki Takeda, Shinri Hoshiko, Kenji Yorita, Takashi Baba, Akira Sawaguchi, Yuriko Nezu, Tsutomu Yoshikawa, Tsuyoshi Fukushima, Hiroaki Kataoka

    AMERICAN JOURNAL OF PATHOLOGY   179 ( 4 )   1815 - 1826   2011.10

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.ajpath.2011.06.038

    Web of Science

    PubMed

  • Hepatocyte growth factor activator inhibitor type 1 suppresses metastatic pulmonary colonization of pancreatic carcinoma cells

    Tsuyoshi Fukushima, Makiko Kawaguchi, Masatoshi Yamasaki, Hiroyuki Tanaka, Kenji Yorita, Hiroaki Kataoka

    CANCER SCIENCE   102 ( 2 )   407 - 413   2011.2

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1111/j.1349-7006.2010.01808.x

    Web of Science

  • Hepatocyte growth factor activator inhibitor type 1 suppresses metastatic pulmonary colonization of pancreatic carcinoma cells

    Tsuyoshi Fukushima, Makiko Kawaguchi, Masatoshi Yamasaki, Hiroyuki Tanaka, Kenji Yorita, Hiroaki Kataoka

    CANCER SCIENCE   102 ( 2 )   407 - 413   2011.2

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1111/j.1349-7006.2010.01808.x

    Web of Science

    PubMed

  • Hepatocyte growth factor activator is a serum activator of single-chain precursor macrophage-stimulating protein

    Makiko Kawaguchi, Hiroshi Orikawa, Takashi Baba, Tsuyoshi Fukushima, Hiroaki Kataoka

    FEBS JOURNAL   276 ( 13 )   3481 - 3490   2009.7

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1111/j.1742-4658.2009.07070.x

    Web of Science

    PubMed

  • Tissue injury alters the site of expression of hepatocyte growth factor activator inhibitor type 1 in bronchial epithelial cells

    Hiroyuki Tanaka, Tsuyoshi Fukushima, Kenji Yorita, Makiko Kawaguchi, Hiroaki Kataoka

    HUMAN CELL   22 ( 1 )   11 - 17   2009.2

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1111/j.1749-0774.2008.00062.x

    Web of Science

    PubMed

  • Defect of Hepatocyte Growth Factor Activator Inhibitor Type 1/Serine Protease Inhibitor, Kunitz Type 1 (Hai-1/Spint1) Leads to Ichthyosis-Like Condition and Abnormal Hair Development in Mice

    Koki Nagaike, Makiko Kawaguchi, Naoki Takeda, Tsuyoshi Fukushima, Akira Sawaguchi, Kazuyo Kohama, Mitsuru Setoyama, Hiroaki Kataoka

    AMERICAN JOURNAL OF PATHOLOGY   173 ( 5 )   1464 - 1475   2008.11

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.2353/ajpath.2008.071142

    Web of Science

    PubMed

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

    Miyuki Nagai, Nobuyasu Takahashi, Keiji Miyazawa, Makiko Kawaguchi, Kazuo Chijiiwa, Hiroaki Kataoka

    PATHOLOGY INTERNATIONAL   58 ( 7 )   462 - 464   2008.7

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1111/j.1440-1827.2008.02255.x

    Web of Science

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MISC

  • Hepatocyte growth factor activator inhibitors (HAI-1 and HAI-2): emerging key players in epithelial integrity and cancer. Invited Reviewed

    Kataoka H, Kawaguchi M, Fukushima T, Shimomura T

    Pathology International   68 ( 3 )   145 - 158   2018.3

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    Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

    The growth, survival, and metabolic activities of multicellular organisms at the cellular level are regulated by intracellular signaling, systemic homeostasis and the pericellular microenvironment. Pericellular proteolysis has a crucial role in processing bioactive molecules in the microenvironment and thereby has profound effects<br />
    on cellular functions. Hepatocyte growth factor activator inhibitor type 1 (HAI-1) and HAI-2 are type I transmembrane serine protease inhibitors expressed by most epithelial cells. They regulate the pericellular activities of circulating hepatocyte growth factor activator and cellular type II transmembrane serine proteases (TTSPs), proteases required for the activation of hepatocyte growth factor (HGF)/scatter factor (SF). Activated HGF/SF transduces pleiotropic signals through its receptor tyrosine kinase, MET (coded by the protooncogene<br />
    MET), which are necessary for cellular migration,<br />
    survival, growth and triggering stem cells for<br />
    accelerated healing. HAI-1 and HAI-2 are also required for normal epithelial functions through regulation of TTSP-mediated activation of other proteases and protease-activated receptor 2, and also through suppressing excess d

    DOI： 10.1111/pin.12647

  • Silencing of membrane-bound serine protease inhibitor, HAI-1, enhances metastatic capability of pancreatic cancer cells in mouse models

    Tsuyoshi Fukushima, Jingjia Ye, Makiko Kawaguchi, Yukihiro Haruyama, Ai Kanemaru, Koji Yamamoto, Hiroaki Kataoka

    CLINICAL & EXPERIMENTAL METASTASIS   32 ( 3 )   202 - 202   2015.3

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    Language：English   Publishing type：Research paper, summary (international conference)  

    Web of Science

  • Ghrelin administration suppresses inflammation-associated colorectal carcinogenesis in mice

    Hiroaki Kataoka, Makiko Kawaguchi, Ai Kanemaru, Tsuyoshi Fukushima, Nobuhiro Matsumoto, Masamitsu Nakazato

    CANCER RESEARCH   74 ( 19 )   2014.10

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    Language：English   Publishing type：Research paper, summary (international conference)  

    DOI： 10.1158/1538-7445.AM2014-LB-4

    Web of Science

  • Hepatocyte growth factor activator inhibitor type 1 suppresses invasion of pancreatic adenocarcinoma cells through inhibition of matriptase/protease-activated receptor-2 axis

    Yukihiro Haruyama, Jing-Jia Ye, Makiko Kawaguchi, Ai Kanemaru, Tsuyoshi Fukushima, Hiroaki Kataoka

    CANCER RESEARCH   74 ( 19 )   2014.10

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    Language：English   Publishing type：Research paper, summary (international conference)  

    DOI： 10.1158/1538-7445.AM2014-4859

    Web of Science

  • プロテアーゼによるがん間質モジュレーション

    片岡寛章, 川口真紀子, 田中弘之, 福島 剛

    病理と臨床   32 ( 1 )   31 - 36   2014.1

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    Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)   Publisher：文光堂  

  • MST1 (macrophage stimulating 1 (hepatocyte growth factor-like))

    Kawaguchi M, Kataoka H

    Atlas Genet Cytogenet Oncol Haematol.   2013.8

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    Language：English   Publishing type：Article, review, commentary, editorial, etc. (other)   Publisher：Atlas Genet Cytogenet Oncol Haematol Organization  

  • Hepatocyte growth factor activator inhibitor type 1 (HAI-1) suppresses tumor growth and metastasis of pancreatic adenocarcinoma cells

    Jing-Jia Ye, Makiko Kawaguchi, Yukihiro Haruyama, Ai Kanemaru, Tsuyoshi Fukushima, Hiroaki Kataoka

    CANCER RESEARCH   73   2013.2

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    Language：English   Publishing type：Research paper, summary (international conference)  

    DOI： 10.1158/1538-7445.TIM2013-B24

    Web of Science

  • Defect of Hepatocyte Growth Factor Activator Inhibitor Type I, a Cell Surface Serine Protease Inhibitor, Enhances Intestinal Tumorigenesis in ApcMin/+ Mice

    Shinri Hoshiko, Makiko Kawaguchi, Kenji Yorita, Tsuyoshi Fukushima, Hiroaki Kataoka

    GASTROENTEROLOGY   140 ( 5 )   S815 - S815   2011.5

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    Language：English   Publishing type：Research paper, summary (international conference)  

    Web of Science

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

    Hiroaki Kataoka, Makiko Kawaguchi

    FEBS JOURNAL   277 ( 10 )   2230 - 2237   2010.5

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    Language：English   Publishing type：Book review, literature introduction, etc.  

    DOI： 10.1111/j.1742-4658.2010.07640.x

    Web of Science

    PubMed

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

    Miyuki Nagai, Nobuyasu Takahashi, Keiji Miyazawa, Makiko Kawaguchi, Kazuo Chijiiwa, Hiroaki Kataoka

    PATHOLOGY INTERNATIONAL   58 ( 7 )   462 - 464   2008.7

    　More details

    Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

    DOI： 10.1111/j.1440-1827.2008.02255.x

    Web of Science

    PubMed

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Presentations

  • LRP11はUBA7を抑制し,肺腺癌の増殖を亢進させる(LRP11 suppresses UBA7 and promotes proliferation of lung adenocarcinoma cells)

    木脇 拓道, 川口 真紀子, 福島 剛, 佐藤 勇一郎

    日本癌学会総会記事  2024.9  (一社)日本癌学会

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    Language：English  

  • Matriptase欠損マウスはNF-κB/Stat3/c-Myc経路活性化を介して浸潤性大腸癌を発生する(Matriptase deletion induces colon carcinogenesis through activation of NF-κB/Stat3/c-Myc axis)

    梁 いてい, 川口 真紀子, 木脇 拓道, 福島 剛, 川口 真紀子

    日本癌学会総会記事  2024.9  (一社)日本癌学会

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    Language：English  

  • Excess activation of PAR-2 increased frequency of tumor formation in HAI-1 deficient ApcMin+ mice

    Kawaguchi M, Yamamoto K, Fukushima T, Kataoka H

    第76回日本癌学会学術総会  2017.9  日本癌学会

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    Language：English   Presentation type：Poster presentation  

    Venue：横浜市  

  • 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

    川口真紀子, 山本晃士, 福島剛, 片岡寛章

    2017年度生命科学系学会合同年次大会  2017.12  日本分子生物学会

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    Language：Japanese   Presentation type：Poster presentation  

    Venue：神戸市  

  • 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

    川口真紀子, 福島剛, 金丸愛, 山本晃士, 田中弘之, 片岡 寛章

    第33回 日本ヒト細胞学会学術集会  2015.8  日本ヒト細胞学会

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

    Venue：宮崎県宮崎市  

  • 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

    川口真紀子, 山本晃士, 福島剛, 片岡寛章

    第34回日本ヒト細胞学会学術集会  2016.7  日本ヒト細胞学会

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    Language：Japanese   Presentation type：Oral presentation (general)  

    Venue：奈良市  

  • 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

    川口真紀子, 山本晃士, 福島剛, 片岡寛章

    第22回日本病態プロテアーゼ学会学術集会  2017.8  日本病態プロテアーゼ学会

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    Language：Japanese   Presentation type：Poster presentation  

    Venue：大阪府豊中市  

  • 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

    川口真紀子, 山本晃士, 福島剛, 片岡寛章

    第21回日本病態プロテアーゼ学会  2016.8  日本病態プロテアーゼ学会

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    Language：Japanese   Presentation type：Poster presentation  

    Venue：豊中市  

  • HGF activator inhibitors (HAIs) may have fundamental roles in biology of colon adenocarcinoma cells

    Kawaguchi M, Fukushima T, Kataoka H

    第74回 日本癌学会学術集会  2015.10  日本癌学会

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    Language：Japanese   Presentation type：Poster presentation  

    Venue：愛知県名古屋市  

  • Loss of HAI-1 upregulates MMP-9 expression and induces degradation of epidermal basement membrane

    Kawaguchi M, Fukushima T, Kataoka H

    第75回日本癌学会学術総会  2016.10  日本癌学会

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    Language：English   Presentation type：Poster presentation  

    Venue：横浜市  

  • 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

    川口真紀子, 山本晃士, 福島剛, 片岡寛章

    第39回日本分子生物学会年会  2016.11  日本分子生物学会

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    Language：Japanese   Presentation type：Poster presentation  

    Venue：横浜市  

  • Protease-activated receptor-2 is not involved in the susceptibility to DSS-induced colitis associated with HAI-1deficiency International conference

    Kawaguchi M, Kanemaru A, Yamamoto K, Fukushima T, Camerer E, Kataoka H

    ASBMB Special Symposia Series; Membrane-Anchored Serine Proteases  2015.9  ASBMB

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    Language：English   Presentation type：Poster presentation  

    Venue：Potomac, MD, USA  

  • Protease-activated receptor-2 is not involved in the susceptibility to DSS-induced colitis observed in HAI-1-deficient mice

    Kawaguchi M, Kanemaru A, Yamamoto K, Fukushima T, Kataoka H

    第38回 日本分子生物学会年会  2015.12  日本分子生物学会

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    Language：Japanese   Presentation type：Poster presentation  

    Venue：兵庫県神戸市  

  • 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

    川口真紀子, 山本晃士, 福島剛, 片岡寛章

    第106回日本病理学会総会  2017.4  日本病理学

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    Language：Japanese   Presentation type：Poster presentation  

    Venue：東京都  

  • Accelerated tumor formation induced by Hai-1 deficiency in the ApcMin/+ model is prevented by concomitant deficiency of Par-2 International conference

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

    ASBMB Special Symposia Series; Membrane-Anchored Serine Protease  2017.9  ASBMB

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    Language：English   Presentation type：Oral presentation (general)  

    Venue：Potomac, MD, USA  

  • 膠芽腫におけるMGMT以外の抗がん剤耐性因子の探索(Drug resistant factors besides MGMT status in glioblastoma)

    福島 剛, 玉田 達大, 川口 真紀子, 佐藤 勇一郎

    日本癌学会総会記事  2024.9  (一社)日本癌学会

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    Language：English  

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Research Projects

  • 先天性ナトリウム下痢症の発症メカニズム解明と治療法の開発

    2025.4 - 2028.3

    科学研究費助成事業  

    川口 真紀子

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    Authorship：Principal investigator 

    CiNii Research

  • 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

    2022.4 - 2025.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    川口 真紀子

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    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

  • Regulation of membrane-anchored serine protease activities and its significance in epithelial pathophysiology

    2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Kawaguchi Makiko

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    Grant amount：\4420000 （ Direct Cost: \3400000 、 Indirect Cost：\1020000 ）

    In this study, we generated conditional Spint2 knockout mouse model based on the Cre recombinase and LoxP system. We found that spint2 knockout mouse showed severe epithelial damage in the whole intestinal tracts. The intestinal epithelium showed enhanced exfoliation, villous atrophy, enterocyte tufts and elongated crypts. Organoid crypt culture indicated that Spint2 ablation induced Epcam cleavage with decreased claudin-7 levels and resulted in organoid rupture. These organoid changes could be rescued by addition of serine protease inhibitors and matriptase selective inhibitor as well as by co-deletion of prostasin. These results indicate that HAI-2 is an essential cellular inhibitor for maintaining intestinal epithelium architecture.

  • The analysis of microRNA localization using fluorescence resonance energy transfer based in situ hybridization

    2016.4 - 2019.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Hishikawa Yoshitaka

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    Grant amount：\4810000 （ Direct Cost: \3700000 、 Indirect Cost：\1110000 ）

    We have developed a new application of fluorescence resonance energy transfer based molecular beacon probe for in situ hybridization (FRET-ISH) for detection of specific microRNA at the tissue and cellular level.

  • 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

    2015.4 - 2018.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

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    Grant type：Competitive

    Grant amount：\3700000 （ Direct Cost: \2590000 、 Indirect Cost：\1110000 ）

    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

    2013.4 - 2014.3

    日本学術振興会  科学研究費助成事業  基盤研究(B)

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    Grant type：Competitive

    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

  • Regulation of protease activities on the epithelial cell surface and its significance in epithelial disorders.

    2012.4 - 2016.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    KATAOKA HIROAKI, TAKEDA NAOKI, ISHIDA YOICHI, KAWAGUCHI MAKIKO, FUKUSHIMA TSUYOSHI

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    Grant amount：\18720000 （ Direct Cost: \14400000 、 Indirect Cost：\4320000 ）

    Membrane-associated protease inhibitors HAI-1 and -2 are important in regulating the pericellular serine protease activities of epithelial cells. This study aimed to analyze the roles for HAIs in normal homeostasis of epithelial cells and the effects of HAI insufficiency on cancer progression. We revealed that HAI-1 had suppressive roles in pericellular activations of HGF and PAR-2. HAI-1 was a suppressor of intestinal carcinogenesis and inhibited EMT, invasion, and metastasis of oral squamous cell carcinoma and pancreatic adenocarcinoma cells. Moreover, we found that HAI-1 maintained the assembly of keratin into desmosomes in keratinocytes by regulating PAR-2-dependent p38 signaling. Also, we have generated HAI-2floxed/floxed mouse that will be critically required for the development of the conditional HAI-1 knockout mouse. Those mice would accelerate the studies for in vivo functions of HAI-2.

  • 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

    2011.4 - 2012.3

    日本学術振興会  科学研究費助成事業  若手研究(B)

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    Grant type：Competitive

    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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Teaching Experience (On-campus)

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