The E-cadherin repressor Snail is associated with lower overall survival of ovarian cancer patients

Blechschmidt, Kareen; Sassen, Stefanie; Schmalfeldt, Barbara; Schuster, Tibor; Höfler, Heinz; Becker, Karl‐Friedrich

doi:10.1038/sj.bjc.6604115

Cited by 114 publications

(109 citation statements)

References 42 publications

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“…Several studies have demonstrated that nuclear localization of Snail correlates with tumor progression, with enhanced Snail immunoreactivity in metastatic lesions (70,71). Furthermore, patients with both primary and metastatic tumors positive for Snail expression showed a significant decrease in overall survival (72). LRP6 functions as a Wnt coreceptor that recruits Axin and Dishevelled to the plasma membrane, thereby disrupting the degradation of ␤-catenin and facilitating ␤-catenin nuclear translocation.…”

Section: Discussionmentioning

confidence: 99%

Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

Burkhalter

Symowicz

Hudson

et al. 2011

Journal of Biological Chemistry

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Reversible modulation of integrin-regulated cell-matrix adhesion and epithelial (E)-cadherin-mediated cell-cell adhesion plays a critical role in the establishment of ovarian cancer metastases. In contrast to most epithelial cell-derived tumors that down-regulate E-cadherin expression during progression, acquisition of E-cadherin expression accompanies malignant transformation of the ovarian surface epithelium and is maintained in peritoneal metastases. Metastatic epithelial ovarian cancer cells are disseminated intraperitoneally and preferentially adhere via integrins to interstitial collagens in the peritoneal cavity. This study was undertaken to determine whether integrin engagement influences E-cadherin and ␤-catenin localization and function. The data demonstrate that multivalent integrin engagement results in increased internalization of E-cadherin, inhibition of GSK-3␤, elevated levels of nuclear ␤-catenin, increased ␤-catenin-regulated promoter activation, and transcriptional activation of Wnt/␤-catenin target genes. Blocking ␤-catenin transcriptional control with inhibitor of ␤-catenin and Tcf-4 reduces cellular invasion, suggesting a key role for ␤-catenin nuclear signaling in EOC invasion and metastasis. These studies support a model wherein cell-matrix engagement regulates the functional integrity of cell-cell contacts, leading to increased ␤-catenin nuclear signaling and enhanced cellular invasive activity. Furthermore, these results provide a mechanism for activation of Wnt/␤-catenin signaling in the absence of activating mutations in this pathway.Epithelial (E) 3 -cadherin is a single-span transmembrane glycoprotein that mediates calcium-dependent cell-cell adhesion via interaction with the extracellular domains of cadherins on the surface of neighboring cells (1, 2). Key functions of E-cadherin include the regulation of cell polarity and the maintenance of epithelial organization (3). Although most normal epithelia express high levels of E-cadherin, this cadherin is absent in the mesenchymally derived normal ovarian surface epithelium, which expresses neural (N)-cadherin. In most carcinomas, E-cadherin expression is down-regulated or lost, facilitating cellular dispersal, invasion, and metastasis (4). However, a unique feature of EOC is that E-cadherin becomes more abundant in primary differentiated carcinomas, with all histotypes displaying strong immunoreactivity (reviewed in Refs. 5, 6). There is less clarity regarding relative E-cadherin levels during ovarian tumor progression and metastasis. Although complete loss of E-cadherin is uncommon, reduced staining is often detected in late stage tumors and in ascites-derived tumor cells (7-9), and negative E-cadherin is predictive of poor overall survival (10, 11).␤-Catenin is found predominantly in association with the E-cadherin cytoplasmic domain at cell-cell junctions (12). In the absence of cell-cell contact and Wnt signaling, cytosolic ␤-catenin forms a complex with adenomatous poliosis coli, Axin/conductin, casein kinases 1␣ and 1⑀, and glyc...

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Section: Discussionmentioning

confidence: 99%

Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

Burkhalter

Symowicz

Hudson

et al. 2011

Journal of Biological Chemistry

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“…Snail was first identified as the most important transcriptional repressor of E-cadherin [43] . Snail can down-regulate expression of E-cadherin, inducing EMT and promoting cell migration and invasion [22,44] . Overexpression of Snail was detected in various tumor cell lines, including breast, pancreatic and gastric cancers [45][46][47] .…”

Section: Discussionmentioning

confidence: 99%

“…Modulation of TNF-α-induced invasiveness-associated genes expression by GA Considering that Snail regulates the expression of invasiveness-associated genes, such as E-cadherin, MMP-9, and fibronectin [21,22] , we determined whether GA could regulate the expression of invasiveness-associated genes in TNF-α-stimulated PC3 cells. It was demonstrated that TNF-α-treated PC3 cells exhibited up-regulated mRNA and protein expression levels of both MMP-9 and fibronectin.…”

Section: Wwwnaturecom/aps Lü L Et Almentioning

confidence: 99%

Gambogic acid inhibits TNF-α-induced invasion of human prostate cancer PC3 cells in vitro through PI3K/Akt and NF-κB signaling pathways

et al. 2012

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Aim: To investigate the mechanisms underlying the inhibitory effect of gambogic acid (GA) on TNF-α-induced metastasis of human prostate cancer PC3 cells in vitro. Methods: TNF-α-mediated migration and invasion of PC3 cells was examined using migration and invasion assays, respectively. NF-κB transcriptional activity and nuclear translocation were analyzed with luciferase reporter gene assays, immunofluorescence assays and Western blots. The ability of p65 to bind the promoter of Snail, an important mesenchymal molecular marker, was detected using a chromatin immunoprecipitation (ChIP) assay. After treatment with Snail-specific siRNA, the expression of invasiveness-associated genes was measured using quantitative real-time PCR and Western blot. Results: GA significantly inhibited the viability of PC3 cells at 1-5 μmol/L, but did not produce cytotoxic effect at the concentrations below 0.5 μmol/L. GA (0.125-0.5 μmol/L) dose-dependently inhibited the migration and invasion of PC3 cells induced by TNF-α (10 ng/mL). Moreover, the TNF-α-mediated activation of phosphatidylinositol-3-OH kinase/protein kinase B (PI3K/Akt) and NF-κB pathways was suppressed by GA (0.5 μmol/L). Furthermore, this anti-invasion effect of GA was associated with regulation of Snail. Snail expression was significantly down-regulated by treatment with GA (0.5 μmol/L) in the TNF-α-stimulated PC3 cells. Conclusion: GA inhibits TNF-α-induced invasion of PC3 cells via inactivation of the PI3K/Akt and NF-κB signaling pathways, which may offer a novel approach for the treatment of human prostate cancer.

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“…Snail immunoreactivity in metastases was found to correlate with higher grade and reduced E-cadherin expression. A subsequent study by Blechschmidt et al (2008) on 48 primary ovarian neoplasms and 50 metastases found Snail immunoreactivity in 37.5% and 52%, respectively. A borderline significant difference in overall survival with Snail expression in metastases was noted.…”

Section: Neoplasms Of the Genitourinary Tractmentioning

confidence: 99%