The claudin gene family: expression in normal and neoplastic tissues

Hewitt, Kyle J.; Agarwal, Rachana; Morin, Patrice J.

doi:10.1186/1471-2407-6-186

Cited by 428 publications

(407 citation statements)

References 22 publications

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“…[13][14][15][16][17][19][20][21]27 Tight junctions' alterations have been observed in thyroid neoplasms by freeze-fracture analysis. 28,29 In these studies, aberrant tight junction formation characterized poorly differentiated carcinomas or compact oncocytic tumors.…”

Section: Discussionmentioning

confidence: 99%

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Tight junctions in thyroid carcinogenesis: diverse expression of claudin-1, claudin-4, claudin-7 and occludin in thyroid neoplasms

et al. 2008

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Claudins and occludin are integral constituents of tight junctions and are deregulated in a variety of malignancies. Their role in thyroid carcinogenesis has not yet been elucidated. This study investigates the expression of occludin and claudin-1, -4 and -7 in thyroid neoplasms. Ninety-one thyroid neoplasms (15 follicular adenomas, 15 follicular carcinomas, 26 papillary carcinomas, 16 papillary microcarcinomas, 8 medullary carcinomas, 3 poorly differentiated carcinomas, 8 undifferentiated carcinomas) were immunostained with antibodies against occludin and claudin-1, -4 and -7. Occludin was mainly expressed in the form of intracytoplasmic vesicles, whereas all claudins tested exhibited membranous immunostaining. Thirteen out of 15 follicular adenomas, 10/15 follicular carcinomas, 24/26 papillary carcinomas, 15/16 papillary microcarcinomas, 1/8 medullary carcinomas, 2/3 poorly differentiated carcinomas and 2/8 undifferentiated carcinomas exhibited claudin-1 expression, whereas claudin-4 was expressed in 13/15, 12/15, 23/26, 13/16, 7/8, 2/3 and 2/8 of the tumors, respectively, and claudin-7 expression was found in 67, 33, 73, 69, 25, 0 and 13% of the cases, respectively. Occludin was expressed in 100% follicular adenomas, 80% follicular carcinomas, 96% papillary carcinomas, 50% papillary microcarcinomas, 50% medullary carcinomas, 33% poorly differentiated carcinomas and 88% undifferentiated carcinomas. Occludin expression was reduced in papillary microcarcinomas, medullary carcinomas and poorly differentiated carcinomas. All claudins exhibited reduced expression in undifferentiated carcinomas. Claudin-1 was additionally reduced in medullary carcinomas and claudin-7 in follicular, medullary and poorly differentiated carcinomas. A correlation between loss of claudin-1 expression and worse disease-free survival was noted on univariate analysis. Dedifferentiation of the thyroid carcinomas is accompanied by reduction in claudin-1, -4 and -7 expression. A differential expression of tight junction proteins in the different histologic types of thyroid gland is noted. Additionally, claudin-1 expression may be an important prognostic indicator of recurrence in thyroid carcinomas.

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Section: Discussionmentioning

confidence: 99%

“…18 On the other hand, various cancers (ie ovarian, colon, cervical cancer) are associated with elevated tight junctions proteins expression levels or protein dislocation to the cytoplasm. [19][20][21] These reports emphasize the complex and diverse actions of tight junctions proteins in cancer progression.…”

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confidence: 99%

Tight junctions in thyroid carcinogenesis: diverse expression of claudin-1, claudin-4, claudin-7 and occludin in thyroid neoplasms

et al. 2008

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“…23,26 Claudin-3 and -4 regulate paracellular permeability, maintain epithelial cell polarity and are often overexpressed in epithelial tumors, such as colon, breast, pancreas, prostate, ovarian or endometrial cancer. [27][28][29][30][31][32] Thus, particularly these two claudins are attractive targets for the selective CPE treatment of solid tumors. Application of recombinant CPE protein leads to the dose-dependent rapid eradication of claudin-4-or claudin-3-overexpressing pancreas, breast or colon cancer cells in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Novel Clostridium perfringens enterotoxin suicide gene therapy for selective treatment of claudin-3- and -4-overexpressing tumors

et al. 2011

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Bacterial toxins are known to be effective for cancer therapy. Clostridium perfringens enterotoxin (CPE) is produced by the bacterial Clostridium type A strain. The transmembrane proteins claudin-3 and -4, often overexpressed in numerous human epithelial tumors (for example, colon, breast, pancreas, prostate and ovarian), are the targeted receptors for CPE. CPE binding to them triggers formation of membrane pore complexes leading to rapid cell death. In this study, we aimed at selective tumor cell killing by CPE gene transfer. We generated expression vectors bearing the bacterial wild-type CPE cDNA (wtCPE) or translationoptimized CPE (optCPE) cDNA for in vitro and in vivo gene therapy of claudin-3-and -4-overexpressing tumors. The CPE expression analysis at messenger RNA and protein level revealed more efficient expression of optCPE compared with wtCPE. Expression of optCPE showed rapid cytotoxic activity, hightened by CPE release as bystander effect. Cytotoxicity of up to 100% was observed 72 h after gene transfer and is restricted to claudin-3-and -4-expressing tumor lines. MCF-7 and HCT116 cells with high claudin-4 expression showed dramatic sensitivity toward CPE toxicity. The claudin-negative melanoma line SKMel-5, however, was insensitive toward CPE gene transfer. The non-viral intratumoral in vivo gene transfer of optCPE led to reduced tumor growth in MCF-7 and HCT116 tumor-bearing mice compared with the vector-transfected control groups. This novel approach demonstrates that CPE gene transfer can be employed for a targeted suicide gene therapy of claudin-3-and -4-overexpressing tumors, leading to the rapid and efficient tumor cell killing in vitro and in vivo.

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“…CLDN4 has been shown to be overexpressed in a variety of cancers, including ovarian carcinoma, 15 breast carcinoma, 16 prostate cancer, 17 and pancreatic ductal adenocarcinoma. [18][19][20][21][22] Importantly, CLDN4 has been reported as having an important role in the growth, invasion, and metastasis of pancreatic cancer. CLDN4 is also known to function as a high-affinity receptor for Clostridium perfringens enterotoxin (CPE) 23 and is, therefore, expected to be a therapeutic target.…”

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confidence: 99%

Expression of claudin-4 (CLDN4) mRNA in intraductal papillary mucinous neoplasms of the pancreas

et al. 2011

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Claudin-4, encoding a protein for tight junction formation and function, is highly overexpressed in pancreatic ductal adenocarcinoma and is also associated with invasive adenocarcinomas arising in intraductal papillary mucinous neoplasms of the pancreas. However, the expression pattern of claudin-4 during neoplastic progression of intraductal papillary mucinous neoplasms remains unknown. Using quantitative real-time reverse transcription-PCR, we analyzed claudin-4 mRNA in a panel of 14 pancreatic cancer cell lines and in formalin-fixed paraffinembedded tissues from 80 patients with intraductal papillary mucinous neoplasms of different histological grades and papillary subtypes. Increased expression of claudin-4 was confirmed in all the pancreatic cancer cell lines tested as compared with normal ductal epithelial cells and fibroblast cultures. The claudin-4 expression was significantly higher in high-grade intraductal papillary mucinous neoplasms (borderline neoplasm and carcinoma) than in low-grade intraductal papillary mucinous neoplasms (adenoma) (Po0.0001). In addition, claudin-4 mRNA levels were significantly higher in intestinal-type intraductal papillary mucinous neoplasms than in non-intestinaltype intraductal papillary mucinous neoplasms based on papillary subclassification (Po0.0001). Our findings suggest that claudin-4 expression is associated with neoplastic progression of intraductal papillary mucinous neoplasms and, especially, with a distinct pathway to intestinal differentiation.

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The claudin gene family: expression in normal and neoplastic tissues

Cited by 428 publications

References 22 publications

Tight junctions in thyroid carcinogenesis: diverse expression of claudin-1, claudin-4, claudin-7 and occludin in thyroid neoplasms

Tight junctions in thyroid carcinogenesis: diverse expression of claudin-1, claudin-4, claudin-7 and occludin in thyroid neoplasms

Novel Clostridium perfringens enterotoxin suicide gene therapy for selective treatment of claudin-3- and -4-overexpressing tumors

Expression of claudin-4 (CLDN4) mRNA in intraductal papillary mucinous neoplasms of the pancreas

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