Differential Gene Expression in Ovarian Carcinoma

Hibbs, Kathleen; Skubitz, Keith M.; Pambuccian, Stefan E.; Casey, Rachael C.; Burleson, Kathryn M.; Oegema, Theodore R.; Thiele, Jeannine J.; Grindle, Suzanne; Bliss, Robin; Skubitz, Amy P.N.

doi:10.1016/s0002-9440(10)63306-8

Cited by 211 publications

(175 citation statements)

References 66 publications

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“…27 Significant increase of claudin-4 has been detected in pancreatic, 22,28 prostate, 20 cervical 26 and ovarian cancers. 29 For the first time, our study detected high expression of claudin-4 in biliary tract cancers in contrast to hepatocellular carcinomas at both RNA and protein levels. This is in correlation with its expression in normal extrahepatic and intrahepatic bile ducts, gallbladder mucosa and its absence from hepatocytes shown by immunohistochemistry.…”

Section: Discussionmentioning

confidence: 52%

Claudin-4 differentiates biliary tract cancers from hepatocellular carcinomas

et al. 2006

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The recently identified claudins are dominant components of tight junctions, responsible for cell adhesion, polarity and paracellular permeability. Certain claudins have been shown to have relevance in tumor development, with some of them, especially claudin-4, even suggested as future therapeutic target. The aim of the present study was to analyze the expression of claudin-4 in the biliary tree, biliary tract cancers and hepatocellular carcinomas. A total of 107 cases were studied: 53 biliary tract cancers, 50 hepatocellular carcinomas, 10 normal liver and 10 normal extrahepatic biliary duct samples. Immunohistochemical analysis was performed on conventional specimens and on tissue microarrays as well. Claudin-4 was further investigated by Western blot analysis and real-time RT-PCR. Intense membranous immunolabeling was found for claudin-4 in all biliary tract cancers unrelated to the primary site of origin, namely intrahepatic, extrahepatic or gallbladder cancers. Normal biliary epithelium showed weak positivity for claudin-4. In contrast, normal hepatocytes and tumor cells of hepatocellular carcinomas did not express claudin-4. The results of Western immunoblot analysis and real-time RT-PCR were in correlation with the immunohistochemical findings. Cytokeratins, as CK7 (92%) and CK19 (83%) were mostly positive in biliary tract cancers, however, one-third of hepatocellular carcinomas also expressed CK7 (34%). HSA antibody (HepPar1) reacted with the majority of hepatocellular carcinomas (86%), while being positive in a low percentage of the biliary tract cancers (8%). In conclusion, this is the first report of a significantly increased claudin-4 expression in biliary tract cancers, which represents a novel feature of tumors of biliary tract origin. Claudin-4 expression seems to be a useful marker in differentiating biliary tract cancers from hepatocellular carcinomas and could well become a potential diagnostic tool.

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Section: Discussionmentioning

confidence: 52%

Claudin-4 differentiates biliary tract cancers from hepatocellular carcinomas

et al. 2006

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“…Several studies have confirmed the overexpression of claudin-3 and claudin-4 in ovarian cancer [7][8][9][10][11][12][13][14], but the roles of these proteins in tumorigenesis or the mechanisms regulating them are unclear. As a first step in elucidating the role of claudin phosphorylation in ovarian cancer, we have recently shown that claudin-3 can be phosphorylated by PKA at Thr192, and that phosphorylation of this residue could lead to the disruption of TJs in ovarian cancer cells [38].…”

Section: Discussionmentioning

confidence: 99%

“…However, paradoxically, claudins have also been shown to be elevated in several cancers [5]. For example, we and others have shown that claudin-3 and claudin-4 are highly increased in ovarian cancer [7][8][9][10][11][12][13][14]. These claudins have also been shown to be elevated in prostate, pancreatic, uterine, and breast cancer [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

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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“…We and others have shown that CLDN3 and CLDN4 are highly increased in ovarian cancer. [5][6][7][8][9][10][11][12] These claudins have also been shown to be elevated in prostate, pancreatic, uterine and breast cancer. [13][14][15] The functional roles for the overexpressed claudin proteins in human cancer are still unclear.…”

Section: Introductionmentioning

confidence: 99%

Regulation of the CLDN3 gene in ovarian cancer cells

Honda¹,

Pazin²,

D’Souza³

et al. 2007

Cancer Biology & Therapy

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AcKnowleDgeMenTSWe thank Dr. Ashani Weeraratna and the members of our laboratory for useful comments on the manuscript. This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. Research PaperRegulation of the CLDN3 Gene in Ovarian Cancer Cells AbSTrAcTThe claudin (CLDN) genes encode a family of proteins involved in the formation and function of tight junctions. CLDN gene expression is frequently altered in several human cancers, and in particular, CLDN3 and CLDN4 are commonly overexpressed in ovarian cancer. However, the mechanisms leading to the deregulation of these genes in cancer remain unclear. In the present study, we have examined the CLDN3 promoter and have identified a minimal region containing an Sp1 site crucial for its activity. In addition, we find that the CLDN3 promoter is regulated through epigenetic processes. Cells that express high levels of CLDN3 exhibit low DNA methylation and high histone H3 acetylation of the critical CLDN3 promoter region, and the reverse is observed in cells that do not express this gene. CLDN3-negative cells can be induced to express CLDN3 through treatment with DNA methyltransferase or histone deacetylase inhibitors. Interestingly, in vitro binding experiments, as well as chip assays show that Sp1 binds the unmethylated promoter much more efficiently, providing a mechanism for CLDN3 silencing in non-expressing cells. Finally, siRNA-mediated knockdown of Sp1 led to a significant decrease of CLDN3 expression at both the mRNA and protein levels, demonstrating a crucial role for this transcription factor in the regulation of CLDN3. Our data provide a basis for CLDN3 expression in ovarian cancer cells, as well as a mechanism for the silencing of this promoter in tumors lacking expression of claudin-3.

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Differential Gene Expression in Ovarian Carcinoma

Cited by 211 publications

References 66 publications

Claudin-4 differentiates biliary tract cancers from hepatocellular carcinomas

Claudin-4 differentiates biliary tract cancers from hepatocellular carcinomas

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

Regulation of the CLDN3 gene in ovarian cancer cells

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