Skip to main content

Advertisement

SpringerLink
Log in

Claudins in cancer: bench to bedside

  • Invited Review
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

The claudin family, in mammals, encoded by at least 27 members of a single ancestral gene, CLDN, is the main constituent as integral membrane proteins of tight junctions. It has been shown that the expression levels of claudins are often decreased or that their expressions are absent in human neoplasias. These findings are consistent with the well-accepted concept that carcinogenesis is accompanied by the disruption or loss of functional tight junctions. In contrast, accumulating data have showed elevated or aberrant expression of claudins in various cancers, indicating specific roles of claudins in tumorigenesis. Importantly, dysregulated claudins play an oncogenic role or conversely have a tumor-suppressive effect depending on target tissues or cell types, and thus, they contribute to tumor development and progression. Although tight junctions are intercellular structures in epithelial cells, specific roles of claudins in cancer are supported by the evidence that TJs are not simple static constituents for establishing cell adhesion structures but are also cell signaling components that have functions in receiving environmental cues and transmitting signals inside cells. Since the expression profile of claudins is associated with patients’ outcome and prognosis in several cancer types, an understanding of the expression pattern and subcellular localization of claudins in various pathologies will lead to the establishment of claudins as useful biomarkers for the detection and diagnosis of cancers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Agarwal R, D’Souza T, Morin PJ (2005) Claudin-3 and claudin-4 expression in ovarian epithelial cells enhances invasion and is associated with increased matrix metalloproteinase-2 activity. Cancer Res 65:7378–7385

    Article  CAS  PubMed  Google Scholar 

  2. Agarwal R, Mori Y, Cheng Y, Jin Z, Olaru AV, Hamilton JP, David S, Selaru FM, Yang J, Abraham JM, Montgomery E, Morin PJ, Meltzer SJ (2009) Silencing of claudin-11 is associated with increased invasiveness of gastric cancer cells. PLoS One 4:e8002

    Article  PubMed  PubMed Central  Google Scholar 

  3. Akasaka H, Sato F, Morohashi S, Wu Y, Liu Y, Kondo J, Odagiri H, Hakamada K, Kijima H (2010) Anti-apoptotic effect of claudin-1 in tamoxifen-treated human breast cancer MCF-7 cells. BMC Cancer 10:548

    Article  PubMed  PubMed Central  Google Scholar 

  4. Akimoto T, Takasawa A, Murata M, Kojima Y, Takasawa K, Nojima M, Aoyama T, Hiratsuka Y, Ono Y, Tanaka S, Osanai M, Hasegawa T, Saito T, Sawada N (2016) Analysis of the expression and localization of tight junction transmembrane proteins, claudin-1, -4, -7, occludin and JAM-A, in human cervical adenocarcinoma. Histol Histopathol 31:921–931

    PubMed  Google Scholar 

  5. Blanchard AA, Skliris GP, Watson PH, Murphy LC, Penner C, Tomes L, Young TL, Leygue E, Myal Y (2009) Claudins 1, 3, and 4 protein expression in ER negative breast cancer correlates with markers of the basal phenotype. Virchows Arch 454:647–656

    Article  CAS  PubMed  Google Scholar 

  6. Blanchard AA, Ma X, Dueck KJ, Penner C, Cooper SC, Mulhall D, Murphy LC, Leygue E, Myal Y (2013) Claudin 1 expression in basal-like breast cancer is related to patient age. BMC Cancer 13:268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chang TL, Ito K, Ko TK, Liu Q, Salto-Tellez M, Yeoh KG, Fukamachi H, Ito Y (2010) Claudin-1 has tumor suppressive activity and is a direct target of RUNX3 in gastric epithelial cells. Gastroenterology 138:255–265

    Article  CAS  PubMed  Google Scholar 

  8. Chiba H, Osanai M, Murata M, Kojima T, Sawada N (2008) Transmembrane proteins of tight junctions. Biochim Biophys Acta 1778:588–600

    Article  CAS  PubMed  Google Scholar 

  9. De Oliveira SS, de Oliveira IM, de Souza W, Morgado-Diaz JA (2005) Claudins upregulation in human colorectal cancer. FEBS Lett 579:6179–6185

    Article  PubMed  Google Scholar 

  10. Dhawan P, Singh AB, Deane NG, No Y, Shiou SR, Schmidt C, Neff J, Washington MK, Beauchamp RD (2005) Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer. J Clin Invest 115:1765–1776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Di Cello F, Cope L, Li H, Jeschke J, Wang W, Baylin SB, Zahnow CA (2013) Methylation of the claudin 1 promoter is associated with loss of expression in estrogen receptor positive breast cancer. PLoS One 8:e68630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, Gilcrease MZ, Krishnamurthy S, Lee JS, Fridlyand J, Sahin A, Agarwal R, Joy C, Liu W, Stivers D, Baggerly K, Carey M, Lluch A, Monteagudo C, He X, Weigman V, Fan C, Palazzo J, Hortobagyi GN, Nolden LK, Wang NJ, Valero V, Gray JW, Perou CM, Mills GB (2009) Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res 69:4116–4124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Honda H, Pazin MJ, Ji H, Wernyj RP, Morin PJ (2006) Crucial roles of Sp1 and epigenetic modifications in the regulation of the CLDN4 promoter in ovarian cancer cells. J Biol Chem 281:21433–21444

    Article  CAS  PubMed  Google Scholar 

  14. Huang YH, Bao Y, Peng W, Goldberg M, Love K, Bumcrot DA, Cole G, Langer R, Anderson DG, Sawicki JA (2009) Claudin-3 gene silencing with siRNA suppresses ovarian tumor growth and metastasis. Proc Natl Acad Sci U S A 106:3426–3430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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 (2015) An immunohistochemical marker panel including claudin-18, maspin, and p53 improves diagnostic accuracy of bile duct neoplasms in surgical and presurgical biopsy specimens. Virchows Arch 466:265–277

    Article  CAS  PubMed  Google Scholar 

  16. Kinugasa T, Huo Q, Higashi D, Shibaguchi H, Kuroki M, Tanaka T, Futami K, Yamashita Y, Hachimine K, Maekawa S, Nabeshima K, Iwasaki H, Kuroki M (2007) Selective up-regulation of claudin-1 and claudin-2 in colorectal cancer. Anticancer Res 27:3729–3734

    CAS  PubMed  Google Scholar 

  17. Krishnan M, Singh AB, Smith JJ, Sharma A, Chen X, Eschrich S, Yeatman TJ, Beauchamp RD, Dhawan P (2010) HDAC inhibitors regulate claudin-1 expression in colon cancer cells through modulation of mRNA stability. Oncogene 29:305–312

    Article  CAS  PubMed  Google Scholar 

  18. Kuhn S, Koch M, Nübel T, Ladwein M, Antolovic D, Klingbeil P, Hildebrand D, Moldenhauer G, Langbein L, Franke WW, Weitz J, Zöller M (2007) A complex of EpCAM, claudin-7, CD44 variant isoforms, and tetraspanins promotes colorectal cancer progression. Mol Cancer Res 5:553–567

    Article  CAS  PubMed  Google Scholar 

  19. Kulka J, Szász AM, Németh Z, Madaras L, Schaff Z, Molnár IA, Tokés AM (2009) Expression of tight junction protein claudin-4 in basal-like breast carcinomas. Pathol Oncol Res 15:59–64

    Article  CAS  PubMed  Google Scholar 

  20. Kwon MJ (2013) Emerging roles of claudins in human cancer. Int J Mol Sci 14:18148–18180

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kwon MJ, Kim SH, Jeong HM, Jung HS, Kim SS, Lee JE, Gye MC, Erkin OC, Koh SS, Choi YL, Park CK, Shin YK (2011) Claudin-4 overexpression is associated with epigenetic derepression in gastric carcinoma. Lab Investig 91:1652–1667

    Article  CAS  PubMed  Google Scholar 

  22. Kyuno D, Kojima T, Yamaguchi H, Ito T, Kimura Y, Imamura M, Takasawa A, Murata M, Tanaka S, Hirata K, Sawada N (2013) Protein kinase Cα inhibitor protects against downregulation of claudin-1 during epithelial-mesenchymal transition of pancreatic cancer. Carcinogenesis 34:1232–1243

    Article  CAS  PubMed  Google Scholar 

  23. Kyuno D, Yamaguchi H, Ito T, Kono T, Kimura Y, Imamura M, Konno T, Hirata K, Sawada N, Kojima T (2014) Targeting tight junctions during epithelial to mesenchymal transition in human pancreatic cancer. World J Gastroenterol 20:10813–10824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lal-Nag M, Battis M, Santin AD, Morin PJ (2012) Claudin-6: a novel receptor for CPE-mediated cytotoxicity in ovarian cancer. Oncogenesis 1:e33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lan M, Kojima T, Osanai M, Chiba H, Sawada N (2004) Oncogenic Raf-1 regulates epithelial to mesenchymal transition via distinct transduction pathways in an immortalized mouse hepatic cell line. Carcinogenesis 25:2385–2395

    Article  CAS  PubMed  Google Scholar 

  26. Lan M, Kojima T, Yamaguchi H, Kyuno D, Kimura Y, Imamura M, Takasawa A, Murata M, Tanaka S, Hirata K, Sawada N (2011) Transcriptional regulation of claudin-18 via specific protein kinase C signaling pathways and modification of DNA methylation in human pancreatic cancer cells. J Cell Biochem 112:1761–1772

    Article  Google Scholar 

  27. Leotlela PD, Wade MS, Duray PH, Rhode MJ, Brown HF, Rosenthal DT, Dissanayake SK, Earley R, Indig FE, Nickoloff BJ, Taub DD, Kallioniemi OP, Meltzer P, Morin PJ, Weeraratna AT (2007) Claudin-1 overexpression in melanoma is regulated by PKC and contributes to melanoma cell motility. Oncogene 26:3846–3856

    Article  CAS  PubMed  Google Scholar 

  28. Li XM, Wang H, Zhu LL, Zhao RZ, Ji HL (2015) Genes regulating epithelial polarity are critical suppressors of esophageal oncogenesis. J Cancer 6:694–700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lioni M, Brafford P, Andl C, Rustgi A, El-Deiry W, Herlyn M, Smalley KS (2007) Dysregulation of claudin-7 leads to loss of E-cadherin expression and the increased invasion of esophageal squamous cell carcinoma cells. Am J Pathol 170:709–721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Litkouhi B, Kwong J, Lo CM, JG S 3rd, McClane BA, Aponte M, Gao Z, Sarno JL, Hinners J, Welch WR, Berkowitz RS, Mok SC, Garner EI (2007) Claudin-4 overexpression in epithelial ovarian cancer is associated with hypomethylation and is a potential target for modulation of tight junction barrier function using a C-terminal fragment of Clostridium perfringens enterotoxin. Neoplasia 9:304–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lu S, Singh K, Mangray S, Tavares R, Noble L, Resnick MB, Yakirevich E (2013) Claudin expression in high-grade invasive ductal carcinoma of the breast: correlation with the molecular subtype. Mod Pathol 26:485–495

    Article  CAS  PubMed  Google Scholar 

  32. Matter K, Balda MS (2003) Signalling to and from tight junctions. Nat Rev Mol Cell Biol 4:225–236

    Article  CAS  PubMed  Google Scholar 

  33. Michl P, Barth C, Buchholz M, Lerch MM, Rolke M, Holzmann KH, Menke A, Fensterer H, Giehl K, Löhr M, Leder G, Iwamura T, Adler G, Gress TM (2003) Claudin-4 expression decreases invasiveness and metastatic potential of pancreatic cancer. Cancer Res 63:6265–6271

    CAS  PubMed  Google Scholar 

  34. Miwa N, Furuse M, Tsukita S, Niikawa N, Nakamura Y, Furukawa Y (2001) Involvement of claudin-1 in the β-catenin/Tcf signaling pathway and its frequent upregulation in human colorectal cancers. Oncol Rep 12:469–476

    Article  CAS  Google Scholar 

  35. Morin PJ (2005) Claudin proteins in human cancer: promising new targets for diagnosis and therapy. Cancer Res 65:9603–9606

    Article  CAS  PubMed  Google Scholar 

  36. Morohashi S, Kusumi T, Sato F, Odagiri H, Chiba H, Yoshihara S, Hakamada K, Sasaki M, Kijima H (2007) Decreased expression of claudin-1 correlates with recurrence status in breast cancer. Int J Mol Med 20:139–143

    PubMed  Google Scholar 

  37. Myal Y, Leygue E, Blanchard AA (2010) Claudin 1 in breast tumorigenesis: revelation of a possible novel “claudin high” subset of breast cancers. J Biomed Biotechnol 2010:956897

    Article  PubMed  PubMed Central  Google Scholar 

  38. Nübel T, Preobraschenski J, Tuncay H, Weiss T, Kuhn S, Ladwein M, Langbein L, Zöller M (2009) Claudin-7 regulates EpCAM-mediated functions in tumor progression. Mol Cancer Res 7:2852–2899

    Article  Google Scholar 

  39. Oku N, Sasabe E, Ueta E, Yamamoto T, Osaki T (2006) Tight junction protein claudin-1 enhances the invasive activity of oral squamous cell carcinoma cells by promoting cleavage of laminin-5 gamma2 chain via matrix metalloproteinase (MMP)-2 and membrane-type MMP-1. Cancer Res 66:5251–5257

    Article  CAS  PubMed  Google Scholar 

  40. Osanai M, Murata M, Chiba H, Kojima T, Sawada N (2007) Epigenetic silencing of claudin-6 promotes anchorage-independent growth of breast carcinoma cells. Cancer Sci 98:1557–1562

    Article  CAS  PubMed  Google Scholar 

  41. Oshima T, Miwa H, Joh T (2008) Aspirin induces gastric epithelial barrier dysfunction by activating p38 MAPK via claudin-7. Am J Physiol Cell Physiol 295:C800–C806

    Article  CAS  PubMed  Google Scholar 

  42. Pope JL, Ahmad R, Bhat AA, Washington MK, Singh AB, Dhawan P (2014) Claudin-1 overexpression in intestinal epithelial cells enhances susceptibility to adenamatous polyposis coli-mediated colon tumorigenesis. Mol Cancer 13:167

    Article  PubMed  PubMed Central  Google Scholar 

  43. Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, He X, Perou CM (2010) Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 12:R68

    Article  PubMed  PubMed Central  Google Scholar 

  44. Qin W, Ren Q, Liu T, Huang Y, Wang J (2013) MicroRNA-155 is a novel suppressor of ovarian cancer-initiating cells that targets CLDN1. FEBS Lett 587:1434–1439

    Article  CAS  PubMed  Google Scholar 

  45. Sawada N (2013) Tight junction-related human diseases. Pathol Int 63:1–12

    Article  CAS  PubMed  Google Scholar 

  46. Sawada N, Murata M, Kikuchi K, Osanai M, Tobioka H, Kojima T, Chiba H (2003) Tight junctions and human diseases. Med Electron Microsc 36:147–156

    Article  PubMed  Google Scholar 

  47. Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29:4741–4751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Singh AB, Sharma A, Dhawan P (2010) Claudin family of proteins and cancer: an overview. J Oncol 2010:541957

    Article  PubMed  PubMed Central  Google Scholar 

  49. Sobel G, Németh J, Kiss A, Lotz G, Szabó I, Udvarhelyi N, Schaff Z, Páska C (2006) Claudin 1 differentiates endometrioid and serous papillary endometrial adenocarcinoma. Gynecol Oncol 103:591–598

    Article  CAS  PubMed  Google Scholar 

  50. Soini Y (2005) Expression of claudins 1, 2, 3, 4, 5 and 7 in various types of tumours. Histopathology 46:551–560

    Article  CAS  PubMed  Google Scholar 

  51. Soini Y, Kinnula V, Kahlos K, Pääkkö P (2006) Claudins in differential diagnosis between mesothelioma and metastatic adenocarcinoma of the pleura. J Clin Pathol 59:250–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Soini Y, Takasawa A, Eskelinen M, Juvonen P, Kärjä V, Hasegawa T, Murata M, Tanaka S, Kojima T, Sawada N (2012) Expression of claudins 7 and 18 in pancreatic ductal adenocarcinoma: association with features of differentiation. J Clin Pathol 65:431–436

    Article  CAS  PubMed  Google Scholar 

  53. Sung CO, Han SY, Kim SH (2011) Low expression of claudin-4 is associated with poor prognosis in esophageal squamous cell carcinoma. Ann Surg Oncol 18:273–281

    Article  PubMed  Google Scholar 

  54. Takehara M, Nishimura T, Mima S, Hoshino T, Mizushima T (2009) Effect of claudin expression on paracellular permeability, migration and invasion of colonic cancer cells. Biol Pharm Bull 32:825–831

    Article  CAS  PubMed  Google Scholar 

  55. Tokés AM, Kulka J, Paku S, Szik A, Páska C, Novák PK, Szilák L, Kiss A, Bögi K, Schaff Z (2005) Claudin-1, −3 and −4 proteins and mRNA expression in benign and malignant breast lesions: a research study. Breast Cancer Res 7:R296–R305

    Article  PubMed  PubMed Central  Google Scholar 

  56. Tsujiwaki M, Murata M, Takasawa A, Hiratsuka Y, Fukuda R, Sugimoto K, Ono Y, Nojima M, Tanaka S, Hirata K, Kojima T, Sawada N (2015) Aberrant expression of claudin-4 and -7 in hepatocytes in the cirrhotic human liver. Med Mol Morphol 48:33–43

    Article  CAS  PubMed  Google Scholar 

  57. Tsukita S, Furuse M (2002) Claudin-based barrier in simple and stratified cellular sheets. Curr Opin Cell Biol 14:531–536

    Article  CAS  PubMed  Google Scholar 

  58. Tsukita S, Furuse M, Itoh M (2001) Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol 2:285–293

    Article  CAS  PubMed  Google Scholar 

  59. Tsukita S, Yamazaki Y, Katsuno T, Tamura A, Tsukita S (2008) Tight junction-based epithelial microenvironment and cell proliferation. Oncogene 27:6930–6938

    Article  CAS  PubMed  Google Scholar 

  60. Van Itallie C, Rahner C, Anderson JM (2001) Regulated expression of claudin-4 decreases paracellular conductance through a selective decrease in sodium permeability. J Clin Invest 107:1319–1327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wu CJ, Mannan P, Lu M, Udey MC (2013) Epithelial cell adhesion molecule (EpCAM) regulates claudin dynamics and tight junctions. J Biol Chem 288:12253–12268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Yamada G, Murata M, Takasawa A, Nojima M, Mori Y, Sawada N, Takahashi H (2016) Increased expressions of claudin 4 and 7 in atypical adenomatous hyperplasia and adenocarcinoma of the lung. Med Mol Morphol (in press).

  63. Zhou B, Moodie A, Blanchard AA, Leygue E, Myal Y (2015) Claudin 1 in breast cancer: new insights. J Clin Med 27:1960–1976

    Article  Google Scholar 

Download references

Acknowledgment

The works in this review were supported in part by grants from the Grants-in-Aid for Scientific Research program from the Japan Society for the Promotion of Science (JSPS KAKENHI) grant numbers JP16K08693, JP24390089, JP26460421, and JP24790355.

Author information

Authors and Affiliations

  1. Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556, Japan

    Makoto Osanai, Akira Takasawa, Masaki Murata & Norimasa Sawada

Authors
  1. Makoto Osanai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akira Takasawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masaki Murata
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Norimasa Sawada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Makoto Osanai.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Osanai, M., Takasawa, A., Murata, M. et al. Claudins in cancer: bench to bedside. Pflugers Arch - Eur J Physiol 469, 55–67 (2017). https://doi.org/10.1007/s00424-016-1877-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-016-1877-7

Keywords

Search

Navigation