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

• Project/Area Number: 24390099
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: University of Miyazaki
• Principal Investigator: KATAOKA HIROAKI 宮崎大学, 医学部, 教授 (10214321)
• Co-Investigator(Kenkyū-buntansha): TAKEDA NAOKI 熊本大学, 生命資源研究支援センター, 助教 (90304998) ; ISHIDA YOICHI 明治薬科大学, 薬学部, 講師 (90510454)
• Co-Investigator(Renkei-kenkyūsha): KAWAGUCHI MAKIKO 宮崎大学, 医学部, 助教 (90405598) ; FUKUSHIMA TSUYOSHI 宮崎大学, 医学部, 助教 (10452913)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2015: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2014: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 病理学 / 実験病理学 / プロテアーゼ / プロテアーゼインヒビター / 上皮細胞 / 発癌 / 浸潤転移 / HAI-1 / 上皮組織 / がん細胞微小環境 / 浸潤・転移 / 遺伝子改変マウス / HAI / 発がん / HAI-2 / マトリプターゼ / 癌

Outline of Final Research Achievements

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.

Research Products

• [Int'l Joint Research] INSERM U670/Cardiovascular Research Center(フランス)
• [Int'l Joint Research] Georgetown University/Lambardi Compresensive Cancer Center(米国)
• [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: American Journal of Pathology Volume: 185 Pages: 1610-1615
  • DOI: 10.1016/j.ajpath.2015.02.009
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] High preoperative levels of serum glypican-3 containing N-terminal subunit are associated with poor prognosis in patients with hepatocellular carcinoma after partial hepatectomy. (2015)
  • Author(s): Haruyama Y, Yorita K, Yamaguchi T, Kitajima S, Amano J, Ohtomo T, Ohno A, Kondo K, Kataoka H.
  • Journal Title: International Journal of Cancer Volume: 未定 Pages: 1643-1651
  • DOI: 10.1002/ijc.29518
  • Peer Reviewed / 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 Science Volume: 106 Pages: 1130-1136
  • DOI: 10.1111/cas.12725
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Matriptase and MET are prominently expressed at the site of bone metastasis in renal cell carcinoma: immunohistochemical analysis. (2015)
  • Author(s): Mukai S, Yorita K, Kawagoe Y, Katayama Y, Nakahara K, Kamibeppu T, Sugie S, Tukino H, Kamoto T, Kataoka H.
  • Journal Title: Human Cell Volume: 28(1) Pages: 44-50
  • DOI: 10.1007/s13577-014-0101-3
  • Peer Reviewed
• [Journal Article] Expression of human kallikrein 1-related peptidase 4 (KLK4) and MET phosphorylation in prostate cancer tissue: immunohistochemical analysis. (2015)
  • Author(s): Mukai S, Yorita K, Yamasaki K, Nagai T, Kamibeppu T, Sugie S, Kida K, Onizuka C, Tsukino H, Kamimura T, Kamoto T, Kataoka H
  • Journal Title: Human Cell Volume: 28 Pages: 133-142
  • DOI: 10.1007/s13577-015-0114-6
  • Peer Reviewed
• [Journal Article] he protease inhibitor HAI-2, but not HAI-1, regulates matriptase activation and shedding through prostasin. (2014)
  • Author(s): Friis S, Sales KU, Schafer JM, Vogel LK, Kataoka H, Bugge TH
  • Journal Title: Journal of Biological Chemistry Volume: 289 Pages: 22319-22332
  • DOI: 10.1074/jbc.m114.574400
  • Peer Reviewed
• [Journal Article] Aberrant expression of monocarboxylate transporter 4 (MCT4) in tumor cells predicts an unfavorable outcome in patients with hepatocellular carcinoma. (2014)
  • Author(s): Ohno A, Yorita K, Haruyama Y, Kondo K, Kato A, Ohtomo T, Kawaguchi M, Marutuska K, Chijiiwa K, Kataoka H
  • Journal Title: Liver International Volume: 34 Pages: 942-952
  • DOI: 10.1111/liv.12466
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Factor XII inhibition reduces thrombus formation in a primate thrombosis model. (2014)
  • Author(s): Matafonov A, Leung PY, Gailani AE, Grach SL, Cheng Q, Sun M, McCarty OJT, Tucker EI, Kataoka H, Renne T, Morrissey JH, Gruber A, Gailani D
  • Journal Title: Blood Volume: 123 Pages: 1739-1746
  • DOI: 10.1182/blood-2013-04-499111
  • Peer Reviewed
• [Journal Article] Tumor budding in colorectal carcinoma assessed by cytokeratin immunostaining and budding areas: Possible involvement of c-Met. (2014)
  • Author(s): Satoh K, Nimura S, Hamasaki M, Aoki M, Koga K, Iwasaki H, Yamashita Y, Kataoka H, Nabeshima K
  • Journal Title: Cancer Sci Volume: 105 Pages: 1487-1495
  • DOI: 10.1111/cas.12530
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Loss of HAI-1 participates in metastatic spreading of human pancreatic cancer cells in a mouse orthotopic transplantation model. (2014)
  • Author(s): Ye J, Kawaguchi M, Haruyama Y, Kanemaru A, Fukushima T, Yamamoto K, Lin C-Y, Kataoka H
  • Journal Title: Cancer Sci. Volume: 105 Pages: 44-51
  • DOI: 10.1111/cas.12306
  • Peer Reviewed
• [Journal Article] Matriptase expression and zymogen activation in human pilosebaceous unit. (2014)
  • Author(s): Wu B-Y, Lee S-P, Hsiao H-C, Chiu H, Chen C-Y, Yeo YH, Lee H-S, Chen Y-W, Kaul M, Kataoka H, Johnson M, Wang J-K, Lin C-Y.
  • Journal Title: Journal of Histochemistry and Cytochemistry Volume: 62 Pages: 50-59
  • DOI: 10.1369/0022155413505599
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor activator inhibitor type 1 is a suppressor of intestinal tumorigenesis. (2013)
  • Author(s): Hoshiko S, Kawaguchi M, Fukushima T, Haruyama Y, Yorita K, Tanaka H, Seiki M, Inatsu H, Kitamura K, Kataoka H.
  • Journal Title: Cancer Res Volume: 73(8) Pages: 2659-2670
  • DOI: 10.1158/0008-5472.can-12-3337
  • Peer Reviewed
• [Journal Article] Antithrombin regulates matriptase activity involved in plasmin generation, syndecan shedding, and HGF activation in keratinocytes. (2013)
  • Author(s): Chen YW, Xu ZH, Baksh ANH, Wang JK, Chen CY, Swanson R, Olson ST, Kataoka H, Johnson MD, Lin CY.
  • Journal Title: PLoS One Volume: 8
  • DOI: 10.1371/journal.pone.0062826
  • Peer Reviewed
• [Journal Article] Imbalanced matriptase pericellular proteolysis contributes to the pathogenesis of malignant B-cell lymphomas. (2013)
  • Author(s): Chou FP, Chen YW, Zhao XF, Xu-Monette ZY, Young KH, Gartenhaus RB, Wang JK, Kataoka H, Annie H. Zuo AH, Johnson M, Lin CY.
  • Journal Title: American Journal of Pathology Volume: 183 Pages: 1306-1317
  • DOI: 10.1016/j.ajpath.2013.06.024
  • Peer Reviewed
• [Journal Article] Association of c-Met phospholrylation with micropapillary pattern and small cluster invasion in pT1-size lung adenocarcinoma. (2013)
  • Author(s): Koga K, Hamasaki M, Kato F, Aoki M, Hayashi H, Iwasaki A, Kataoka H, Nabeshima K
  • Journal Title: Lung Cancer Volume: 82 Pages: 413-419
  • DOI: 10.1016/j.lungcan.2013.09.005
  • Peer Reviewed
• [Journal Article] Identification of a lung adenocarcinoma cell line with CCDC6-RET fusion gene and the effect of RET inhibitors in vitro and in vivo. (2013)
  • Author(s): Makito Suzuki
  • Journal Title: Journal of Thoracic Oncology Volume: in press Pages: 1872-1876
  • DOI: 10.1111/cas.12175
  • Peer Reviewed
• [Journal Article] Regulation of pericellular proteolysis by hepatocyte growth factor activator inhibitor type 1 (HAI-1) in trophoblast cells. (2013)
  • Author(s): Kohama K, Kawaguchi M, Fukushima T, Lin C-Y, Kataoka H
  • Journal Title: Human Cell Volume: 25 Pages: 100-110
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor activator inhibitor-1 (HAI-1) induced by bonemorphogenetic proteins regulates proliferation and cell fate of neural progenitor cells. (2013)
  • Author(s): Koivuniemi R, Makela J, Hokkanen ME, Korhonen L, Schroder J, Kataoka H, Lin CY, Ola R, Lindholm D.
  • Journal Title: PLoS ONE Volume: 8
  • DOI: 10.1371/journal.pone.0056117
  • Peer Reviewed
• [Journal Article] Loss of membrane-bound serine protease inhibitor HAI-1 inducesoral squamous cell carcinoma cells' invasiveness (2012)
  • Author(s): Baba T, Kawaguchi M, Fukushima T, Sato Y, Orikawa H, Yorita K, Tanaka H, Lin CY, Sakoda S, Kataoka H
  • Journal Title: J Pathol. Volume: (Epub ahead of print) Pages: 181-192
  • DOI: 10.1002/path.3993
  • Peer Reviewed
• [Journal Article] Loss of HGF activator inhibits foveolar hyperplasia induced by oxynticatrophy without altering gastrin levels. (2012)
  • Author(s): Yamagata Y, Aikou S, FukushimaT, Kataoka H, Seto Y, Esumi H, Kaminishi M, James R GoldenringJR, Nomura S
  • Journal Title: American Journal of Physiology Volume: 303
  • Peer Reviewed
• [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: 2015-09-18
  • Int'l Joint Research
• [Presentation] The insufficient pericellular activity of hepatocyte growth factor activator inhibitor type 1 (HAI-1) induces recruitment of cancer-associated fibroblasts. (2015)
  • Author(s): Kanemaru A, Yamamoto K, Kawaguchi M, Camerer E, Kataoka H.
  • Organizer: ASBMB Special Symposia Series; Membrane-Anchored Serine Proteases
  • Place of Presentation: Potomac, MD, USA
  • Year and Date: 2015-09-18
  • Int'l Joint Research
• [Presentation] 口腔扁平上皮癌におけるHepatocyte growth factor activator inhibitor type-2(HAI-2)の発現と意義 (2015)
  • Author(s): 山本晃士、上條苑子、小成一臣、川口真紀子、福島剛、金丸愛、馬場貴、山下義弘、片岡寛章
  • Organizer: 第33回 日本ヒト細胞学会学術集会
  • Place of Presentation: ホテルスカイタワー（宮崎県・宮崎市）
  • Year and Date: 2015-08-22
• [Presentation] 癌細胞 におけるHAI-1発現の減弱は腫瘍随伴線維芽細胞の遊走を惹起する (2015)
  • Author(s): 金丸 愛、川口真紀子、山本晃士、福島剛、片岡寛章
  • Organizer: 第33回 日本ヒト細胞学会学術集会
  • Place of Presentation: ホテルスカイタワー（宮崎県・宮崎市）
  • Year and Date: 2015-08-22
• [Presentation] 膠芽腫における HAI-2 遺伝子の DNA メチル化状態 (2015)
  • Author(s): 福島剛、藤田聡、川口真紀子、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: ホテルスカイタワー（宮崎県・宮崎市）
  • Year and Date: 2015-08-22
• [Presentation] 癌随伴線維芽細胞の遊走における癌細胞周囲微小環境トリプシン様セリンプロテアーゼ活性の意義 (2015)
  • Author(s): 片岡寛章、金丸 愛、川口真紀子、山本晃士、福島 剛
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-05-01
• [Presentation] がん細胞浸潤・転移における細胞周囲微小環境の役割． (2014)
  • Author(s): 片岡寛章
  • Organizer: 第127回日本耳鼻咽喉科学会宮崎県地方部会講演会
  • Place of Presentation: 宮崎市
  • Year and Date: 2014-12-06
  • Invited
• [Presentation] Antitumor effect of DHMEQ, a small molecule inhibitor of nuclear factor-κ B, on Hai-1-deficient ApcMin+ mice. (2014)
  • Author(s): Kawaguchi M, Haruyama Y, Umezawa K, Fukushima T, Kataoka H
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Effect of CD24 silencing on pancreatic ductal cell adenocarcinoma cells. (2014)
  • Author(s): Fukushima T, Haruyama Y, Kawaguchi M, Tanaka H, and Kataoka H
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] High preoparative levels of serum N-terminal fragments of glypican 3 are associated with poor prognosis in patients with hepatocellular carcinoma after hepatectomy. (2014)
  • Author(s): Haruyama Y, Yorita K, Kondo K, Yamaguchi T, Kitajima S, Amano J, Ohtomo T, Kataoka H
  • Organizer: 8th Annual Conference of International Liver Cancer Association
  • Place of Presentation: 京都市
  • Year and Date: 2014-09-05 – 2014-09-07
• [Presentation] HAI-1 はマトリプテースによる PAR2 活性化制御を介してケラチノサイトの細胞間接着維持に働く． (2014)
  • Author(s): 片岡寛章、川口真紀子、金丸愛、福島剛
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島市
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] Hepatocyte growth factor activator inhibitor type 1 suppresses invasion of pancreatic adenocarcinoma cells through inhibition of matriptase/protease-activated receptor-2 axis. (2014)
  • Author(s): Haruyama Y, Ye J-J, Kawaguchi M, Kanemaru A, Fukushima T, Kataoka H
  • Organizer: The 105th Annual Meeting of American Association of Cancer Research
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] Hepatocyte growth factor activator inhibitor type 1 (HAI-1) suppresses tumor growth and metastasis of pancreatic adenocarcinoma cells. (2013)
  • Author(s): Ye J-J, Kawaguchi M, HaruyamaY, Ai Kanemaru A, Fukushima T, Kataoka H
  • Organizer: AACR Special Conference of Tumor Invasion andMetastasis
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2013-01-21
• [Presentation] Hepatocyte growth factor activator inhibitor type 1 (HAI-1)は膵癌細胞の浸潤・転移を抑制する． (2013)
  • Author(s): 春山幸洋、福島 剛、片岡寛章
  • Organizer: 第22回日本がん転移学会総会
  • Place of Presentation: 松本市
• [Presentation] HGF activatorの欠損はガストリンに影響を及ぼすことなく胃底腺委縮によって引き起こされた腺窩上皮過形成を阻害する． (2013)
  • Author(s): 山形幸徳、野村幸世、愛甲 丞、小川雅子、片岡寛章、瀬戸泰之
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜市
• [Presentation] MT1-MMPによる細胞膜結合型セリンプロテアーゼインヒビターHAI-1の切断は発がんと浸潤性の亢進をもたらす. (2012)
  • Author(s): 片岡寛章
  • Organizer: MT1-MMPシンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2012-11-30
• [Presentation] HGF activator inhibitor type 1 (HAI-l) suppresses tumor growth and metastasis of pancreatic adenocarcinoma cells. (2012)
  • Author(s): Kawaguchi M, Haruyama Y, Kataoka H
  • Organizer: 第71回日本癌学会学術集会
  • Place of Presentation: 札幌市
  • Year and Date: 2012-09-19
• [Presentation] 細胞膜結合型プロテアーゼインヒビターHAI-1は表皮角化細胞の形態形成に必須である. (2012)
  • Author(s): 川口真紀子、竹田直樹、星子新理、福島剛、片岡寛章
  • Organizer: 第17回日本病態プロテアーゼ学会学術集会
  • Place of Presentation: 浜松市
  • Year and Date: 2012-08-17
• [Presentation] 膜型プロテアーゼインヒビターHAT-1による口腔扁平上皮癌の浸潤制御,膜型プロテアーゼインヒビターHAI-1による口腔扁平上皮癌の臍潤制御. (2012)
  • Author(s): 片岡寛章、馬場貴、福島剛、川口真紀子、迫田隅男
  • Organizer: 第21回日本がん転移学会学術集会
  • Place of Presentation: 広島市
  • Year and Date: 2012-07-12
• [Presentation] 細胞周囲プロテオリシスと増殖因子:がん・間質相互作用からみた統括病理学 (2012)
  • Author(s): 片岡寛章
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-04-27
• [Presentation] 口腔扁平上皮癌におけるHepatocyte growth factor activator inhibitor type1 (HAI-1)の発現と意義 (2012)
  • Author(s): 馬場 貴、川口真紀子、頼田顕辞、福島 剛、迫田隅男、片岡寛章
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-04-26
• [Presentation] Roles for HAI-1, a cell surface inhibitor of membrane-anchored serine proteases, in epithelial integrity and cancer progression.
  • Author(s): Kataoka H, Kawaguchi M.
  • Organizer: ASBMB Special Symposia Series: Membrane-Anchored Serine Proteases
  • Place of Presentation: Potomac MD, USAPotomac MD, USA
  • Invited
• [Presentation] Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is required for maintaining keratinocyte morphology through regulation of PAR-2-dependent p38 MAP kinase signaling.
  • Author(s): Kawaguchi M, Takeda N, Kanemaru A, Sawaguchi A, Fukushima T, Kataoka H.
  • Organizer: ASBMB Special Symposia Series: Membrane-Anchored Serine Proteases
  • Place of Presentation: Potomac MD, USAPotomac MD, USA
• [Presentation] 細胞膜上プロテアーゼ制御機構の破綻がもたらす発がん環境とがん進展．
  • Author(s): 片岡寛章
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌市
  • Invited
• [Presentation] 細胞膜上プロテオリシス制御が演出するがん間質相互作用とがんの生物像．
  • Author(s): 片岡寛章
  • Organizer: 第10回日本病理学会カンファレンス
  • Place of Presentation: 神戸市
  • Invited
• [Presentation] 腸管発癌におけるHepatocyte growth factor activator inhibitor type 1 (HAI-1)の意義．
  • Author(s): 川口真紀子、星子新理、金丸 愛、梅澤一夫、片岡寛章
  • Organizer: 第10回病理学会カンファレンス
  • Place of Presentation: 神戸市
• [Presentation] 組織としてのがん：がん間質相互作用と細胞周囲プロテオリシスのがん進展における意義
  • Author(s): 片岡寛章
  • Organizer: 第31回日本ヒト細胞学会学術集会
  • Place of Presentation: 所沢市
  • Invited
• [Presentation] 表皮ケラチノサイト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
  • Author(s): 川口真紀子、金丸愛、山本晃士、片岡寛章
  • Organizer: 第18回日本病態プロテアーゼ学会
  • Place of Presentation: 豊中市
• [Book] Hepatocyte Growth Factor Activator [ln : Rawlings ND & Salvesen GS, (Eds.), Handbook of Proteolytic Enzymes, third edition] (2013)
  • Author(s): Kataoka H
  • Publisher: Academic Press(チャプター分担)
• [Remarks] 宮崎大学医学部病理学講座 腫瘍・再生病態学分野ホームページ
  • URL: http://www.med.miyazaki-u.ac.jp/patho2/index.html