Role of claudins in tumorigenesis

Swisshelm, Karen; Macek, Robert; Kubbies, Manfred

doi:10.1016/j.addr.2005.01.006

Cited by 197 publications

(160 citation statements)

References 53 publications

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“…TJs are composed of several proteins including the claudin proteins, a family of related transmembrane proteins that form the backbone of TJs. Recently, a number of claudin proteins have been implicated in human cancer [5,6]. Consistent with the observation that TJs are dismantled in tumors, certain claudin family members have been found to be down-regulated in cancer.…”

Section: Introductionmentioning

confidence: 56%

Phosphorylation of claudin-4 by PKCε regulates tight junction barrier function in ovarian cancer cells

D’Souza

Indig

Morin

2007

Experimental Cell Research

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Claudin proteins belong to a large family of transmembrane proteins essential to the formation and maintenance of tight junctions (TJs). In ovarian cancer, TJ protein claudin-4 is frequently overexpressed and may have roles in survival and invasion, but the molecular mechanisms underlying its regulation are poorly understood. In this report, we show that claudin-4 can be phosphorylated by protein kinase C (PKC) at Thr189 and Ser194 in ovarian cancer cells and overexpression of a claudin-4 mutant protein mimicking the phosphorylated state results in the disruption of the barrier function. Furthermore, upon phorbol ester-mediated PKC activation of OVCA433 cells, TJ strength is decreased and claudin-4 localization is altered. Analyses using PKC inhibitors and siRNA suggest that PKCε, an isoform typically expressed in ovarian cancer cells, may be important in the TPAmediated claudin-4 phosphorylation and weakening of the TJs. Furthermore, immunofluorescence studies showed that claudin-4 and PKCε are co-localized at the TJs in these cells. The modulation of claudin-4 activity by PKCε may not only provide a mechanism for disrupting TJ function in ovarian cancer, but may also be important in the regulation of TJ function in normal epithelial cells.

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Section: Introductionmentioning

confidence: 56%

Phosphorylation of claudin-4 by PKCε regulates tight junction barrier function in ovarian cancer cells

D’Souza

Indig

Morin

2007

Experimental Cell Research

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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%

“…Reduced claudins' expression and associated loss of functional tight junctions are usually a feature of poorly differentiated tumors of various origins (ie breast, esophageal, gastric, colon and thyroid carcinomas). [14][15][16]30,31 Apparently, loss of claudins expression results in loss of cell-to-cell adhesion, thereby preventing the cells to form organized epithelial structures and leading in an undifferentiated phenotype. Undifferentiated carcinomas of the thyroid gland are the result of anaplastic transformation of a pre-existing well-differentiated tumor.…”

Section: Discussionmentioning

confidence: 99%

“…Different claudins are found at the tight junction of diverse epithelial cells, 11 and this accounts for the observed differences in permeability and electrical resistance of various epithelia. 2,8,10 Previous studies have shown that occludin and claudin-1, -4 and -7 are deregulated in a variety of malignancies; for example, loss of occludin expression or upregulation of claudin-3 and -4 accompanies the progression of endometrial carcinoma, 12,13 reduced expression of claudin-1 correlates with poorer differentiation, disease recurrence and poor survival in stage II colonic cancer, 14 claudin-7 expression has been found reduced in mammary, 15 esophageal, 16 and head and neck carcinomas, 17 whereas claudin-4 overexpression decreases the invasiveness and metastatic potential of pancreatic cancer cells. 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.…”

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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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“…Tumors exhibit a loss of organization associated with a decrease in TJ integrity (Swisshelm et al, 2005), potentially allowing diffusion of nutrients and other growth factors, and facilitating the escape of the tumor cells into the vasculature (Sawada et al, 2003). Thus, the regulation of TJs is of significant interest in cancer biology, and claudins in particular, have been the focus of some attention, as these proteins are frequently upregulated and mislocalized in cancer, suggesting abnormal processing (reviewed in Morin, 2005).…”

Section: Introductionmentioning

confidence: 99%

Claudin-1 overexpression in melanoma is regulated by PKC and contributes to melanoma cell motility

et al. 2006

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Serial analysis of gene expression followed by pathway analysis implicated the tight junction protein claudin-1 (CLDN1) in melanoma progression. Tight junction proteins regulate the paracellular transport of molecules, but staining of a tissue microarray revealed that claudin-1 was overexpressed in melanoma, and aberrantly expressed in the cytoplasm of malignant cells, suggesting a role other than transport. Indeed, melanoma cells in culture demonstrate no tight junction function. It has been shown that protein kinase C (PKC) can affect expression of claudin-1 in rat choroid plexus cells, and we observed a correlation between levels of activated PKC and claudin expression in our melanoma cells. To determine if PKC could affect the expression of CLDN1 in human melanoma, cells lacking endogenous claudin-1 were treated with 200 nM phorbol myristic acid (PMA). PKC activation by PMA caused an increase in CLDN1 transcription in 30 min, and an increase in claudin-1 protein by 12 h. Inhibition of PKC signaling in cells with high claudin-1 expression resulted in decreased claudin-1 expression. CLDN1 appears to contribute to melanoma cell invasion, as transient transfection of melanoma cells with CLDN1 increased metalloproteinase 2 (MMP-2) secretion and activation, and subsequently, motility of melanoma cells as demonstrated by wound-healing assays. Conversely, knockdown of CLDN1 by siRNA resulted in the inhibition of motility, as well as decreases in MMP-2 secretion and activation. These data implicate claudin-1 in melanoma progression.

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Role of claudins in tumorigenesis

Cited by 197 publications

References 53 publications

Phosphorylation of claudin-4 by PKCε regulates tight junction barrier function in ovarian cancer cells

Phosphorylation of claudin-4 by PKCε regulates tight junction barrier function in ovarian cancer cells

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

Claudin-1 overexpression in melanoma is regulated by PKC and contributes to melanoma cell motility

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