Common Activation of Canonical Wnt Signaling in Pancreatic Adenocarcinoma

Magliano, Marina Pasca di; Biankin, Andrew V.; Heiser, Patrick W.; Cano, David A.; Gutiérrez, Pedro J. A.; Deramaudt, Thérèse B.; Segara, Davendra; Dawson, Amanda; Kench, James G.; Henshall, Susan M.; Sutherland, Robert L.; Dlugosz, Andrzej A.; Rustgi, Anil K.; Hebrok, Matthias

doi:10.1371/journal.pone.0001155

Cited by 206 publications

(184 citation statements)

References 47 publications

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“…The potent soluble activators of FZD3/6/7 are very likely those ligands to be found overexpressed in HCCs (WNT3/4/5A). These data correlate with FZD3/6 and WNT3 found overexpressed in other malignancies as leukaemia, FZD7 in solid tumours like nasopharynx, oesophagus, and stomach carcinomas, WNT5A in leukaemia, melanoma, and nasopharynx carcinoma (Tanaka et al, 1998;Kirikoshi et al, 2001;Holcombe et al, 2002;Weeraratna et al, 2002;Qiang et al, 2003;Lu et al, 2004;Zeng ZY et al, 2007), whereas WNT4 has been previously found overexpressed in pancreatic cancers (Pasca di Magliano et al, 2007). Concerning the soluble activators of FZD, previous studies have shown the common downregulation of sFRP1 due to promoter hypermethylation in HCC as well as in colon cancer (Suzuki et al, 2004;Shih et al, 2006Shih et al, , 2007.…”

Section: Discussionsupporting

confidence: 82%

Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellular carcinoma

et al. 2008

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Dysregulation of growth factors and their receptors is central to human hepatocellular carcinoma (HCC). We previously demonstrated that the Frizzled-7 membrane receptor mediating the Wnt signalling can activate the b-catenin pathway and promotes malignancy in human hepatitis B virus-related HCCs. Expression patterns of all the 10 Frizzled receptors, and their extracellular soluble autoparacrine regulators (19 Wnt activators and 4 sFRP inhibitors) were assessed by real-time RT -PCR in 62 human HCC of different etiologies and their matched peritumorous areas. Immunostaining was performed to localise Frizzled on cell types in liver tissues. Regulation of three known Frizzled-dependent pathways (b-catenin, protein kinase C, and C-Jun NH 2 -terminal kinase) was measured in tissues by western blot. We found that eight Frizzled-potentially activating events were pleiotropically dysregulated in 95% HCC and 68% peritumours as compared to normal livers (upregulations of Frizzled-3/6/7 and Wnt3/4/5a, or downregulation of sFRP1/5), accumulating gradually with severity of fibrosis in peritumours and loss of differentiation status in tumours. The hepatocytes supported the Wnt/Frizzled signalling since specifically overexpressing Frizzled receptors in liver tissues. Dysregulation of the eight Frizzled-potentially activating events was associated with differential activation of the three known Frizzled-dependent pathways. This study provides an extensive analysis of the Wnt/Frizzled receptor elements and reveals that the dysregulation may be one of the most common and earliest events described thus far during hepatocarcinogenesis.

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Section: Discussionsupporting

confidence: 82%

Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellular carcinoma

et al. 2008

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“…Activation of the Wnt target gene will contribute to the development of cancer in terms of proliferation, invasion and metastasis, and angiogenesis (Taketo, 2006;Neth et al, 2007). Additionally, inhibition of Wnt signalling could reduce cell proliferation and increase apoptosis in pancreatic adenocarcinoma cells (Miao et al, 2003;Pasca di Magliano et al, 2007;Nawroth et al, 2007). Here, the b-catenin/Tcf assay showed that the TOPflash luciferase activity was obviously decreased whereas FOPflash luciferase activity has no change.…”

Section: Discussionmentioning

confidence: 91%

Blockade of SDF-1/CXCR4 signalling inhibits pancreatic cancer progression in vitro via inactivation of canonical Wnt pathway

et al. 2008

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Extra-pancreatic metastasis is a difficult problem for surgical intervention in pancreatic cancer. CXC chemokine receptor 4 (CXCR4) was considered to have an important role in this process. We hypothesized it may contribute to the pancreatic cancer progression through influencing canonical Wnt pathway. The purpose of this study was to examine the functional role of CXCR4 in the progression of pancreatic cancers and explore the possible mechanism. To this end, the relation between CXCR4 and clinical characteristics was analysed. shRNA against CXCR4 was applied to disrupt the SDF-1/CXCR4 signal transduction pathways in pancreatic cancer cell lines. Our results showed that overall survival in the case of patients positive for CXCR4 expression was significantly lower than that in the case of patients negative for CXCR4 expression. Notably, in vitro studies we observed that the abrogation of CXCR4 could obviously influence the pancreatic cancer cell phenotype including cell proliferation, colony formation, cell invasion and also inhibit the TOPflash activity. In addition, Wnt target genes and mesenchymal markers such as Vimentin and Slug were also inhibited in CXCR4 knockdown cells. Collectively, these data reported here demonstrate CXCR4 could modulate the canonical Wnt pathway and perhaps be a promising therapeutic target for pancreatic cancer progression.

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“…The effect of the Wnt down-regulation was a reduction of cell proliferation [Pasca di Magliano et al, 2007] and an induction of terminal cell differentiation [Boyden et al, 2002;van der Horst et al, 2005]. Many Wnt effects are mediated through β-catenin, which accumulates in the cytoplasm and translocates to the nucleus if the Wnt pathway is activated.…”

Section: Discussionmentioning

confidence: 99%

In vitro study of the effects of ELF electric fields on gene expression in human epidermal cells

Collard

Mertens

Hinsenkamp

2010

Bioelectromagnetics

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An acceleration of differentiation, at the expense of proliferation, is observed after exposure of various biological models to low frequency and low amplitude electric and electromagnetic fields. Following these results showing significant modifications, we try to identify the biological mechanism involved at the cell level through microarray screening. For this study, we use epidermis cultures harvested from human abdominoplasty. Two platinum electrodes are used to apply the electric signal. The gene expressions of 38,500 well-characterized human genes are analyzed using Affymetrix® microarray U133 Plus 2.0 chips. The protocol is repeated on three different patients. After three periods of exposure, a total of 24 chips have been processed. After the application of ELF electric fields, the microarray analysis confirms a modification of the gene expression of epidermis cells. Particularly, four up-regulated genes (DKK1, TXNRD1, ATF3, and MME) and one down-regulated gene (MACF1) are involved in the regulation of proliferation and differentiation. Expression of these five genes was also confirmed by real-time rtPCR in all samples used for microarray analysis. These results corroborate an acceleration of cell differentiation at the expense of cell proliferation.

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Common Activation of Canonical Wnt Signaling in Pancreatic Adenocarcinoma

Cited by 206 publications

References 47 publications

Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellular carcinoma

Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellular carcinoma

Blockade of SDF-1/CXCR4 signalling inhibits pancreatic cancer progression in vitro via inactivation of canonical Wnt pathway

In vitro study of the effects of ELF electric fields on gene expression in human epidermal cells

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