Abstract
Tight junction (TJ) composes of an intriguing class of cell junction molecules, for which these molecules share similar organizations and structure features among different organs. Four types of transmembrane molecules namely occludins, claudins, junctional adhesion molecules and coxsackievirus and adenovirus receptors act as core units and each link directly and indirectly with a panel of peripheral molecules and underlying cytoskeletons to constitute the functional protein complexes at TJs. Individual TJ complex alone or in co-operation with other complexes via cross-talk mediated by peripheral molecules activate signaling pathways pertinent to various physiological and pathological processes in livers. In human livers, TJs are located at two regions in association with hepatocytes and cholangiocytes and perform major roles in controlling bile flow and metabolism. Apart from this physiological function, the other functions of TJs relating to liver diseases of hepatitis and liver cancer are gradually uncovered. The understanding of how TJs are involved in these clinical conditions hint for the development of new treatments at the molecular level.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol 2009; 9:799–809.
Marchiando AM, Graham WV, Turner JR. Epithelial barriers in homeostasis and disease. Annu Rev Pathol 2010; 5:119–144.
Koch S, Nusrat A. Dynamic regulation of epithelial cell fate and barrier function by intercellular junctions. Ann N Y Acad Sci 2009; 1165:220–227.
Thomason HA, Scothern A, McHarg S et al. Desmosomes: adhesive strength and signalling in health and disease. Biochem J 2010; 429:419–433.
Matter K, Aijaz S, Tsapara A et al. Mammalian tight junctions in the regulation of epithelial differentiation and proliferation. Curr Opin Cell Biol 2005; 17:453–458.
Foss B, Tronstad KJ, Bruserud O. Connexin-based signaling in acute myelogenous leukemia (AML). Biochim Biophys Acta 2010; 1798:1–8.
Lee NP, Poon RT, Shek FH et al. Role of cadherin-17 in oncogenesis and potential therapeutic implications in hepatocellular carcinoma. Biochim Biophys Acta 2010; 1806:138–145.
Gavert N, Ben-Ze’ev A. b-Catenin signaling in biological control and cancer. J Cell Biochem 2007; 102:820–828.
Green KJ, Getsios S, Troyanovsky S et al. Intercellular junction assembly, dynamics, and homeostasis. Cold Spring Harb Perspect Biol 2010; 2:a000125.
Franke WW. Discovering the molecular components of intercellular junctions—a historical view. Cold Spring Harb Perspect Biol 2009; 1:a003061.
Lee NP, Yeung WS, Luk JM. Junction interaction in the seminiferous epithelium: regulatory roles of connexin-based gap junction. Front Biosci 2007; 12:1552–1562.
Litjens SH, de Pereda JM, Sonnenberg A. Current insights into the formation and breakdown of hemidesmosomes. Trends Cell Biol 2006; 16:376–383.
A bbott NJ, Patabendige AA, Dolman DE et al. Structure and function of the blood-brain barrier. Neurobiol Dis 2010; 37:13–25.
Lee NP, Cheng CY. Nitric oxide/nitric oxide synthase, spermatogenesis, and tight junction dynamics. Biol Reprod 2004; 70:267–276.
Malarkey DE, Johnson K, Ryan L et al. New insights into functional aspects of liver morphology. Toxicol Pathol 2005; 33:27–34.
Si-Tayeb K, Lemaigre FP, Duncan SA. Organogenesis and development of the liver. Dev Cell 2010; 18:175–189.
Cao Y, Chang H, Li L et al. Alteration of adhesion molecule expression and cellular polarity in hepatocellular carcinoma. Histopathology 2007; 51:528–538.
Kojima T, Yamamoto T, Murata M et al. Regulation of the blood-biliary barrier: interaction between gap and tight junctions in hepatocytes. Med Electron Microsc 2003; 36:157–164.
Vinken M, Henkens T, De Rop E et al. Biology and pathobiology of gap junctional channels in hepatocytes. Hepatology 2008; 47:1077–1088.
Lee NP, Luk JM. Hepatic tight junctions: from viral entry to cancer metastasis. World J Gastroenterol 2010; 16:289–295.
Kojima T, Murata M, Yamamoto T et al. Tight junction proteins and signal transduction pathways in hepatocytes. Histol Histopathol 2009; 24:1463–1472.
Raynaud P, Carpentier R, Antoniou A et al. Biliary differentiation and bile duct morphogenesis in development and disease. Int J Biochem Cell Biol 2011; 43:245–256.
Esteller A. Physiology of bile secretion. World J Gasteroenterol 2008; 14:5641–5649.
Chiba H, Osanai M, Murata M et al. Transmembrane proteins of tight junctions. Biochim Biophys Acta 2008; 1778:588–600.
Paris L, Tonutti L, Vannini C et al. Structural organization of the tight junctions. Biochim Biophys Acta 2008; 1778:646–659.
Van Itallie CM, Anderson JM. The molecular physiology of tight junction pores. Physiology (Bethesda) 2004; 19:331–338.
Shen L, Weber CR, Raleigh DR et al. Tight junction pore and leak pathways: a dynamic duo. Annu Rev Physiol 2011; 73:283–309.
Raschperger E, Thyberg J, Pettersson S et al. The coxsackie-and adenovirus receptor (CAR) is an in vivo marker for epithelial tight junctions, with a potential role in regulating permeability and tissue homeostasis. Exp Cell Res 2006; 312:1566–1580.
Jakab C, Kiss A, Schaff Z et al. Claudin-7 protein differentiates canine cholangiocarcinoma from hepatocellular carcinoma. Histol Histopathol 2010; 25:857–864.
Krause G, Winkler L, Mueller SL et al. Structure and function of claudins. Biochim Biophys Acta 2008; 1778:631–645.
Schneeberger EE, Lynch RD. The tight junction: a multifunctional complex. Am J Physiol Cell Physiol 2004; 286:C1213–C1228.
Bauer H, Zweimueller-Mayer J, Steinbacher P et al. The dual role of zonula occludens (ZO) proteins. J Biomed Biotechnol 2010; 402–593.
Fanning AS, Anderson JM. Zonula occludens-1 and-2 are cytosolic scaffolds that regulate the assembly of cellular junctions. Ann N Y Acad Sci 2009; 1165:113–120.
Meng W, Takeichi M. Adherens junction: molecular architecture and regulation. Cold Spring Harb Perspect Biol 2009; 1:a002899.
Dusek RL, Attardi LD. Desmosomes: new perpetrators in tumour suppression. Nat Rev Cancer 2011; 11:317–323.
Hartsock A, Nelson WJ. Adherens and tight junctions: structure, function and connections to the actin cytoskeleton. Biochim Biophys Acta 2008; 1778:660–669.
Richardson HE. Actin up for Hippo. The EMBO Journal 2011; 30:2307–2309.
Olson EN, Nordheim A. Linking actin dynamics and gene transcription to drive cellular motile functions. Nat Rev Mol Cell Biol 2010; 11:353–365.
Mruk DD, Cheng CY. Tight junctions in the testis: new perspectives. Philos Trans R Soc Lond B Biol Sci 2010; 365:1621–1635.
Lee NP, Cheng CY. Adaptors, junction dynamics and spermatogenesis. Biol Reprod 2004; 71:392–404.
Yan HH, Mruk DD, Lee WM et al. Cross-talk between tight and anchoring junctions-lesson from the testis. Adv Exp Med Biol 2008; 636:234–254.
Kojima T, Murata M, Go M et al.Connexins induce and maintain tight junctions in epithelial cells. J Membr Biol 2007; 217:13–19.
Murata M, Kojima T, Yamamoto T et al. Tight junction protein MAGI-1 is up-regulated by transfection with connexin 32 in an immortalized mouse hepatic cell line: cDNA microarray analysis. Cell Tissue Res 2005; 319:341–347.
Konopka G, Tekiela J, Iverson M et al. Junctional adhesion molecule-A is critical for the formation of pseudocanaliculi and modulates E-cadherin expression in hepatic cells. J Biol Chem 2007; 282:28137–28148.
Munir S, Saleem S, Idrees M et al. Hepatitis C treatment: current and future perspectives. Virol J 2010; 7:296.
Younger HM, Bathgate AJ, Hayes PC. Review article: Nucleoside analogues for the treatment of chronic hepatitis B. Aliment Pharmacol Ther 2004; 20:1211–1230.
Wiegand J, van Bommel F, Berg T. Management of chronic hepatitis B: status and challenges beyond treatment guidelines. Semin Liver Dis 2010; 30:361–377.
Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008; 134:1655–1669.
Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 2002; 31:339–346.
Jemal A, Bray F, Center MM et al. Global cancer statistics. CA Cancer J Clin 2011; 61:69–90.
Nakamoto Y, Kaneko S. Mechanisms of viral hepatitis induced liver injury. Curr Mol Med 2003; 3:537–544.
Bouchard MJ, Navas-Martin S. Hepatitis B and C virus hepatocarcinogenesis: lessons learned and future challenges. Cancer Lett 2011; 305:123–143.
Rosen HR. Clinical practice. Chronic hepatitis C infection. N Engl J Med 2011; 364:2429–2438.
Ciesek S, Manns MP. Hepatitis in 2010: the dawn of a new era in HCV therapy. Nat Rev Gastroenterol Hepatol 2011; 8:69–71.
Evans MJ, von Hahn T, Tscherne DM et al. Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature 2007; 446:801–805.
Zheng A, Yuan F, Li Y et al. Claudin-6 and claudin-9 function as additional coreceptors for hepatitis C virus. J Virol 2007; 81:12465–12471.
Benedicto I, Molina-Jimenez F, Bartosch B et al. The tight junction-associated protein occludin is required for a postbinding step in hepatitis C virus entry and infection. J Virol 2009; 83:8012–8020.
Gonzalez-Mariscal L, Garay E, Lechuga S. Virus interaction with the apical junctional complex. Front Biosci 2009; 14:731–768.
Brazzoli M, Bianchi A, Filippini S et al. CD81 is a central regulator of cellular events required for hepatitis C virus infection of human hepatocytes. J Virol 2008; 82:8316–8329.
Burlone ME, Budkowska A. Hepatitis C virus cell entry: role of lipoproteins and cellular receptors. J Gen Virol 2009; 90:1055–1070.
Benedicto I, Molina-Jimenez F, Barreiro O et al. Hepatitis C virus envelope components alter localization of hepatocyte tight junction-associated proteins and promote occludin retention in the endoplasmic reticulum. Hepatology 2008; 48:1044–1053.
Yang W, Hood BL, Chadwick SL et al. Fatty acid synthase is up-regulated during hepatitis C virus infection and regulates hepatitis C virus entry and production. Hepatology 2008; 48:1396–1403.
Farquhar MJ, Harris HJ, Diskar M et al. Protein kinase A-dependent step(s) in hepatitis C virus entry and infectivity. J Virol 2008; 82:8797–8811.
Schutte K, Bornschein J, Malfertheiner P. Hepatocellular carcinoma—epidemiological trends and risk factors. Dig Dis 2009; 27:80–92.
Worns MA, Galle PR. Future perspectives in hepatocellular carcinoma. Dig Liver Dis 2010; 42 Suppl 3:S302–S309.
Wall WJ, Marotta PJ. Surgery and transplantation for hepatocellular cancer. Liver Transpl 2000; 6:S16–S22.
Cabrera R, Nelson DR. Review article: the management of hepatocellular carcinoma. Aliment Pharmacol Ther 2010; 31:461–476.
Livraghi T, Makisalo H, Line PD. Treatment options in hepatocellular carcinoma today. Scand J Surg 2011; 100:22–29.
Spangenberg HC, Thimme R, Blum HE. Targeted therapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2009; 6:423–432.
Villanueva A, Llovet JM. Targeted therapies for hepatocellular carcinoma. Gastroenterology 2011; 140:1410–1426.
Cabibbo G, Craxi A. Epidemiology, risk factors and surveillance of hepatocellular carcinoma. Eur Rev Med Pharmacol Sci 2010; 14:352–355.
Outwater EK. Imaging of the liver for hepatocellular cancer. Cancer Control 2010; 17:72–82.
Sherman M. Hepatocellular carcinoma: epidemiology, surveillance, and diagnosis. Semin Liver Dis 2010; 30:3–16.
Chen L, Ho DW, Lee NP et al. Enhanced detection of early hepatocellular carcinoma by serum SELDI-TOF proteomic signature combined with alpha-fetoprotein marker. Ann Surg Oncol 2010; 17:2518–2525.
Sun S, Poon RT, Lee NP et al. Proteomics of hepatocellular carcinoma: serum vimentin as a surrogate marker for small tumors (= 2 cm). J Proteome Res 2010; 9:1923–1930.
Sun S, Day PJ, Lee NP et al. Biomarkers for early detection of liver cancer: focus on clinical evaluation. Protein Pept Lett 2009; 16:473–478.
Lee NP, Chen L, Lin MC et al. Proteomic expression signature distinguishes cancerous and nonmalignant tissues in hepatocellular carcinoma. J Proteome Res 2009; 8:1293–1303.
Zhao L, Mou DC, Peng JR et al. Diagnostic value of cancer-testis antigen mRNA in peripheral blood from hepatocellular carcinoma patients. World J Gasteroenterol 2010; 16:4072–4078.
Grizzi F, Franceschini B, Hamrick C et al. Usefulness of cancer-testis antigens as biomarkers for the diagnosis and treatment of hepatocellular carcinoma. J Transl Med 2007; 5:3.
Sato F, Hatano E, Kitamura K et al. MicroRNA profile predicts recurrence after resection in patients with hepatocellular carcinoma within the Milan Criteria. PLoS One 2011; 6:e16435.
Imbeaud S, Ladeiro Y, Zucman-Rossi J. Identification of novel oncogenes and tumor suppressors in hepatocellular carcinoma. Semin Liver Dis 2010; 30:75–86.
Lee NP, Cheung ST, Poon RT et al. Genomic and proteomic biomarkers for diagnosis and prognosis of hepatocellular carcinoma. Biomarkers Med 2007; 1:273–284.
Woo HG, Park ES, Thorgeirsson SS et al. Exploring genomic profiles of hepatocellular carcinoma. Mol Carcinog 2011; 50:235–243.
Liu Z, Ma Y, Yang J et al. Upregulated and downregulated proteins in hepatocellular carcinoma: a systematic review of proteomic profiling studies. Omics 2011; 15:61–71.
Lee NP, Tsang FH, Shek FH et al. Prognostic significance and therapeutic potential of eukaryotic translation initiation factor 5A (eIF5A) in hepatocellular carcinoma. Int J Cancer 2010; 127:968–976.
Liu LX, Lee NP, Chan VW et al. Targeting cadherin-17 inactivates Wnt signaling and inhibits tumor growth in liver carcinoma. Hepatology 2009; 50:1453–1463.
Yi X, Luk JM, Lee NP et al. Association of mortalin (HSPA9) with liver cancer metastasis and prediction for early tumor recurrence. Mol Cell Proteomics 2008; 7:315–325.
Cheung ST, Leung KL, Ip YC et al. Claudin-10 expression level is associated with recurrence of primary hepatocellular carcinoma. Clin Cancer Res 2005; 11:551–556.
Halasz J, Holczbauer A, Paska C et al. Claudin-1 and claudin-2 differentiate fetal and embryonal components in human hepatoblastoma. Hum Pathol 2006; 37:555–561.
Higashi Y, Suzuki S, Sakaguchi T et al. Loss of claudin-1 expression correlates with malignancy of hepatocellular carcinoma. J Surg Res 2007; 139:68–76.
Huang GW, Ding X, Chen SL et al. Expression of claudin 10 protein in hepatocellular carcinoma: impact on survival. J Cancer Res Clin Oncol 2011; 137:1213–1218.
Ip YC, Cheung ST, Lee YT et al. Inhibition of hepatocellular carcinoma invasion by suppression of claudin-10 in HLE cells. Mol Cancer Ther 2007; 6:2858–2867.
Borlak J, Meier T, Halter R et al. Epidermal growth factor-induced hepatocellular carcinoma: gene expression profiles in precursor lesions, early stage and solitary tumours. Oncogene 2005; 24:1809–1819.
Korn WM, Macal M, Christian C et al. Expression of the coxsackievirus-and adenovirus receptor in gastrointestinal cancer correlates with tumor differentiation. Cancer Gene Ther 2006; 13:792–797.
Furuse M, Fujita K, Hiiragi T et al. Claudin-1 and-2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol 1998; 141:1539–1550.
Aung PP, Mitani Y, Sanada Y et al. Differential expression of claudin-2 in normal human tissues and gastrointestinal carcinomas. Virchows Arch 2006; 448:428–434.
Rahner C, Mitic LL, Anderson JM. Heterogeneity in expression and subcellular localization of claudins 2, 3, 4, and 5 in the rat liver, pancreas and gut. Gastroenterology 2001; 120:411–422.
Morita K, Furuse M, Fujimoto K et al. Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands. Proc Natl Acad Sci U S A 1999; 96:511–516.
Charoenphandhu N, Wongdee K, Tudpor K et al. Chronic metabolic acidosis upregulated claudin mRNA expression in the duodenal enterocytes of female rats. Life Sci 2007; 80:1729–1737.
Inai T, Sengoku A, Guan X et al. Heterogeneity in expression and subcellular localization of tight junction proteins, claudin-10 and-15, examined by RT-PCR and immunofluorescence microscopy. Arch Histol Cytol 2005; 68:349–360.
Tureci O, Koslowski M, Helftenbein G et al. Claudin-18 gene structure, regulation, and expression is evolutionary conserved in mammals. Gene 2011; 481:83–92.
Aurrand-Lions M, Johnson-Leger C, Wong C et al. Heterogeneity of endothelial junctions is reflected by differential expression and specific subcellular localization of the three JAM family members. Blood 2001; 98:3699–3707.
Orban E, Szabo E, Lotz G et al. Different expression of occludin and ZO-1 in primary and metastatic liver tumors. Pathol Oncol Res 2008; 14:299–306.
Muresan Z, Paul DL, Goodenough DA. Occludin 1B, a variant of the tight junction protein occludin. Mol Biol Cell 2000; 11:627–634.
Zhong Y, Saitoh T, Minase T et al. Monoclonal antibody 7H6 reacts with a novel tight junction-associated protein distinct from ZO-1, cingulin and ZO-2. J Cell Biol 1993; 120:477–483.
Citi S, Amorosi A, Franconi F et al. Cingulin, a specific protein component of tight junctions, is expressed in normal and neoplastic human epithelial tissues. Am J Pathol 1991; 138:781–789.
Mandai K, Nakanishi H, Satoh A et al. Afadin: A novel actin filament-binding protein with one PDZ domain localized at cadherin-based cell-to-cell adherens junction. J Cell Biol 1997; 139:517–528.
Laura RP, Ross S, Koeppen H et al. MAGI-1: a widely expressed, alternatively spliced tight junction protein. Exp Cell Res 2002; 275:155–170.
Dobrosotskaya I, Guy RK, James GL. MAGI-1, a membrane-associated guanylate kinase with a unique arrangement of protein-protein interaction domains. J Biol Chem 1997; 272:31589–31597.
Wu Y, Dowbenko D, Spencer S et al. Interaction of the tumor suppressor PTEN/MMAC with a PDZ domain of MAGI3, a novel membrane-associated guanylate kinase. J Biol Chem 2000; 275:21477–21485.
Ullmer C, Schmuck K, Figge A et al. Cloning and characterization of MUPP1, a novel PDZ domain protein. FEBS Letters 1998; 424:63–68.
Keon BH, Schafer S, Kuhn C et al. Symplekin, a novel type of tight junction plaque protein. J Cell Biol 1996; 134:1003–1018.
Jesaitis LA, Goodenough DA. Molecular characterization and tissue distribution of ZO-2, a tight junction protein homologous to ZO-1 and the Drosophila discs-large tumor suppressor protein. J Cell Biol 1994; 124:949–961.
Inoko A, Itoh M, Tamura A et al. Expression and distribution of ZO-3, a tight junction MAGUK protein, in mouse tissues. Genes Cells 2003; 8:837–845.
Kim SO, Choi YH. The ethyl alcohol extract of Hizikia fusiforme inhibits matrix metalloproteinase activity and regulates tight junction related protein expression in Hep3B human hepatocarcinoma cells. J Med Food 2010; 13:31–38.
Sakaguchi T, Suzuki S, Higashi H et al. Expression of tight junction protein claudin-5 in tumor vessels and sinusoidal endothelium in patients with hepatocellular carcinoma. J Surg Res 2008; 147:123–131.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Landes Bioscience and Springer Science+Business Media
About this chapter
Cite this chapter
Lee, N.P. (2013). The Blood-Biliary Barrier, Tight Junctions and Human Liver Diseases. In: Cheng, C.Y. (eds) Biology and Regulation of Blood-Tissue Barriers. Advances in Experimental Medicine and Biology, vol 763. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4711-5_8
Download citation
DOI: https://doi.org/10.1007/978-1-4614-4711-5_8
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-4710-8
Online ISBN: 978-1-4614-4711-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)