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Degree 【 display / non-display 】
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Doctor (Medical Science) ( 1988.9 Miyazaki Medical College )
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医学士 ( 1982.3 宮崎医科大学 )
Research Areas 【 display / non-display 】
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Life Science / Experimental pathology
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Life Science / Human pathology
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Life Science / Molecular biology
Papers 【 display / non-display 】
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Combined Therapy Targeting MET and Pro-HGF Activation Shows Significant Therapeutic Effect Against Liver Metastasis of CRPC Reviewed International journal
Kimura S., Iwano S., Akioka T., Kuchimaru T., Kawaguchi M., Fukushima T., Sato Y., Kataoka H., Kamoto T., Mukai S., Sawada A.
International Journal of Molecular Sciences 26 ( 5 ) 2025.3
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Molecular Sciences
The liver is the most lethal metastatic site in castration-resistant prostate cancer (CRPC). Overexpression of MET protein has been reported in CRPC, and MET is an important driver gene in androgen-independent CRPC cells. Mouse CRPC cell line CRTC2 was established by subcutaneous injection of hormone-sensitive PC cells (TRAMP-C2) in castrated nude mice. CRCT2/luc2 cells were injected into the spleen of castrated nude mice, and liver metastasis was confirmed at 2 weeks post-injection. We administered MET inhibitor (MET-I) and HGF activator inhibitor (HGFA-I) to this liver metastasis model and assessed the therapeutic effect. After intrasplenic injection, CRTC2 showed a higher incidence of liver metastasis whereas no metastasis was observed in TRAMP-C2. Microarray analysis revealed increased expression of HGF, MET, and HPN, HGFAC (encoding HGF activating proteases) in liver metastasis. Proliferation of CRCT2 was significantly inhibited by co-administration of MET-I and HGFA-I by in vitro analysis with HGF-enriched condition. In an analysis of the mouse model, the combination-therapy group showed the strongest reduction for liver metastasis. Immunohistochemical staining also revealed the strongest decrease in phosphorylation of MET in the combination-therapy group. Co-culture with HGF-expressed mouse fibroblasts showed attenuation of the inhibitory effect of MET-I; however, additional HGFA-I overcame the resistance. We established an androgen-independent CRPC cell line, CRTC2, and liver metastasis model in mice. Significant effect was confirmed by combined treatment of MET-I and HGFA-I by in vitro and in vivo analysis. The results suggested the importance of combined treatment with both MET- and HGF-targeting agents in the treatment of HGF-enriched conditions including liver metastasis.
DOI： 10.3390/ijms26052308
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Loss of tumor cell surface hepatocyte growth factor activator inhibitor-1 predicts worse prognosis in esophageal squamous cell carcinoma. Reviewed International journal
Umekita Y, Kiwaki T, Kawaguchi M, Yamamoto K, Ikenoue M, Takeno S, Fukushima T, Sato Y, Kataoka H
Pathology, research and practice 266 155809 2025.1
Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：Pathology, research and practice
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.
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A new type of sulfation reaction: C-sulfonation for α,β-unsaturated carbonyl groups by a novel sulfotransferase SULT7A1 Reviewed International journal
Kurogi K., Sakakibara Y., Hashiguchi T., Kakuta Y., Kanekiyo M., Teramoto T., Fukushima T., Bamba T., Matsumoto J., Fukusaki E., Kataoka H., Suiko M.
PNAS Nexus 3 ( 3 ) pgae097 2024.3
Language：English Publishing type：Research paper (scientific journal) Publisher：PNAS Nexus
Cytosolic sulfotransferases (SULTs) are cytosolic enzymes that catalyze the transfer of sulfonate group to key endogenous compounds, altering the physiological functions of their substrates. SULT enzymes catalyze the O-sulfonation of hydroxy groups or N-sulfonation of amino groups of substrate compounds. In this study, we report the discovery of C-sulfonation of α,β-unsaturated carbonyl groups mediated by a new SULT enzyme, SULT7A1, and human SULT1C4. Enzymatic assays revealed that SULT7A1 is capable of transferring the sulfonate group from 3′-phosphoadenosine 5′-phosphosulfate to the α-carbon of α,β-unsaturated carbonyl-containing compounds, including cyclopentenone prostaglandins as representative endogenous substrates. Structural analyses of SULT7A1 suggest that the C-sulfonation reaction is catalyzed by a novel mechanism mediated by His and Cys residues in the active site. Ligand-activity assays demonstrated that sulfonated 15-deoxy prostaglandin J2 exhibits antagonist activity against the prostaglandin receptor EP2 and the prostacyclin receptor IP. Modification of α,β-unsaturated carbonyl groups via the new prostaglandin-sulfonating enzyme, SULT7A1, may regulate the physiological function of prostaglandins in the gut. Discovery of C-sulfonation of α,β-unsaturated carbonyl groups will broaden the spectrum of potential substrates and physiological functions of SULTs.
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Matriptase-2 Regulates Iron Homeostasis Primarily by Setting the Basal Levels of Hepatic Hepcidin Expression through A Nonproteolytic Mechanism. Reviewed International coauthorship International journal
Enns CA, Weiskopf T, Zhang RH, Wu J, Jue S, Kawaguchi M, Kataoka H, Zhang AS
Journal of Biological Chemistry 299 ( 10 ) 105238 2023.9
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.
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Early-onset tufting enteropathy in HAI-2-deficient mice is independent of matriptase-mediated cleavage of EpCAM Reviewed International coauthorship International journal
Szabo R., Kawaguchi M., Kataoka H., Bugge T.H.
Development (Cambridge, England) 150 ( 17 ) 2023.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Development (Cambridge, England)
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
Books 【 display / non-display 】
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Extracellular targeting of cell signaling in cancer.
Kataoka H, Shimomura T（ Role： Contributor , HGF Activator (HGFA) and its inhibitors HAI-1 and HAI-2: Key players in tissue repair and cancer ）
Wiley 2018.7
Total pages：462 Responsible for pages：69-90 Language：English Book type：Scholarly book
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Regulation of Signal Transduction in Human Cell Research
Kataoka H, Fukushima T（ Role： Contributor , Pericellular activation of peptide growth factors by serine proteases.）
Springer Nature 2018.3
Total pages：218 Responsible for pages：183-197 Language：English Book type：Scholarly book
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Handbook of Proteolytic Enzymes (Third Edition)
Kataoka H（ Role： Joint author , Chapter 660: Hepatocyte Growth Factor Activator）
Academic Press (Elsevier) 2013.1
Language：English Book type：Scholarly book
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Glutathione
Ishida Y, Yukizaki C, Okayama A, Kataoka H（ Role： Joint author）
Nova Science Publishers 2015.3
Total pages：215 Responsible for pages：127-144 Language：English Book type：Scholarly book
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Molecular Targets of CNS Tumors
Fukushima T, Kataoka H（ Role： Joint author）
InTech 2011.9
Language：English Book type：Scholarly book
MISC 【 display / non-display 】
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Glypican 3-targeted therapy in hepatocellular carcinoma. Reviewed
Nishida T, Kataoka H
Cancers 11 2019.9
Authorship：Last author, Corresponding author Language：English Publishing type：Article, review, commentary, editorial, etc. (scientific journal) Publisher：Multidisciplinary Digital Publishing Institute
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Hepatocyte growth factor activator: a proteinase linking tissue injury with repair. Invited Reviewed
Fukushima T, Uchiyama S, Tanaka T, Kataoka H
International Journal of Molecular Sciences 19 ( 11 ) 3435 2018.11
Authorship：Last author, Corresponding author Language：English Publishing type：Article, review, commentary, editorial, etc. (scientific journal)
DOI： 10.3390/ijms19113435
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Hepatocyte growth factor activator inhibitors (HAI-1 and HAI-2): emerging key players in epithelial integrity and cancer. Invited Reviewed International journal
Kataoka H, Kawaguchi M, Fukushima T, Shimomura T
Pathology International 68 ( 3 ) 145 - 158 2018.3
Authorship：Lead author, Corresponding author 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
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
MET), which are necessary for cellular migration,
survival, growth and triggering stem cells for
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 degradation of epithelial junctional proteins. This review summarizes current knowledge regarding the mechanism of pericellular HGF/SF activation and highlights emerging roles of HAIs in epithelial development
and integrity, as well as tumorigenesis and progression of transformed epithelial cells.DOI： 10.1111/pin.12647
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新たな上皮完全性維持機構 － 細胞膜結合型セリンプロテアーゼとインヒビター． Invited
片岡 寛章
実験医学 36 ( 3 ) 438 - 444 2018.2
Authorship：Lead author, Corresponding author Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (scientific journal) Publisher：羊土社
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Mechanisms of hepatocyte growth factor activation in cancer tissues. International journal
Kawaguchi M, Kataoka H.
Cancers 6 ( 4 ) 1890 - 1904 2014.9
Authorship：Corresponding author Language：English Publishing type：Article, review, commentary, editorial, etc. (scientific journal) Publisher：MDPI AG
Hepatocyte growth factor/scatter factor (HGF/SF) plays critical roles in cancer progression through its specific receptor, MET. HGF/SF is usually synthesized and secreted as an inactive proform (pro-HGF/SF) by stromal cells, such as fibroblasts. Several serine proteases are reported to convert pro-HGF/SF to mature HGF/SF and among these, HGF activator (HGFA) and matriptase are the most potent activators. Increased activities of both proteases have been observed in various cancers. HGFA is synthesized mainly by the liver and secreted as an inactive pro-form. In cancer tissues, pro-HGFA is likely activated by thrombin and/or human kallikrein 1-related peptidase (KLK)-4 and KLK-5. Matriptase is a type II transmembrane serine protease that is expressed by most epithelial cells and is also synthesized as an inactive zymogen. Matriptase activation is likely to be mediated by autoactivation or by other trypsin-like proteases. Recent studies revealed that matriptase autoactivation is promoted by an acidic environment. Given the mildly acidic extracellular environment of solid tumors, matriptase activation may, thus, be accelerated in the tumor microenvironment. HGFA and matriptase activities are regulated by HGFA inhibitor (HAI)-1 (HAI-1) and/or HAI-2 in the pericellular microenvironment. HAIs may have an important role in cancer cell biology by regulating HGF/SF-activating proteases.
Presentations 【 display / non-display 】
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HAI-2/SPINT2 maintains epithelial architecture in digestive tracts Invited International conference
Kataoka H, Yamamoto K, Kawaguchi M
ASBMB Special Symposia Series; Serine Proteases in Pericellular Proteolysis and Signaling
Event date： 2019.9.12 - 2019.9.15
Language：Japanese Presentation type：Oral presentation (invited, special)
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プロテアーゼと腫瘍間質 Invited
片岡 寛章
第107回 日本病理学会総会
Event date： 2018.6.21 - 2018.6.23
Language：Japanese Presentation type：Symposium, workshop panel (nominated)
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Hai-2 is essential for the maintenance of intestinal epithelium in mice. International conference
Kataoka H, Kawaguchi M, Yamamoto K, Seto A, Fukushima T, Shimomura T, Takeda N
ASBMB Special Symposia Series; Membrane-Anchored Serine Proteases (Potomac, MD, USA) American Society for Biochemistry and Molecular Biology
Event date： 2017.9.14 - 2017.9.17
Language：English Presentation type：Oral presentation (general)
Venue：Potomac, MD, USA
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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, Fukushima T, Camerer E, Kataoka H
ASBMB Special Symposia Series; Membrane-Anchored Serine Proteases (Potomac, MD, USA) American Society for Biochemistry and Molecular Biology
Event date： 2017.9.14 - 2017.9.17
Language：English Presentation type：Oral presentation (general)
Venue：Potomac, MD, USA
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細胞周囲微小環境におけるプロテアーゼ活性制御とその破綻がもたらす上皮組織の病態（病理学会宿題報告）． Invited
片岡 寛章
第106回日本病理学会総会 (東京都) 日本病理学会
Event date： 2017.4.27 - 2017.4.30
Language：Japanese Presentation type：Oral presentation (invited, special)
Venue：東京都
Awards 【 display / non-display 】
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日本病理学賞
2017.4 日本病理学会 細胞周囲微小環境におけるプロテアーゼ活性制御とその破綻がもたらす上皮組織の病態
片岡寛章
Award type：Award from Japanese society, conference, symposium, etc. Country：Japan
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日本病理学会学術研究賞（Ａ演説）
2000.11 日本病理学会
片岡寛章
Award type：Award from Japanese society, conference, symposium, etc. Country：Japan
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日本ヒト細胞学会学術賞
2000.8 日本ヒト細胞学会
片岡寛章
Award type：Award from Japanese society, conference, symposium, etc. Country：Japan
Grant-in-Aid for Scientific Research 【 display / non-display 】
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細胞膜結合型セリンプロテアーゼインヒビターによる上皮完全性維持と癌抑制機構
Grant number：16H05175 2016.04 - 2020.03
科学研究費補助金 基盤研究(B)
Authorship：Principal investigator
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上皮組織における細胞膜上プロテアーゼ制御機構の破綻が引き起こす病態の解析
Grant number：24390099 2012.04 - 2016.03
科学研究費補助金 基盤研究(B)
Authorship：Principal investigator
上皮組織における細胞膜上プロテアーゼ制御機構の破綻が引き起こす病態の解析
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上皮細胞膜上におけるプロテアーゼ活性調節とその異常による病態の解析
Grant number：20390114 2008.04 - 2012.03
科学研究費補助金 基盤研究(B)
Authorship：Principal investigator
上皮細胞膜上におけるプロテアーゼ活性調節とその異常による病態の解析
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胃腸管粘膜上皮組織の修復と再生における分子機構
Grant number：17390116 2005.04 - 2008.03
科学研究費補助金 基盤研究(B)
Authorship：Principal investigator
胃腸管の粘膜再生修復のプロセスには様々な因子が複雑に関わっているが、なかでも増殖因子産生とその活性化、細胞周囲微小環境におけるプロテアーゼ活性調節、そして上皮細胞の分化誘導因子が重要な役割を果たすと考えられる。我々はこれまでに、強力な胃腸管粘膜再生因子である肝細胞増殖因子（HGF）の活性化機構について精力的に研究を行い、その分子機構を明らかにしてきた。その結果、HGF活性化酵素の一つである HGF activator 遺伝子を破壊したマウスでは、傷害腸管粘膜上皮の初期再生が顕著に遅延することを明らかにした。更に細胞周囲におけるHGF activator の至適活性は、粘膜上皮細胞の細胞膜上に存在する膜結合クニッツ型インヒビター “HGF activator inhibitor type 1 (HAI-1)”により調節されることも明らかにした。そこで、HAI-1遺伝子破壊マウスを作成したところ、ホモマウスは胎生致死であり、HAI-1が代償の効かない重要な生体内機能を有することが明らかとなった。類似の膜型インヒビターであるHAI-2とamyloid β protein precursor (APP)も粘膜上皮に発現し増殖に関与することも示した。更に、胃腸管上皮の分化に伴い核に移行するが、傷害粘膜修復初期には細胞質にとどまる新規ペプチドH2RSP (HAI-2-related small peptide) を見出した。
上記のこれまでの研究成果をもとに、本研究では傷害粘膜上皮の修復・再生におけるこれらHGF活性化関連蛋白と膜結合型インヒビター、そしてH2RSPの機能を主にin vivoで解明し、傷害粘膜の修復・再生、特に初期修復における分子機構を解明することを目的としている。具体的には；(1) HGF activator ノックアウトマウスを用いた傷害粘膜初期修復遅延モデルを用い、再生上皮の遺伝子発現の網羅的解析を対照マウスと比較して行い、上皮の初期再生に重要なシグナルの流れを解析する。(2) HAI-1 ノックアウトマウスの表現形を解析すると共に、培養上皮細胞を用いてHAI-1 発現のノックダウンと、HAI-1 に結合している細胞内蛋白の同定を行い、HAI-1の機能を解明する。(3) 培養細胞を用いてH2RSP発現のノックダウンを行い、H2RSPの機能の一端を明らかにする。(4) これらの蛋白の消化管粘膜疾患における臨床病理学的意義を検討し、また、これらを利用した粘膜再生治療のための基礎実験を行う。 -
胃腸管粘膜の再生修復における分子機構の解明
Grant number：14370079 2002.04 - 2005.03
科学研究費補助金 基盤研究(B)
Authorship：Principal investigator
細胞膜表面においては、種々の増殖因子前駆体や細胞外基質分解酵素前駆体の活性化とその制御が活発に行なわれ、細胞の増殖や分化、遊走・浸潤に重要な意義を持っている。研究代表者はプロテアーゼと細胞膜結合型プロテアーゼインヒビターによるこれらの活性化反応とその制御機構、そしてこれらの反応がさまざまな病態において持つ意義について研究を行なってきた。
本研究では、これらのプロテアーゼと膜型インヒビターによる生理活性物質活性化調節機構の胃腸管粘膜上皮の再生修復における意義を、多機能増殖因子として胃腸管粘膜再生においても重要な役割を有することが分っている肝細胞増殖因子 (HGF) の活性化機構に焦点をあて、研究を行なった。その結果、胃腸管粘膜上皮初期再生における HGF 活性化機構の重要性を証明することが出来た。また、HGF活性化酵素 (HGF activator) のインヒビターである、細胞膜結合型プロテアーゼインヒビター“HAI-1”が、予想外の、しかし極めて重要な生体内機能を有していることも明らかとなった。本研究の過程で作成した HGF activator のノックアウトマウスと、HAI-1 のノックアウトマウスは、今後、当該分野における必要不可欠なツールとなると思われる。
本研究では、更に、胃腸管上皮細胞に発現している新規の核移行蛋白である H2RSP についても検討を行なった。その結果、H2RSP が上皮細胞の増殖停止と分化に伴って核に移行することを見出した。
なお、本研究の遂行にあたっては研究分担者の伊藤浩史助教授をはじめ、宮崎大学医学部病理学第二講座の教室員と大学院生の諸君（秋山裕、瀬口智子、長沼誠二、宮田史朗、内之倉俊朗、内山周一郎、田中弘之、長池幸樹、福島剛、長井美由紀、小濱和代）の多大な協力があった。
Other research activities 【 display / non-display 】
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Editor-in-Chief, Human Cell (Springer Nature)
2013.04
Editor-in-Chief, Human Cell (Electronic ISSN: 1749-0774, Springer Nature)
Available Technology 【 display / non-display 】
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がん組織微小環境に着目した、がん細胞の浸潤・転移分子機構の解明
上皮細胞膜上プロテアーゼ活性制御の破綻によって生じる病態の解明
難治性がんの新規診断マーカー、治療分子標的の探索Related fields where technical consultation is available：病理組織学的診断
病理組織標本の作製指導、免疫組織染色の技術指導
培養がん細胞の樹立、取り扱いと維持管理・遺伝子改変マウスの解析Message：共同研究が可能なテーマ： 疾患モデル動物の病理組織学的解析、組織標本を用いた
機能分子の発現解析、培養がん細胞を用いた機能性分子の活性解析