A novel frizzled gene identified in human esophageal carcinoma mediates APC/β-catenin signals

Tanaka, Shinji; Akiyoshi, Tsuyoshi; Mori, Masaki; Wands, Jack R.; Sugimachi, Keizō

doi:10.1073/pnas.95.17.10164

Cited by 112 publications

(99 citation statements)

References 27 publications

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“…Indeed, 65% of HBVrelated HCCs had higher levels of FZD7 expression in HCC compared to peritumoral tissues, which also had upregulation of FZD7 compared to normal liver. Enhanced FZD7 gene expression has also been reported in esophageal and gastric tumors [42,43]. These findings suggest that overexpression of FZD7 is closely related to activation of the canonical Wnt pathway in these cancers as well.…”

Section: Discussionmentioning

confidence: 61%

Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/β-catenin signaling pathway in hepatocellular carcinoma cells

Kim¹,

Lee²,

Tsedensodnom³

et al. 2008

Journal of Hepatology

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171

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Background/Aims-The canonical Wnt signaling is frequently activated in human hepatocellular carcinoma (HCC). We previously demonstrated that up-regulation of Frizzled-7 receptor (FZD7) in HCC was associated with nuclear accumulation of wild-type β-catenin. Here, we investigated Wnt ligand(s) that may activate the Wnt/β-catenin pathway through FZD7 in HCC cells. Results-In hepatitis B virus (HBV)-induced HCC, Wnt3 was upregulated in tumor and peritumoral tissues compared to normal liver and downstream β-catenin target genes were also increased in these samples. Activation of the Wnt/β-catenin pathway in FOCUS-Wnt3 cells was demonstrated by β-catenin accumulation, enhanced TCF transcriptional activity and proliferation rate. The activation of Wnt/β-catenin signaling in FOCUS-Wnt3 was abolished by a knockdown of FZD7 expression by siRNA. More important, a specific Wnt3-FZD7 interaction was observed by co-immunoprecipitation experiments, which suggest that the action of Wnt3 was mediated via FZD7. Methods-To identifyConclusions-These findings demonstrate a functional interaction between Wnt3 and FZD7 leading to activation of the Wnt/β-catenin signaling pathway in HCC cells and may play a role during hepatocarcinogenesis.

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Section: Discussionmentioning

confidence: 61%

Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/β-catenin signaling pathway in hepatocellular carcinoma cells

Kim¹,

Lee²,

Tsedensodnom³

et al. 2008

Journal of Hepatology

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171

173

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“…This can be a consequence of genetic alteration of ␤-catenin itself or of other molecules in the Wnt signaling pathway (5,(22)(23)(24). We evaluated the cellular localization of ␤-catenin from two different points of view; membranous and nuclear expression pattern, since these patterns reflect the dual function of ␤-catenin which involves both cadherin mediated cell-to-cell adhesion and Wnt signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

“…In colorectal cancer, deletion of APC as well as mutation of ␤-catenin seems important to activate ␤-catenin (23). It was reported that there is genetic alteration of molecules such as Wnt (28,29), Wnt receptor (22) and axin (24) which activate the ␤-catenin pathway in human cancers. In ICC, Kang et al reported the loss of heterozygosity of APC gene in ICCs (30), but deletion or mutation of APC was not discussed.…”

Section: Discussionmentioning

confidence: 99%

Altered Expression of β-Catenin without Genetic Mutation in Intrahepatic Cholangiocarcinoma

et al. 2001

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␤-catenin which has a role in E-cadherin mediated cell-to-cell adhesion, and is also involved in Wnt signaling pathways as a downstream signaling molecule accumulating in the cytoplasm and nucleus constitutively activates Tcf/LEF-associated transcription of oncogenic genes. We examined the expression pattern and the genetic alteration of ␤-catenin to determine the role of ␤-catenin in cancer formation and/or progression in intrahepatic cholangiocarcinoma (ICC). ␤-catenin expression was immunohistochemically examined in 71 surgically resected ICC samples, and correlation between the expression pattern and clinicopathologic factors was investigated. Mutation analysis of ␤-catenin exon 3, which included the responsible element for Wnt signaling was done in 55 samples, using PCR-SSCP and direct sequence methods. Immunohistochemical analysis revealed the reduced membranous expression of ␤-catenin in 58 (82%) ICCs and aberrant nuclear expression in 11 (15%) ICCs. The membranous expression was preserved in 62% of the papillary adenocarcinomas, and was frequently reduced in tumors with a poorer histological differentiation (84%), with a significant difference (P ‫؍‬ .01). Genetic analysis showed that none of the 55 ICCs examined carried mutations in ␤-catenin exon 3. The present study indicates that reduced membranous expression of ␤-catenin is associated with non-papillary ICCs which have a more malignant behavior, and that nuclear translocation of ␤-catenin results in oncogenic events. Mutations in ␤-catenin exon 3 do not appear to be responsible for nuclear translocation of ␤-catenin in ICCs.

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“…The effect of mutant TGF-β RII was assessed by transient transfection on a human oesophageal carcinoma cell line using Lipofectamine (Gibco-BRL, Life Technologies, Inc., Gaithersburg, MD, USA) (Tanaka et al, 1998). The expression plasmids of TGF-β RII and Smad4 were kindly provided from Dr Michael Reiss (Yale University) and Dr Joan Massague (Memorial SloanKettering Cancer Center) respectively.…”

Section: Methodsmentioning

confidence: 99%

“…The expression plasmids of TGF-β RII and Smad4 were kindly provided from Dr Michael Reiss (Yale University) and Dr Joan Massague (Memorial SloanKettering Cancer Center) respectively. The mutant TGF-β RII lacking the serine/threonine kinase domain (∆KD) was generated by introduction of a stop codon just before the kinase domain using the PCR method (Tanaka et al, 1998). Following 10 ng ml -1 of TGF-β1 stimulation, the transfected FLAG-tagged protein was detected by indirect immunofluorescent technique using anti-FLAG M2 mouse monoclonal antibody (Eastman Kodak Co., Rochester, NY, USA) and anti-immunoglobulin preparation conjugated with fluorescence (CAPPEL Research Products, Durham, NC, USA), as described previously (Tanaka et al, 1998).…”

Section: Methodsmentioning

confidence: 99%

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et al. 2000

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Recent investigations revealed microsatellite instability in colon cancers are associated with mutations of the transforming growth factor-β receptor type II gene (TGF-β RII) that encodes a transmembrane protein containing an intracellular serine/threonine kinase domain. Activation of TGF-β receptor type I (RI) and RII by TGF-β induces nuclear translocation of Smad proteins including Smad2 and Smad4 that have been originally identified as tumour suppressor genes. We have previously reported six cases with microsatellite instability in 32 oesophageal carcinomas. In this study, we analysed genetic mutations of TGF-β RII, Smad2 and Smad4 in these oesophageal carcinoma tissues and established 16 cell lines. No genetic mutation was detected in any tissues or cell lines except one tissue sample of microsatellite stable oesophageal carcinoma, that is, a mis-sense mutation of glutamic acid to glutamine at codon 526 (E526Q) in the TGF-β RII serine/threonine kinase domain. Interestingly, the mutant TGF-β RII E526Q can completely inhibit TGF-β-induction of nuclear translocation of Smad4 protein in oesophageal carcinoma cells. This mutation of TGF-β RII that is not associated with microsatellite instability might make a dominant negative effect on TGF-β signal transduction in oesophageal carcinoma. © 2000 Cancer Research Campaign

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A novel frizzled gene identified in human esophageal carcinoma mediates APC/β-catenin signals

Abstract: A novel member of the human frizzled (Fz) gene family was cloned and found to be specifically expressed in 3 of 13 well differentiated (23%), 13 of 20 moderately differentiated (62%), and 12 of 14 poorly differentiated (

Cited by 112 publications

References 27 publications

Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/β-catenin signaling pathway in hepatocellular carcinoma cells

Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/β-catenin signaling pathway in hepatocellular carcinoma cells

Altered Expression of β-Catenin without Genetic Mutation in Intrahepatic Cholangiocarcinoma

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