Patho-physiology of the tight junction-mainly focusing on human normal epithelial cells.

• Project/Area Number: 24390089
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Sapporo Medical University
• Principal Investigator: SAWADA Norimasa 札幌医科大学, 医学部, 教授 (30154149)
• Co-Investigator(Renkei-kenkyūsha): KOJIMA Takashi 札幌医科大学, 医学部, 教授 (30260764) ; TANAKA Satoshi 札幌医科大学, 医学部, 講師 (30374250) ; MURATA Masaki 札幌医科大学, 医学部, 講師 (10404592) ; TAKASAWA Akira 札幌医科大学, 医学部, 助教 (00593021) ; GO Mitsuru 札幌医科大学, 医学部, 講師 (80448604) ; IMAMURA Masafumi 札幌医科大学, 医学部, 助教 (00404608)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2014: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2013: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2012: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: タイト結合 / 膵癌 / 肝線維症 / 緑膿菌 / クローディン / PKC / EMT

Outline of Final Research Achievements

The tight junction, intercellular junction, works as barriers between outside and inside of the body, meaning one of drug delivery paths. In polarized cells, the junction performs to maintain cellular polarity. In this project showed the following points. Elastase of Pseudomonas aeruginosa causes transient disruption of tight junctions and downregulation of PAR-2 in human nasal epithelial cells. Tight junction protein claudin-4 is receptor of Clostridium perfringens enterotoxin（CPE） C-CPE recombinant peptides lacking cytotoxic activity also decreased the barrier function. These reversible changes of barrier function are highly applicable for developing new drug delivery techniques. Claudin-4 was up-regulated in human prostate cancer. Cytotoxic effect of CPE depended on the expression level of claudin-4 protein. In normal human prostate epithelial cells, however, the cytotoxic effect was barely detected. These findings suggest that CLDN-4 is a promising target of cancer therapy.

Research Products

• [Journal Article] Aberrant expression of claudin-4 and -7 in hepatocytes in the cirrhotic human liver. (2015)
  • Author(s): Tsujiwaki M, Murata M, Takasawa A, Hiratsuka Y, Fukuda R, Sugimoto K, Ono Y, Nojima M, Tanaka S, Hirata K, Kojima T, Sawada N.
  • Journal Title: Med Mol Morphol. Volume: 48(1) Issue: 1 Pages: 33-43
  • DOI: 10.1007/s00795-014-0074-z
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] An immunohistochemical marker panel including claudin-18, maspin, and p53 improves diagnostic accuracy of bile duct neoplasms in surgical and presurgical biopsy specimens. (2015)
  • Author(s): Keira Y, Takasawa A, Murata M, Nojima M, Takasawa K, Ogino J, Higashiura Y, Sasaki A, Kimura Y, Mizuguchi T, Tanaka S, Hirata K, Sawada N, Hasegawa T.
  • Journal Title: Virchows Arch. Volume: 466(3) Issue: 3 Pages: 265-277
  • DOI: 10.1007/s00428-014-1705-4
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pseudomonas aeruginosa elastase causes transient disruption of tight junctions and downregulation of PAR-2 in human nasal epithelial cells (2014)
  • Author(s): Nomura K, Takano K, Himi T, Kojima T. (10名, 9, 10番)
  • Journal Title: Respir Res Volume: 18 Issue: 1 Pages: 15-21
  • DOI: 10.1186/1465-9921-15-21
  • Peer Reviewed / Open Access
• [Journal Article] Targeting tight junctions during epithelial to mesenchymal transition in human pancreatic cancer. (2014)
  • Author(s): Kyuno D, Yamaguchi H, Ito T, Kono T, Kimura Y, Imamura M, Konno T, Hirata K, Sawada N, Kojima T.
  • Journal Title: World Journal of Gastroenterology Volume: 20(31) Issue: 31 Pages: 10813-10824
  • DOI: 10.3748/wjg.v20.i31.10813
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Tight junction protein claudin-4 is modulated via ΔNp63 in human keratinocytes. (2014)
  • Author(s): Kubo T, Sugimoto K, Kojima T, Sawada N, Sato N, Ichimiya S.
  • Journal Title: Biochemical and Biophysical Research Communications (BBRC). Volume: 455(3-4) Issue: 3-4 Pages: 205-211
  • DOI: 10.1016/j.bbrc.2014.10.148
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Isogladine maleate regulates gap junctional intercellular communication-dependent epithelial barrier in human nasal epithelial cells. (2014)
  • Author(s): Miyata R, Nomura K, Kakuki T, Takano K, Kohno T, Konno T, Sawada N, Himi T, Kojima T.
  • Journal Title: J Membr Biol. Volume: 248(2) Issue: 2 Pages: 327-336
  • DOI: 10.1007/s00232-015-9774-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] c-Jun N-terminal kinase inhibitor SP600125 enhances barrier function and elogation of human pancreatic cancer cell line HPAC in a Ca-switch model. (2014)
  • Author(s): Konno T, Ninomiya T, Kohno T, Kikuchi S, Sawada N, Kojima T.
  • Journal Title: Histochem Cell Biol. Volume: 143(5) Issue: 5 Pages: 471-479
  • DOI: 10.1007/s00418-014-1300-4
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Tight junction-related human diseases. (2013)
  • Author(s): Sawada N.
  • Journal Title: Pathol Int Volume: 63(1) Pages: 1-12
  • Peer Reviewed
• [Journal Article] Protein kinase Cα inhibitor protects against downregulation of claudin-1 during epithelial-mesenchymal transition of pancreatic cancer. (2013)
  • Author(s): Kyuno D, Kojima T, Yamaguchi H, Ito T, Kimura Y, Imamura M, Takasawa A, Murata M, Tanaka S, Hirata K, Sawada N.
  • Journal Title: Carcinogenesis Volume: 34(6) Pages: 1232-1243
  • Peer Reviewed
• [Journal Article] Curcumin prevents replication of respiratory syncytial virus and the epithelial responses to it in human nasal epithelial cells. (2013)
  • Author(s): Obata K, Kojima T, Masaki T, Okabayashi T, Yokota S, Hirakawa S, Nomura K, Takasawa A, Murata M, Tanaka S, Fuchimoto J, Fujii N, Tsutsumi H, Himi T, Sawada N.
  • Journal Title: PLoS One Volume: 8(9)
  • Peer Reviewed
• [Journal Article] Marked induction of matrix metalloproteinase-10 by respiratory syncytial virus infection in human nasal epithelial cells. (2013)
  • Author(s): Hirakawa S, Kojima T, Obata K, Okabayashi T, Yokota SI, Nomura K, Obonai T, Fuchimoto J, Himi T, Tsutsumi H, Sawada N.
  • Journal Title: J Med Virol Volume: 85(12) Pages: 2141-2150
  • Peer Reviewed
• [Journal Article] Regulation of tight junctions by sex hormones in normal human endometrial epithelial cells and uterus cancer cell line Sawano. (2013)
  • Author(s): Someya M, Kojima T, Ogawa M, Ninomiya T, Nomura K, Takasawa A, Murata M, Tanaka S, Saito T, Sawada N.
  • Journal Title: Cell Tissue Res. Volume: 354 Issue: 2 Pages: 481-494
  • DOI: 10.1007/s00441-013-1676-9
  • Peer Reviewed
• [Journal Article] Expression of tricellulin in epithelial cells and non-epithelial cells. (2013)
  • Author(s): Kojima T, Ninomiya T, Konno T, Kohno T, Taniguchi M, Sawada N.
  • Journal Title: Histol Histopathol Volume: 28 Pages: 1383-1392
  • Peer Reviewed
• [Journal Article] The tight-junction protein claudin-6 induces epithelial differentiation from mouse F9 and embryonic stem cells. (2013)
  • Author(s): Sugimoto K, Ichikawa-Tomikawa N, Satohisa S, Akashi Y, Kanai R, Saito T, Sawada N, Chiba H.
  • Journal Title: PLoS One Volume: 8(10)
  • Peer Reviewed
• [Journal Article] Behavior of tricellulin during destruction and formation of tight junctions under various extracellular calcium conditions (2013)
  • Author(s): Takasawa A, Kojima T, Ninomiya T, Tsujiwaki M, Murata M, Tanaka S, Sawada N
  • Journal Title: Cell Tissue Res Volume: 351(1) Issue: 1 Pages: 73-84
  • DOI: 10.1007/s00441-012-1512-7
  • Peer Reviewed
• [Journal Article] The role of IL-33 and its receptor ST2 in human nasal epithelium with allergic rhinitis (2012)
  • Author(s): Kamekura R, Kojima T, Himi T(全6名2, 6番)
  • Journal Title: Clin Exp Allergy Volume: 42(2) Issue: 2 Pages: 218-28
  • DOI: 10.1111/j.1365-2222.2011.03867.x
  • Peer Reviewed
• [Journal Article] Claudin-4-targeted therapy using Clostridium perfringens enterotoxin for prostate cancer (2012)
  • Author(s): Maeda T, Murata M, Chiba H, Takasawa A, Tanaka S, Kojima T, Masumori N, Tsukamoto T, Sawada N
  • Journal Title: Prostate Volume: 72(4) Issue: 4 Pages: 351-360
  • DOI: 10.1002/pros.21436
  • Peer Reviewed
• [Journal Article] Regulation of IL-33 and TSLP in human nasal fibroblasts by proinflammatory cytokines (2012)
  • Author(s): Nomura K, Kojima T, Himi T(全7名2. 6番)
  • Journal Title: Laryngoscope Volume: 122(6) Issue: 6 Pages: 1185-92
  • DOI: 10.1002/lary.23261
  • Peer Reviewed
• [Journal Article] Epidermal growth factor modulates claudins and tight junctional functions in ovarian cancer cell lines (2012)
  • Author(s): Ogawa M, Kojima T, Someya M, Nomura K, Takasawa A, Murata M, Tanaka S, Saito T, Sawada N
  • Journal Title: Histochem Cell Biol Volume: 138(2) Issue: 2 Pages: 323-338
  • DOI: 10.1007/s00418-012-0956-x
  • Peer Reviewed
• [Journal Article] Regulation of tight junctions in human normal pancreatic duct epithelial cells and cancer cells (2012)
  • Author(s): Kojima T, Sawada N
  • Journal Title: Ann N Y Acad Sci Volume: 1257 Issue: 1 Pages: 85-92
  • DOI: 10.1111/j.1749-6632.2012.06579.x
  • Peer Reviewed
• [Journal Article] Targeting claudin-4 in human pancreatic cancer (2012)
  • Author(s): Kojima T, Kyuno D, Sawada N
  • Journal Title: Expert Opinion on Therapeutic Targets Volume: 16 Issue: 9 Pages: 881-887
  • DOI: 10.1517/14728222.2012.708340
  • Peer Reviewed
• [Journal Article] Hop water extract inhibits double-stranded RNA-induced thymic stromal lymphopoietin release from human nasal epithelial cells (2012)
  • Author(s): Fuchimoto J, Kojima T, Himi T(全12名2, 11番)
  • Journal Title: Am J Rhinol Allergy Volume: 26(6) Issue: 6 Pages: 433-8
  • DOI: 10.2500/ajra.2012.26.3814
  • Peer Reviewed