Skip to main content

Advertisement

SpringerLink
Log in

Increased Expression of Claudin-1 and Claudin-7 in Liver Cirrhosis and Hepatocellular Carcinoma

  • Research
  • Published:
Pathology & Oncology Research

Abstract

Claudins have been reported to be differentially regulated in malignancies and implicated in the process of carcinogenesis and tumor progression. Claudin-1 has been described as key factor in the entry of hepatitis C virus (HCV) into hepatocytes and as promoter of epithelial-mesenchymal transition in liver cells. The objective of the current study was to characterize claudin expression in hepatocellular carcinoma (HCC) as well as HCC-surrounding and normal liver samples with respect to cirrhosis and HCV infection. Expression of claudin-1, -2, -3, -4, and −7 was measured by morphometric analysis of immunohistochemistry, and Western blotting in 30 HCCs with 30 corresponding non-tumorous tissues and 6 normal livers. Claudin-1 and −7 protein expression was found significantly elevated in cirrhosis when compared with non-cirrhotic liver. HCCs developed in cirrhotic livers showed even higher expression of claudin-1 contrary to decreased claudin-7 expression when compared with cirrhosis. With reference to HCV status, HCCs or surrounding livers of HCV-infected samples did not show significant alterations in claudin expression when compared with HCV-negative specimens. Cirrhotic transformation associates with elevated claudin-1 and -7 expressions in both non-tumorous liver and HCC. The fact that no significant differences in claudin expression were found regarding HCV-positivity in our sample set suggests that HCV infection alone does not induce a major increase in the total amount of its entry co-factor claudin-1. Increased expression of claudin-1 seems to be a consequence of cirrhotic transformation and might contribute to a more effective HCV entry and malignant transformation.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Ferenci P, Fried M, Labrecque D, Bruix J, Sherman M, Omata M, Heathcote J, Piratsivuth T, Kew M, Otegbayo JA, Zheng SS, Sarin S, Hamid SS, Modawi SB, Fleig W, Fedail S, Thomson A, Khan A, Malfertheiner P, Lau G, Carillo FJ, Krabshuis J, Le Mair A (2010) Hepatocellular carcinoma (HCC): a global perspective. J Clin Gastroenterol 44(4):239–245. doi:10.1097/MCG.0b013e3181d46ef2

    Article  PubMed  Google Scholar 

  2. Bosch FX, Ribes J, Diaz M, Cleries R (2004) Primary liver cancer: worldwide incidence and trends. Gastroenterology 127(5 Suppl 1):S5–S16

    Article  PubMed  Google Scholar 

  3. Furuse M, Sasaki H, Fujimoto K, Tsukita S (1998) A single gene product, claudin-1 or -2, reconstitutes tight junction strands and recruits occludin in fibroblasts. J Cell Biol 143(2):391–401

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Furuse M, Sasaki H, Tsukita S (1999) Manner of interaction of heterogeneous claudin species within and between tight junction strands. J Cell Biol 147(4):891–903

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Morita K, Furuse M, Fujimoto K, Tsukita S (1999) Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands. Proc Natl Acad Sci U S A 96(2):511–516

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R, Weiner AJ, Houghton M, Rosa D, Grandi G, Abrignani S (1998) Binding of hepatitis C virus to CD81. Science 282(5390):938–941

    Article  CAS  PubMed  Google Scholar 

  7. Scarselli E, Ansuini H, Cerino R, Roccasecca RM, Acali S, Filocamo G, Traboni C, Nicosia A, Cortese R, Vitelli A (2002) The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. EMBO J 21(19):5017–5025

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Evans MJ, von Hahn T, Tscherne DM, Syder AJ, Panis M, Wolk B, Hatziioannou T, McKeating JA, Bieniasz PD, Rice CM (2007) Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature 446(7137):801–805. doi:10.1038/nature05654

    Article  CAS  PubMed  Google Scholar 

  9. Ploss A, Evans MJ, Gaysinskaya VA, Panis M, You H, de Jong YP, Rice CM (2009) Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature 457(7231):882–886. doi:10.1038/nature07684

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Harris HJ, Davis C, Mullins JG, Hu K, Goodall M, Farquhar MJ, Mee CJ, McCaffrey K, Young S, Drummer H, Balfe P, McKeating JA (2010) Claudin association with CD81 defines hepatitis C virus entry. J Biol Chem 285(27):21092–21102. doi:10.1074/jbc.M110.104836

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Krieger SE, Zeisel MB, Davis C, Thumann C, Harris HJ, Schnober EK, Mee C, Soulier E, Royer C, Lambotin M, Grunert F, Dao Thi VL, Dreux M, Cosset FL, McKeating JA, Schuster C, Baumert TF (2010) Inhibition of hepatitis C virus infection by anti-claudin-1 antibodies is mediated by neutralization of E2-CD81-claudin-1 associations. Hepatology 51(4):1144–1157. doi:10.1002/hep.23445

    Article  CAS  PubMed  Google Scholar 

  12. Fofana I, Krieger SE, Grunert F, Glauben S, Xiao F, Fafi-Kremer S, Soulier E, Royer C, Thumann C, Mee CJ, McKeating JA, Dragic T, Pessaux P, Stoll-Keller F, Schuster C, Thompson J, Baumert TF (2010) Monoclonal anti-claudin 1 antibodies prevent hepatitis C virus infection of primary human hepatocytes. Gastroenterology 139 (3):953–964, 964 e951-954. doi:10.1053/j.gastro.2010.05.073

    Google Scholar 

  13. Mensa L, Crespo G, Gastinger MJ, Kabat J, Perez-del-Pulgar S, Miquel R, Emerson SU, Purcell RH, Forns X (2011) Hepatitis C virus receptors claudin-1 and occludin after liver transplantation and influence on early viral kinetics. Hepatology 53(5):1436–1445. doi:10.1002/hep.24110

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Reynolds GM, Harris HJ, Jennings A, Hu K, Grove J, Lalor PF, Adams DH, Balfe P, Hubscher SG, McKeating JA (2008) Hepatitis C virus receptor expression in normal and diseased liver tissue. Hepatology 47(2):418–427. doi:10.1002/hep.22028

    Article  PubMed  Google Scholar 

  15. Holczbauer A, Gyongyosi B, Lotz G, Szijarto A, Kupcsulik P, Schaff Z, Kiss A (2013) Distinct claudin expression profiles of hepatocellular carcinoma and metastatic colorectal and pancreatic carcinomas. J Histochem Cytochem: Off J Histochem Soc 61(4):294–305. doi:10.1369/0022155413479123

    Article  Google Scholar 

  16. Yoon CH, Kim MJ, Park MJ, Park IC, Hwang SG, An S, Choi YH, Yoon G, Lee SJ (2010) Claudin-1 acts through c-Abl-protein kinase Cdelta (PKCdelta) signaling and has a causal role in the acquisition of invasive capacity in human liver cells. J Biol Chem 285(1):226–233. doi:10.1074/jbc.M109.054189

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Suh Y, Yoon CH, Kim RK, Lim EJ, Oh YS, Hwang SG, An S, Yoon G, Gye MC, Yi JM, Kim MJ, Lee SJ (2012) Claudin-1 induces epithelial-mesenchymal transition through activation of the c-Abl-ERK signaling pathway in human liver cells. Oncogene 32:4873–4882. doi:10.1038/onc.2012.505

    Google Scholar 

  18. Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, Denk H, Desmet V, Korb G, MacSween RN et al (1995) Histological grading and staging of chronic hepatitis. J Hepatol 22(6):696–699

    Article  CAS  PubMed  Google Scholar 

  19. Lodi C, Szabo E, Holczbauer A, Batmunkh E, Szijarto A, Kupcsulik P, Kovalszky I, Paku S, Illyes G, Kiss A, Schaff Z (2006) Claudin-4 differentiates biliary tract cancers from hepatocellular carcinomas. Mod Pathol: Off J U S Can Acad Pathol, Inc 19(3):460–469. doi:10.1038/modpathol.3800549

    Article  CAS  Google Scholar 

  20. Grotegut S, von Schweinitz D, Christofori G, Lehembre F (2006) Hepatocyte growth factor induces cell scattering through MAPK/Egr-1-mediated upregulation of Snail. EMBO J 25(15):3534–3545. doi:10.1038/sj.emboj.7601213

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Kojima T, Takano K, Yamamoto T, Murata M, Son S, Imamura M, Yamaguchi H, Osanai M, Chiba H, Himi T, Sawada N (2008) Transforming growth factor-beta induces epithelial to mesenchymal transition by down-regulation of claudin-1 expression and the fence function in adult rat hepatocytes. Liver Int: Off J Int Assoc Stud Liver 28(4):534–545. doi:10.1111/j.1478-3231.2007.01631.x

    Article  CAS  Google Scholar 

  22. Takaki Y, Hirai S, Manabe N, Izumi Y, Hirose T, Nakaya M, Suzuki A, Mizuno K, Akimoto K, Tsukita S, Shuin T, Ohno S (2001) Dynamic changes in protein components of the tight junction during liver regeneration. Cell Tissue Res 305(3):399–409

    CAS  PubMed  Google Scholar 

  23. Kominsky SL, Argani P, Korz D, Evron E, Raman V, Garrett E, Rein A, Sauter G, Kallioniemi OP, Sukumar S (2003) Loss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast. Oncogene 22(13):2021–2033. doi:10.1038/sj.onc.1206199

    Article  CAS  PubMed  Google Scholar 

  24. Tokes AM, Kulka J, Paku S, Mathe M, Paska C, Lodi C, Kiss A, Schaff Z (2005) The expression of five different claudins in invasive breast carcinomas: comparison of pT1pN1 and pT1pN0 tumors. Pathol Res Pract 201(8–9):537–544

    Article  CAS  PubMed  Google Scholar 

  25. Michl P, Barth C, Buchholz M, Lerch MM, Rolke M, Holzmann KH, Menke A, Fensterer H, Giehl K, Lohr M, Leder G, Iwamura T, Adler G, Gress TM (2003) Claudin-4 expression decreases invasiveness and metastatic potential of pancreatic cancer. Cancer Res 63(19):6265–6271

    CAS  PubMed  Google Scholar 

  26. Korompay A, Borka K, Lotz G, Somoracz A, Torzsok P, Erdelyi-Belle B, Kenessey I, Baranyai Z, Zsoldos F, Kupcsulik P, Bodoky G, Schaff Z, Kiss A (2012) Tricellulin expression in normal and neoplastic human pancreas. Histopathology 60(6B):E76–E86. doi:10.1111/j.1365-2559.2012.04189.x

    Article  PubMed  Google Scholar 

  27. Sobel G, Paska C, Szabo I, Kiss A, Kadar A, Schaff Z (2005) Increased expression of claudins in cervical squamous intraepithelial neoplasia and invasive carcinoma. Hum Pathol 36(2):162–169. doi:10.1016/j.humpath.2004.12.001

    Article  CAS  PubMed  Google Scholar 

  28. Schmelzer E, Wauthier E, Reid LM (2006) The phenotypes of pluripotent human hepatic progenitors. Stem Cells 24(8):1852–1858. doi:10.1634/stemcells.2006-0036

    Article  CAS  PubMed  Google Scholar 

  29. Schmelzer E, Zhang L, Bruce A, Wauthier E, Ludlow J, Yao HL, Moss N, Melhem A, McClelland R, Turner W, Kulik M, Sherwood S, Tallheden T, Cheng N, Furth ME, Reid LM (2007) Human hepatic stem cells from fetal and postnatal donors. J Exp Med 204(8):1973–1987. doi:10.1084/jem.20061603

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Yovchev MI, Grozdanov PN, Joseph B, Gupta S, Dabeva MD (2007) Novel hepatic progenitor cell surface markers in the adult rat liver. Hepatology 45(1):139–149. doi:10.1002/hep.21448

    CAS  PubMed  Google Scholar 

  31. Gonzalez-Mariscal L, Lechuga S, Garay E (2007) Role of tight junctions in cell proliferation and cancer. Prog Histochem Cytochem 42(1):1–57. doi:10.1016/j.proghi.2007.01.001

    Article  CAS  PubMed  Google Scholar 

  32. Hirohashi S, Kanai Y (2003) Cell adhesion system and human cancer morphogenesis. Cancer Sci 94(7):575–581

    Article  CAS  PubMed  Google Scholar 

  33. Lal-Nag M, Morin PJ (2009) The claudins. Genome Biol 10(8):235. doi:10.1186/gb-2009-10-8-235

    Article  PubMed Central  PubMed  Google Scholar 

  34. Harris HJ, Farquhar MJ, Mee CJ, Davis C, Reynolds GM, Jennings A, Hu K, Yuan F, Deng H, Hubscher SG, Han JH, Balfe P, McKeating JA (2008) CD81 and claudin 1 coreceptor association: role in hepatitis C virus entry. J Virol 82(10):5007–5020. doi:10.1128/JVI.02286-07

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Orban E, Szabo E, Lotz G, Kupcsulik P, Paska C, Schaff Z, Kiss A (2008) Different expression of occludin and ZO-1 in primary and metastatic liver tumors. Pathol Oncol Res POR 14(3):299–306. doi:10.1007/s12253-008-9031-2

    Article  CAS  Google Scholar 

  36. Schluter H, Wepf R, Moll I, Franke WW (2004) Sealing the live part of the skin: the integrated meshwork of desmosomes, tight junctions and curvilinear ridge structures in the cells of the uppermost granular layer of the human epidermis. Eur J Cell Biol 83(11–12):655–665. doi:10.1078/0171-9335-00434

    Article  PubMed  Google Scholar 

  37. Higashi Y, Suzuki S, Sakaguchi T, Nakamura T, Baba S, Reinecker HC, Nakamura S, Konno H (2007) Loss of claudin-1 expression correlates with malignancy of hepatocellular carcinoma. J Surg Res 139(1):68–76. doi:10.1016/j.jss.2006.08.038

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to express our gratitude to Magdolna Pekar for her precious help in tissue processing and performing immunohistochemistry. This work was supported by grants from the Hungarian Scientific Research Found (OTKA)# K101435.

Author information

Authors and Affiliations

  1. 2nd Department of Pathology, Semmelweis University Budapest, Üllői út 93., 1091, Budapest, Hungary

    Ágnes Holczbauer, Benedek Gyöngyösi, Gábor Lotz, Péter Törzsök, Pál Kaposi-Novák, Péter Tátrai, Zsuzsa Schaff & András Kiss

  2. 1st Department of Surgery, Semmelweis University Budapest, Budapest, Hungary

    Attila Szijártó & Péter Kupcsulik

Authors
  1. Ágnes Holczbauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Benedek Gyöngyösi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gábor Lotz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Péter Törzsök
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pál Kaposi-Novák
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Attila Szijártó
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Péter Tátrai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Péter Kupcsulik
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zsuzsa Schaff
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. András Kiss
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to András Kiss.

Additional information

Ágnes Holczbauer and Benedek Gyöngyösi equally contributed to the paper.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 70 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Holczbauer, Á., Gyöngyösi, B., Lotz, G. et al. Increased Expression of Claudin-1 and Claudin-7 in Liver Cirrhosis and Hepatocellular Carcinoma. Pathol. Oncol. Res. 20, 493–502 (2014). https://doi.org/10.1007/s12253-013-9683-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-013-9683-4

Keywords

Search

Navigation