The claudin family of proteins in human malignancy: a clinical perspective

Figures & data

Figure 1 Claudin protein structure.

Notes: The claudin protein consists of four transmembrane domains and two extracellular loops (1 and 2). The N- and C-termini are located in the cytoplasm. The second extracellular loop has a binding site for Clostridium perfringens enterotoxin (CPE) in claudin-3 and -4. The C-terminal region contains phosphorylation sites that may be involved in protein–protein interactions and signal transduction.

Table 1 Changes in claudin protein or mRNA expression in human tumor samples

Protein	Tumor type	Expression	Reference
Claudin-1	Colonic	↑	^Citation29
	Squamous cell carcinoma	↑	^Citation31
	Cervical	↑	^Citation32
	Gastric	↑	^Citation35
	Esophageal	↑	^Citation36
	Biliary tract	↑	^Citation37
	Keratinized (pearl)	↑	^Citation38
	Thyroid	↑	^Citation39
	Squamous cell carcinoma of the tongue	↑	^Citation40
	Urothelial carcinoma	↑	^Citation41
	Hepatoblastoma	↑	^Citation42
	Squamous cell carcinoma of the lung	↑	^Citation45
	Pancreatic	↑	^Citation46
	Breast	↓	^Citation28
	Colonic	↓	^Citation30
	Glioblastoma multiforme	↓	^Citation33
	Melanoma	↓	^Citation34
	Hepatocellular carcinoma	↓	^Citation43
	Adenocarcinoma of the lung	↓	^Citation45
Claudin-2	Esophageal	↑	^Citation36
	Colonic	↑	^Citation48,Citation49
	Hepatoblastoma	↑	^Citation51
	Lung	↑	^Citation26
	Breast	↓	^Citation47
	Cervical	↓	^Citation50
	Prostate	↓	^Citation52
Claudin-3	Gastric	↑	^Citation35
	Esophageal	↑	^Citation36
	Urothelial carcinoma	↑	^Citation41
	Renal cell carcinoma	↑	^Citation44
	Breast	↑	^Citation53
	Colonic	↑	^Citation54
	Prostate	↑	^Citation55
	Ovarian	↑	^Citation56
	Pancreatic	↑	^Citation57
	Breast	↓	^Citation47
	Hepatoblastoma	↓	^Citation51
Claudin-4	Squamous cell carcinoma	↑	^Citation31
	Esophageal	↑	^Citation36
	Biliary tract	↑	^Citation37
	Squamous cell carcinoma of the tongue	↑	^Citation40
	Urothelial carcinoma	↑	^Citation41
	Renal cell carcinoma	↑	^Citation44
	Breast	↑	^Citation53
	Colonic	↑	^Citation54
	Prostate	↑	^Citation55
	Ovarian	↑	^Citation56
	Gastric	↑	^Citation58
	Pancreatic	↑	^Citation60
	Thyroid	↑	^Citation63
	Lung	↑	^Citation27
	Hepatoblastoma	↓	^Citation42
	Breast	↓	^Citation47
	Gastric	↓	^Citation59
	Colonic	↓	^Citation61
	Cervical	↓	^Citation62
Claudin-5	Adenocarcinoma of the lung	↑	^Citation45
	Pancreatic	↑	^Citation57
	Lung	↑	^Citation27
	Glioblastoma multiforme	↓	^Citation33
	Squamous cell carcinoma of the lung	↓	^Citation45
	Breast	↓	^Citation47
Claudin-6	Gastric adenocarcinoma	↑	^Citation35
	Breast (cell)	↓	^Citation64
Claudin-7	Cervical	↑	^Citation32
	Squamous cell carcinoma of the tongue	↑	^Citation40
	Urothelial carcinoma	↑	^Citation41
	Thyroid	↑	^Citation63
	Breast	↑	^Citation67
	Colonic	↑	^Citation69,Citation70
	Gastric	↑	^Citation73
	Esophageal	↑	^Citation74
	Chromophobe renal cell carcinoma	↑	^Citation76
	Ovarian	↑	^Citation78
	Hepatocellular carcinoma (mRNA)	↑	^Citation79
	Hepatoblastoma	↓	^Citation42
	Breast	↓	^Citation66
	Head and neck squamous cell carcinoma	↓	^Citation68
	Colonic	↓	^Citation71,Citation72
	Esophageal	↓	^Citation75
	Uterus	↓	^Citation77
	Lung	↓	^Citation25
Claudin-8	Biliary tract	↓	^Citation37
	Colonic (mRNA)	↓	^Citation80
Claudin-9	Gastric adenocarcinoma (cell)	↑	^Citation65
Claudin-10	Hepatocellular carcinoma (mRNA)	↑	^Citation81
	Lung adenocarcinomas	↑	^Citation82
	Thyroid papillary (mRNA)	↑	^Citation83
	Biliary tract	↓	^Citation37
Claudin-11	Bladder (mRNA)	↓	^Citation84
Claudin-12	Colonic (mRNA)	↑	^Citation80
Claudin-16	Breast (mRNA)	↑	^Citation90
	Ovarian (mRNA)	↑	^Citation85
	Breast	↓	^Citation86
Claudin-18	Lung adenocarcinomas	↑	^Citation82
	Pancreatic	↑	^Citation88
	Cholangiocarcinoma	↑	^Citation88
	Gastric (mRNA)	↓	^Citation87
Claudin-23	Gastric (mRNA)	↓	^Citation89

Abbreviation: mRNA, messenger RNA.

MiwaNFuruseMTsukitaSNiikawaNNakamuraYFurukawaYInvolvement of claudin-1 in the beta-catenin/Tcf signaling pathway and its frequent upregulation in human colorectal cancersOncol Res20011211–1246947611939410

 PubMed Web of Science ®Google Scholar

OubanAHamdanHHakamAAhmedAAClaudin-1 expression in squamous cell carcinomas of different organs: comparative study of cancerous tissues and normal controlsInt J Surg Pathol201220213213821997594

 PubMed Web of Science ®Google Scholar

LeeJWLeeSJSeoJIncreased expressions of claudin-1 and claudin-7 during the progression of cervical neoplasiaGynecol Oncol2005971535915790437

 PubMed Web of Science ®Google Scholar

ResnickMBGavilanezMNewtonEClaudin expression in gastric adenocarcinomas: a tissue microarray study with prognostic correlationHum Pathol200536888689216112005

 PubMed Web of Science ®Google Scholar

GyõrffyHHolczbauerANagyPClaudin expression in Barrett’s esophagus and adenocarcinomaVirchows Arch2005447696196816133365

 PubMed Web of Science ®Google Scholar

NémethZSzászAMTátraiPClaudin-1, -2, -3, -4, -7, -8, and -10 protein expression in biliary tract cancersJ Histochem Cytochem200957211312118854598

 PubMed Web of Science ®Google Scholar

MoritaKTsukitaSMiyachiYTight junction-associated proteins (occludin, ZO-1, claudin-1, claudin-4) in squamous cell carcinoma and Bowen’s diseaseBr J Dermatol2004151232833415327539

 PubMed Web of Science ®Google Scholar

FlugeOBrulandOAkslenLALillehaugJRVarhaugJEGene expression in poorly differentiated papillary thyroid carcinomasThyroid200616216117516676402

 PubMed Web of Science ®Google Scholar

BelloIOVilenSTNiinimaaAKantolaSSoiniYSaloTExpression of claudins 1, 4, 5, and 7 and occludin, and relationship with prognosis in squamous cell carcinoma of the tongueHuman Pathol20083981212122018547615

 PubMed Web of Science ®Google Scholar

NakanishiKOgataSHiroiSTominagaSAidaSKawaiTExpression of occludin and claudins 1, 3, 4, and 7 in urothelial carcinoma of the upper urinary tractAm J Clin Pathol20081301434918550469

 PubMed Web of Science ®Google Scholar

HaidSWindischMPBartenschlagerRPietschmannTMouse-specific residues of claudin-1 limit hepatitis C virus genotype 2a infection in a human hepatocyte cell lineJ Virol201084296497519889758

 PubMed Web of Science ®Google Scholar

PaschoudSBongiovanniMPacheJCCitiSClaudin-1 and claudin-5 expression patterns differentiate lung squamous cell carcinomas from adenocarcinomasMod Pathol200720994795417585317

 PubMed Web of Science ®Google Scholar

Iacobuzio-DonahueCAMaitraAShen-OngGLDiscovery of novel tumor markers of pancreatic cancer using global gene expression technology. Discovery of novel tumor markers of pancreatic cancer using global gene expression technologyAm J Pathol200216041239124911943709

 PubMed Web of Science ®Google Scholar

KramerFWhiteKKubbiesMSwisshelmKWeberBHGenomic organization of claudin-1 and its assessment in hereditary and sporadic breast cancerHuman Genet2000107324925611071387

 PubMed Web of Science ®Google Scholar

ResnickMBKonkinTRouthierJSaboEPricoloVEClaudin-1 is a strong prognostic indicator in stage II colonic cancer: a tissue microarray studyMod Pathol200518451151815475928

 PubMed Web of Science ®Google Scholar

LiebnerSFischmannARascherGClaudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiformeActa Neuropathol2000100332333110965803

 PubMed Web of Science ®Google Scholar

CohnMLGoncharukVNDiwanAHZhangPSShenSSPrietoVGLoss of claudin-1 expression in tumor-associated vessels correlates with acquisition of metastatic phenotype in melanocytic neoplasmsJ Cutan Pathol200532853353616115050

 PubMed Web of Science ®Google Scholar

HigashiYSuzukiSSakaguchiTLoss of claudin-1 expression correlates with malignancy of hepatocellular carcinomaJ Surg Res20071391687617270214

 PubMed Web of Science ®Google Scholar

WeberCRNalleSCTretiakovaMRubinDTTurnerJRClaudin-1 and claudin-2 expression is elevated in inflammatory bowel disease and may contribute to early neoplastic transformationLab Invest200888101110112018711353

 PubMed Web of Science ®Google Scholar

AungPPMitaniYSanadaYNakayamaHMatsusakiKYasuiWDifferential expression of claudin-2 in normal human tissues and gastrointestinal carcinomasVirchows Arch2006448442843416328347

 PubMed Web of Science ®Google Scholar

HalaszJHolczbauerAPaskaCClaudin-1 and claudin-2 differentiate fetal and embryonal components in human hepatoblastomaHum Pathol200637555556116647953

 PubMed Web of Science ®Google Scholar

IkariASatoTWatanabeRYamazakiYSugataniJIncrease in claudin-2 expression by an EGFR/MEK/ERK/c-Fos pathway in lung adenocarcinoma A549 cellsBiochim Biophys Acta2012182361110111822546605

 PubMed Web of Science ®Google Scholar

KimTHHuhJHLeeSKangHKimGIAnHJDown-regulation of claudin-2 in breast carcinomas is associated with advanced diseaseHistopathology2008531485518479414

 PubMed Web of Science ®Google Scholar

TimmonsBCMitchellSMGilpinCMahendrooMSDynamic changes in the cervical epithelial tight junction complex and differentiation occur during cervical ripening and parturitionEndocrinology200714831278128717138657

 PubMed Web of Science ®Google Scholar

SoiniYExpression of claudins 1, 2, 3, 4, 5 and 7 in various types of tumoursHistopathology200546555156015842637

 PubMed Web of Science ®Google Scholar

LechpammerMResnickMBSaboEThe diagnostic and prognostic utility of claudin expression in renal cell neoplasmsMod Pathol200821111320132918587324

 PubMed Web of Science ®Google Scholar

KominskySLValiMKorzDClostridium perfringens enterotoxin elicits rapid and specific cytolysis of breast carcinoma cells mediated through tight junction proteins claudin 3 and 4Am J Pathol200416451627163315111309

 PubMed Web of Science ®Google Scholar

de OliveiraSSde OliveiraIMDe SouzaWMorgado-DíazJAClaudins upregulation in human colorectal cancerFEBS Lett2005579276179618516253248

 PubMed Web of Science ®Google Scholar

MaedaTMurataMChibaHClaudin-4-targeted therapy using Clostridium perfringens enterotoxin for prostate cancerProstate201272435136021656836

 PubMed Web of Science ®Google Scholar

HoughCDSherman-BaustCAPizerESLarge-scale serial analysis of gene expression reveals genes differentially expressed in ovarian cancerCancer Res200060226281628711103784

 PubMed Web of Science ®Google Scholar

MissiagliaEBlaveriETerrisBAnalysis of gene expression in cancer cell lines identifies candidate markers for pancreatic tumorigenesis and metastasisInt J Cancer2004112110011215305381

 PubMed Web of Science ®Google Scholar

KwonMJKimSHJeongHMClaudin-4 overexpression is associated with epigenetic derepression in gastric carcinomaLab Invest201191111652166721844869

 PubMed Web of Science ®Google Scholar

MichlPBuchholzMRolkeMClaudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens enterotoxinGastroenterology2001121367868411522752

 PubMed Web of Science ®Google Scholar

TzelepiVNTsamandasACVlotinouHDVagianosCEScopaCDTight junctions in thyroid carcinogenesis: diverse expression of claudin-1, claudin-4, claudin-7 and occludin in thyroid neoplasmsMod Pathol2008211223017962811

 PubMed Web of Science ®Google Scholar

JungJHJungCKChoiHJDiagnostic utility of expression of claudins in non-small cell lung cancer: different expression profiles in squamous cell carcinomas and adenocarcinomasPathol Res Pract2009205640941619231096

 PubMed Web of Science ®Google Scholar

LeeSKMoonJParkSWSongSYChungJBKangJKLoss of the tight junction protein claudin 4 correlates with histological growth-pattern and differentiation in advanced gastric adenocarcinomaOncology Rep2005132193199

 Web of Science ®Google Scholar

UedaJSembaSChibaHHeterogeneous expression of claudin-4 in human colorectal cancer: decreased claudin-4 expression at the invasive front correlates cancer invasion and metastasisPathobiology2007741324117496431

 PubMed Web of Science ®Google Scholar

SobelGSzabóIPáskaCChanges of cell adhesion and extracellular matrix (ECM) components in cervical intraepithelial neoplasiaPathology Oncol Res20051112631

 Web of Science ®Google Scholar

WuQLiuYRenYTight junction protein, claudin-6, down-regulates the malignant phenotype of breast carcinomaEur J Cancer Prev201019318619420215972

 PubMed Web of Science ®Google Scholar

NachtMFergusonATZhangWCombining serial analysis of gene expression and array technologies to identify genes differentially expressed in breast cancerCancer Res199959215464547010554019

 PubMed Web of Science ®Google Scholar

DaridoCBuchertMPannequinJDefective claudin-7 regulation by Tcf-4 and Sox-9 disrupts the polarity and increases the tumorigenicity of colorectal cancer cellsCancer Res200868114258426818519685

 PubMed Web of Science ®Google Scholar

KuhnSKochMNübelTA complex of EpCAM, claudin-7, CD44 variant isoforms, and tetraspanins promotes colorectal cancer progressionMol Cancer Res20075655356717579117

 PubMed Web of Science ®Google Scholar

JohnsonAHFriersonHFZaikaAExpression of tight-junction protein claudin-7 is an early event in gastric tumorigenesisAm J Pathol2005167257758416049341

 PubMed Web of Science ®Google Scholar

MontgomeryEMamelakAJGibsonMOverexpression of claudin proteins in esophageal adenocarcinoma and its precursor lesionsAppl Immunohistochem Mol Morphol2006141243016540726

 PubMedGoogle Scholar

HornsbyCDCohenCAminMBClaudin-7 immunohistochemistry in renal tumors: a candidate marker for chromophobe renal cell carcinoma identified by gene expression profilingArch Pathol Lab Med2007131101541154617922590

 PubMed Web of Science ®Google Scholar

DahiyaNBeckerKGWoodWH3rdZhangYMorinPJClaudin-7 is frequently overexpressed in ovarian cancer and promotes invasionPloS One201167e2211921789222

 PubMed Web of Science ®Google Scholar

BrokalakiEIWeberFSotiropoulosGCDaoudakiMCicinnatiVRBeckebaumSClaudin-7 expression in hepatocellular carcinomaTransplant Proc20124492737274023146509

 PubMed Web of Science ®Google Scholar

KominskySLArganiPKorzDLoss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breastOncogene200322132021203312673207

 PubMed Web of Science ®Google Scholar

Al MoustafaAEAlaoui-JamaliMABatistGIdentification of genes associated with head and neck carcinogenesis by cDNA microarray comparison between matched primary normal epithelial and squamous carcinoma cellsOncogene200221172634264011965536

 PubMed Web of Science ®Google Scholar

OshimaTKunisakiCYoshiharaKReduced expression of the claudin-7 gene correlates with venous invasion and liver metastasis in colorectal cancerOncology Rep2008194953959

 Web of Science ®Google Scholar

NakayamaFSembaSUsamiYChibaHSawadaNYokozakiHHypermethylation-modulated downregulation of claudin-7 expression promotes the progression of colorectal carcinomaPathobiology200875317718518550915

 PubMed Web of Science ®Google Scholar

UsamiYChibaHNakayamaFReduced expression of claudin-7 correlates with invasion and metastasis in squamous cell carcinoma of the esophagusHum Pathol200637556957716647955

 PubMed Web of Science ®Google Scholar

LiXLiYQiuHWangYDownregulation of claudin-7 potentiates cellular proliferation and invasion in endometrial cancerOncol Lett20136110110523946785

 PubMed Web of Science ®Google Scholar

LuZDingLHongHHoggardJLuQChenYHClaudin-7 inhibits human lung cancer cell migration and invasion through ERK/MAPK signaling pathwayExp Cell Res2011317131935194621641901

 PubMed Web of Science ®Google Scholar

GroneJWeberBStaubEDifferential expression of genes encoding tight junction proteins in colorectal cancer: frequent dysregulation of claudin-1, -8 and -12Int J Colorectal Dis200722665165917047970

 PubMed Web of Science ®Google Scholar

Zavala-ZendejasVETorres-MartinezACSalas-MoralesBFortoulTIMontañoLFRendon-HuertaEPClaudin-6, 7, or 9 overexpression in the human gastric adenocarcinoma cell line AGS increases its invasiveness, migration, and proliferation rateCancer Invest20112911120874001

 PubMed Web of Science ®Google Scholar

CheungSTLeungKLIpYCClaudin-10 expression level is associated with recurrence of primary hepatocellular carcinomaClin Cancer Res2005112 Pt 155155615701840

 PubMed Web of Science ®Google Scholar

MerikallioHPääkköPHarjuTSoiniYClaudins 10 and 18 are predominantly expressed in lung adenocarcinomas and in tumors of nonsmokersInt J Clin Exp Pathol20114766767322076167

 PubMed Web of Science ®Google Scholar

AldredMAHuangYLiyanarachchiSPapillary and follicular thyroid carcinomas show distinctly different microarray expression profiles and can be distinguished by a minimum of five genesJ Clin Oncol200422173531353915337802

 PubMed Web of Science ®Google Scholar

AwsareNSMartinTAHaynesMDMatthewsPNJiangWGClaudin-11 decreases the invasiveness of bladder cancer cellsOncology Rep201125615031509

 Web of Science ®Google Scholar

KuoSJChienSYLinCChanSETsaiHTChenDRSignificant elevation of CLDN16 and HAPLN3 gene expression in human breast cancerOncology Rep2010243759766

 Web of Science ®Google Scholar

RangelLBSherman-BaustCAWernyjRPSchwartzDRChoKRMorinPJCharacterization of novel human ovarian cancer-specific transcripts (HOSTs) identified by serial analysis of gene expressionOncogene200322467225723214562052

 PubMed Web of Science ®Google Scholar

MartinTAHarrisonGMWatkinsGJiangWGClaudin-16 reduces the aggressive behavior of human breast cancer cellsJ Cell Biochem20081051415218442037

 PubMed Web of Science ®Google Scholar

ShinozakiAShibaharaJNodaNClaudin-18 in biliary neoplasms. Its significance in the classification of intrahepatic cholangiocarcinomaVirchows Arch20114591738021607649

 PubMed Web of Science ®Google Scholar

SanadaYOueNMitaniYYoshidaKNakayamaHYasuiWDown-regulation of the claudin-18 gene, identified through serial analysis of gene expression data analysis, in gastric cancer with an intestinal phenotypeJ Pathol2006208563364216435283

 PubMed Web of Science ®Google Scholar

KatohMKatohMCLDN23 gene, frequently down-regulated in intestinal-type gastric cancer, is a novel member of CLAUDIN gene familyInt J Mol Med200311668368912736707

 PubMed Web of Science ®Google Scholar