Involvement of Claudin-1 in the β-Catenin/Tcf Signaling Pathway and its Frequent Upregulation in Human Colorectal Cancers

Miwa, Noriko; Furuse, Mikio; Tsukita, Shöichiro; Niikawa, Norio; Nakamura, Yusuke; Furukawa, Yoichi

doi:10.3727/096504001108747477

Cited by 256 publications

(225 citation statements)

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“…De- spite the fact that the central signals of this pathway (LRP5/6, Frizzled proteins, AXIN, GSK3b, DSH or b-catenin) show no change in gene expression, we did observe downregulation of two major inhibitors of WNT, Wnt inhibitory factor 1 (WIF1) and secreted Frizzle-related protein 3 (FRZB). In accordance with the functional activation of b-catenin, we also observed a significant overexpression of 3 of the b-catenin transcriptional coactivators, lymphoid enhancer-binding factor 1 (LEF1) and T cell factors 3 and 8 (TCF3, TCF8) and, as previously described by Sriuranpong et al 5 , upregulation of Claudin-1, whose expression is controlled by b-catenin 37 (Fig. 3a).…”

Section: Immunohistochemistrysupporting

confidence: 66%

Multiple dysregulated pathways in nasopharyngeal carcinoma revealed by gene expression profiling

Shi¹,

Bastianutto²,

Li³

et al. 2006

Intl Journal of Cancer

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Gene expression profiling was conducted using primary human nasopharyngeal carcinoma (NPC) biopsy samples to improve the understanding of the molecular pathways defining NPC and to identify novel potential therapeutic targets. RNA samples were extracted from 36 patients suspected to have NPC and hybridized onto the Affymetrix U133A chip. NPC was diagnosed in 19 patients, 11 had lymphoid hyperplasia (LH), and 6 were “normal” biopsies. Clinical stages for these NPC patients ranged from I–IV, including one M1. All NPC patients (except the M1) were treated with curative intent, which included radiotherapy alone (4 patients), or combined with chemotherapy (14 patients). Unsupervised clustering demonstrated a distinct NPC expression pattern, compared to normal biopsies. Subsequent Significance Analysis of Microarrays (SAM) derived from 14 NPC and 6 normal samples discovered 1,089 differentially regulated genes. Pathway analyses revealed novel insights into the mechanisms leading to NPC, whereby upregulation of NFκB2 and survivin play central roles in increasing resistance to apoptosis, and changes in integrin and WNT/β‐catenin signaling leading to uncontrolled proliferation. The role of survivin in resisting apoptosis in NPC was confirmed by RNA interference. Our data provide novel insights into the development and progression of NPC, and suggest survivin as a novel therapeutic target for NPC. © 2006 Wiley‐Liss, Inc.

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Section: Immunohistochemistrysupporting

confidence: 66%

Multiple dysregulated pathways in nasopharyngeal carcinoma revealed by gene expression profiling

Shi¹,

Bastianutto²,

Li³

et al. 2006

Intl Journal of Cancer

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“…The expression of several other types of claudins has been shown to change during tumor formation, as claudin-1 in carcinomas of the breast 37 and colon, 38,39 claudin-3 in breast, 19 prostate 20 and ovarian 40 cancers, and claudin-7 in breast carcinomas. 41 Furthermore, increased expression of mRNAs encoding claudin-1, -3, -4 and -7 has been detected in a great variety of human carcinoma cell lines of different origins.…”

Section: Discussionmentioning

confidence: 99%

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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“…Interestingly, a member of the claudin protein family, claudin-1, is involved in the ␤-catenin-TCF/LEF signaling pathway, and that increased expression of claudin-1 may have some role in colorectal tumorigenesis. 31 Cldn7 is responsive to androgen stimulation in the LNCaP prostate cancer cell line and can regulate the expression of prostate-specific antigen. 32 Recently, it was reported that Cldn7 is unlike other claudins, has both structural and regulatory functions and may be related to cell differentiation.…”

Section: Discussionmentioning

confidence: 99%

Expression of Tight-Junction Protein Claudin-7 Is an Early Event in Gastric Tumorigenesis

Johnson

Frierson

Zaika

et al. 2005

The American Journal of Pathology

100

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Trefoil factor-1 (Tff1) expression is remarkably downregulated in nearly all human gastric cancers. Therefore, we used the Tff1 knockout mouse model to detect molecular changes in preneoplastic gastric dysplasia. Oligonucleotide microarray gene expression analysis of gastric dysplasia of Tff1 ؊/؊ mice was compared to that of normal gastric mucosa of wild-type mice. The genes most overexpressed in Tff1؊/؊ mice included claudin-7 (CLDN7), early growth response-1 (EGR1), and epithelial membrane protein-1 (EMP1). Quantitative real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry showed that Cldn7 was overexpressed in all 10 Tff1؊/؊ gastric dysplasia samples. Comparison with our serial analysis of gene expression database of human gastric cancer revealed similar deregulation in human gastric cancers. Quantitative real-time reverse transcriptase-polymerase chain reaction of human gastric adenocarcinoma samples indicated that, of these three genes, CLDN7 was the most frequently up-regulated gene. Using immunohistochemistry, both mouse and human gastric glands overexpressed Cldn7 in dysplastic but not surrounding normal glands. Cldn7 expression was observed in 30% of metaplasia, 80% of dysplasia, and 70% of gastric adenocarcinomas. Interestingly, 82% of human intestinal-type gastric adenocarcinomas expressed Cldn7 whereas diffuse-type gastric adenocarcinomas did not (P < 0.001). These results suggest that Cldn7 expression is an early event in gastric tumorigenesis that is maintained throughout tumor progression. Gastric carcinoma is the second leading cause of cancer mortality worldwide accounting for ϳ10% of newly diagnosed cancers.

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Involvement of Claudin-1 in the β-Catenin/Tcf Signaling Pathway and its Frequent Upregulation in Human Colorectal Cancers

Cited by 256 publications

References 0 publications

Multiple dysregulated pathways in nasopharyngeal carcinoma revealed by gene expression profiling

Multiple dysregulated pathways in nasopharyngeal carcinoma revealed by gene expression profiling

Claudin-4 differentiates biliary tract cancers from hepatocellular carcinomas

Expression of Tight-Junction Protein Claudin-7 Is an Early Event in Gastric Tumorigenesis

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