Oncogenic role of the frizzled-7/β-catenin pathway in hepatocellular carcinoma

Merle, Philippe; Kim, Miran; Herrmann, Marc; Gupte, Anand; Lefrançois, Lydie; Califano, Sophia; ́po, Christian Tre; Tanaka, Shinji; Vitvitski, L.; Monte, Suzanne de la; Wands, Jack R.

doi:10.1016/j.jhep.2005.05.018

Cited by 149 publications

(140 citation statements)

References 32 publications

(54 reference statements)

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“…Previous studies demonstrated that up-regulation of FZD7 was associated with activation of Wnt/β-catenin cascade in HCC [16,17]. The present study suggests that Wnt3 also has a positive effect on canonical Wnt signaling in HCC.…”

Section: Activation Of Wnt/β-catenin Signaling By Wnt3 Was Mediated Tsupporting

confidence: 68%

“…In addition, overexpression of FZD7 was observed not only in tumors but also in matched surrounding dysplastic liver tissues. These observations suggest that it may be an early event during the development of this disease [16,17]. However, there is no information on which Wnt ligand(s) are involved in binding to FZD7 and result in subsequent activation of the Wnt/β-catenin pathway during tumor development.…”

Section: Introductionmentioning

confidence: 99%

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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: Activation Of Wnt/β-catenin Signaling By Wnt3 Was Mediated Tsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

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

Self Cite

171

173

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“…Sustained activation of the canonical Wnt pathway due to mutational deregulation of Wnt cascade components, such as APC, axin or b-catenin, is associated with several cancers (Lustig and Behrens, 2003;Gregorieff et al, 2005). Moreover, abnormal activation of the Wnt signalling pathway could be independent of Wnt component mutations (Bafico et al, 2004;Merle et al, 2005). Recently Liu et al (2008) described activation of the pathway in the absence of activating mutations in NB cell lines and primary NBs.…”

Section: Discussionmentioning

confidence: 99%

“…In a majority of tumours, aberrant activation of the Wnt/b-catenin is the consequence of APC, Axin or b-catenin gene mutations (Lustig and Behrens, 2003). Moreover, it has been shown that overactivation of the Wnt signalling pathway is due to the overexpression of different FZD receptors in a variety of cancers (Milovanovic et al, 2004;Merle et al, 2005;Ueno et al, 2008). In NB, b-catenin has been shown to be strongly expressed and aberrantly localized in the nucleus in highly aggressive NB cells without MYCN amplification, whereas no b-catenin-specific mutations were identified (Liu et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway

et al. 2009

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The development of chemoresistance represents a major obstacle in the successful treatment of cancers such as neuroblastoma (NB), a particularly aggressive childhood solid tumour. The mechanisms underlying the chemoresistant phenotype in NB were addressed by gene expression profiling of two doxorubicin (DoxR)-resistant vs sensitive parental cell lines. Not surprisingly, the MDR1 gene was included in the identified upregulated genes, although the highest overexpressed transcript in both cell lines was the frizzled-1 Wnt receptor (FZD1) gene, an essential component of the Wnt/b-catenin pathway. FZD1 upregulation in resistant variants was shown to mediate sustained activation of the Wnt/b-catenin pathway as revealed by nuclear b-catenin translocation and target genes transactivation. Interestingly, specific microadapted short hairpin RNA (shRNAmir)-mediated FZD1 silencing induced parallel strong decrease in the expression of MDR1, another b-catenin target gene, revealing a complex, Wnt/b-catenin-mediated implication of FZD1 in chemoresistance. The significant restoration of drug sensitivity in FZD1-silenced cells confirmed the FZD1-associated chemoresistance. RNA samples from 21 patient tumours (diagnosis and postchemotherapy), showed a highly significant FZD1 and/or MDR1 overexpression after treatment, underlining a role for FZD1-mediated Wnt/b-catenin pathway in clinical chemoresistance. Our data represent the first implication of the Wnt/b-catenin pathway in NB chemoresistance and identify potential new targets to treat aggressive and resistant NB.

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“…Therefore, the results suggest that multiple FZD/LRP-receptor complexes transducing canonical Wnt signalling could be formed and modulated by inhibitory molecules such as Dkk family members. In first trimester villous cytotrophoblasts canonical Wnt signalling, which is thought to be regulated by specific Wnt-FZD combinations [21], may involve putative ligand-receptor pairs of Wnt-1, Wnt-2, Wnt-2b, Wnt-7a, Wnt-7b, Wnt-9b, Wnt-10a, Wnt-10b with FZD1, FZD5, FZD7 or FZD10 [21][22][23][24][25]. It is likely that complexes of these proteins with LRP-6 control cytotrophoblast proliferation of early pregnancy in an autocrine manner since inhibition of the canonical Wnt pathway by Dkk-1 decreased basal cell growth in vitro [15].…”

Section: Discussionmentioning

confidence: 99%

Complex Expression Pattern of Wnt Ligands and Frizzled Receptors in Human Placenta and its Trophoblast Subtypes

et al. 2007

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Canonical Wingless (Wnt) signalling provoked by exogenous and endogenous Wnt ligands was recently shown to play a crucial role in the invasive differentiation of human trophoblasts. To gain insights into the expression pattern of the developmental regulators, we analysed all human Wnt ligands and their frizzled (FZD) receptors in the human placenta and different trophoblast model systems using semi-quantitative PCR. Fourteen out of 19 Wnt ligands and 8 out of 10 FZD receptors were detectable in placental tissues, however, expression patterns varied with gestational age and between different trophoblast subtypes suggesting cell-specific functions. Besides Wnt ligands acting through the canonical pathway, non-canonical ligands such as Wnt-5a, which may also activate alternative Wnt signalling pathways or inhibit canonical Wnt signalling, could be identified. Western blot analyses revealed secretion of Wnt-5a from primary trophoblast cultures and trophoblastic cell lines. To evaluate the potential role of Wnt-5a, SGHPL-5 trophoblast cells were transfected with luciferase reporter plasmids harbouring eight T-cell factor (TCF) DNArecognition sequences which are exclusively activated through the canonical Wnt signalling pathway. Luciferase assays revealed that Wnt-3a-induced reporter activity was repressed by recombinant Wnt-5a indicating an antagonistic role in trophoblasts. The data suggest that a complex network of Wnt ligands and FZD receptors may regulate developmental processes of the human placenta.

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Oncogenic role of the frizzled-7/β-catenin pathway in hepatocellular carcinoma

Cited by 149 publications

References 32 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

The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway

Complex Expression Pattern of Wnt Ligands and Frizzled Receptors in Human Placenta and its Trophoblast Subtypes

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