β‐Catenin (<i>CTNNB1</i>) gene amplification: A new mechanism of protein overexpression in cancer

Suriano, Gianpaolo; Vrcelj, Nikoleta; Senz, Janine; Ferreira, Paulo Michel Pinheiro; Masoudi, Hamid; Cox, Kelly A; Nabais, Sérgio; Lopes, Carlos; Machado, José Carlos; Seruca, Raquel; Carneiro, Fátima; Huntsman, David G.

doi:10.1002/gcc.20135

Cited by 29 publications

(24 citation statements)

References 41 publications

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“…A recent in situ hybridization analysis revealed CTNNB1 gene amplification in KatoIII (Suriano et al, 2005), and we found boosted TCF/LEF transcriptional activity in the same cells. Thus, CTNNB1 amplification appears to be one mechanism by which b-catenin can be overexpressed, but the frequency of this change in primary GCs is quite low (1 of 49 patients) (Suriano et al, 2005).…”

Section: Discussionsupporting

confidence: 75%

“…A GGA-GAA transition at codon 34 (G34E) in CTNNB1 was found in AGS cells (Caca et al, 1999), and an ACC-GCC change at codon 41 (T41A) in CTNNB1 was detected in SNU638 cells (Ku and Park, 2005). In addition, CTNNB1 gene amplification was recently demonstrated in KatoIII cells (Suriano et al, 2005). The two cell lines with APC mutations and KatoIII cells all showed typical features of constitutive activation of Wnt signaling, that is, dephosphorylation and nuclear accumulation of b-catenin and upregulation of TCF/ LEF-regulated transcription (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

“…Thus, CTNNB1 amplification appears to be one mechanism by which b-catenin can be overexpressed, but the frequency of this change in primary GCs is quite low (1 of 49 patients) (Suriano et al, 2005). AXIN1 mutations are seen more frequently than CTNNB1 mutation in hepatocellular carcinomas in which there is nuclear accumulation of b-catenin , but AXIN1 mutations have not yet been reported in GC, and no mutations were observed in gastro-esophageal junction adenocarcinomas (Koppert et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

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Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer

et al. 2007

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Activation of Wnt signaling has been implicated in gastric tumorigenesis, although mutations in APC (adenomatous polyposis coli), CTNNB1 (b-catenin) and AXIN are seen much less frequently in gastric cancer (GC) than in colorectal cancer. In the present study, we investigated the relationship between activation of Wnt signaling and changes in the expression of secreted frizzled-related protein (SFRP) family genes in GC. We frequently observed nuclear b-catenin accumulation (13/15; 87%) and detected the active form of b-catenin in most (12/16; 75%) GC cell lines. CpG methylation-dependent silencing of SFRP1, SFRP2 and SFRP5 was frequently seen among GC cell lines (SFRP1, 16/16, 100%; SFRP2, 16/ 16, 100%; SFRP5, 13/16, 81%) and primary GC specimens (SFRP1, 42/46, 91%; SFRP2, 44/46, 96%; SFRP5, 30/46, 65%), and treatment with the DNA methyltransferase inhibitor 5-aza-2 0 -deoxycytidine rapidly restored SFRP expression. Ectopic expression of SFRPs downregulated T-cell factor/lymphocyte enhancer factor transcriptional activity, suppressed cell growth and induced apoptosis in GC cells. Analysis of global expression revealed that overexpression of SFRP2 repressed Wnt target genes and induced changes in the expression of numerous genes related to proliferation, growth and apoptosis in GC cells. It thus appears that aberrant SFRP methylation is one of the major mechanisms by which Wnt signaling is activated in GC.

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Section: Discussionsupporting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer

et al. 2007

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“…Thus, PLA2G2A expression in GC cells seems to be highly correlated with constitutive activation of the Wnt signaling pathway. Furthermore, supporting this model, AGS cells possess a gain of function phosphorylation site mutation in the CTNNB1 (h-catenin) gene (13), and Kato III cells have both a genomic amplification of the CTNNB1 gene and a promoter methylation of APC, a negative regulator of Wnt signaling (14). Similarly, we found that YCC3 cells exhibited CTNNB1 gene amplification and high CTNNB1 mRNA expression levels ( Supplementary Fig.…”

Section: Resultssupporting

confidence: 57%

Inhibition of Gastric Cancer Invasion and Metastasis by PLA2G2A, a Novel β-Catenin/TCF Target Gene

Ganesan¹,

Ivanova²,

Wu³

et al. 2008

Cancer Research

106

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Elevated expression of the PLA2G2A phospholipase in gastric cancer (GC) is associated with improved patient survival. To elucidate function and regulation of PLA2G2A in GC, we analyzed a panel of GC cell lines. PLA2G2A was specifically expressed in lines with constitutive Wnt activity, implicating B-catenin-dependent Wnt signaling as a major upstream regulator of PLA2G2A expression. The invasive ability of PLA2G2A-expressing AGS cells was enhanced by PLA2G2A silencing, whereas cellular migration in non-PLA2G2A -expressing N87 cells was inhibited by enforced PLA2G2A expression, indicating that PLA2G2A is both necessary and sufficient to function as an inhibitor of GC invasion in vitro. We provide evidence that antiinvasive effect of PLA2G2A occurs, at least in part, through its ability to inhibit the S100A4 metastasis mediator gene. Consistent with its invasion inhibitor role, PLA2G2A expression was elevated in primary gastric, colon, and prostrate early-stage tumors, but was decreased in metastatic and late-stage tumors. There was a strong association between PLA2G2A promoter methylation status and PLA2G2A expression, suggesting that the loss of PLA2G2A expression in late-stage cancers may be due to epigenetic silencing. Supporting this, among the non-PLA2G2A-expressing lines, pharmacologic inhibition of epigenetic silencing reactivated PLA2G2A in Wnt-active lines, but in non-Wnt-active lines, a combination of Wnt hyperactivation and inhibition of epigenetic silencing were both required for PLA2G2A reactivation. Our results highlight the complexity of PLA2G2A regulation and provide functional evidence for PLA2G2A as an important regulator of invasion and metastasis in GC.

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“…About 85% of GCs can be categorized as the IT or DT histologic type based on the Lauren classification, and the remaining GCs usually are comprised of a mixture of IT and DT and are thus classified as MT. Little is known regarding the molecular alterations in MT carcinomas, except for mutation of the E-cadherin gene (CDH1) [27] and the β-catenin gene (CTNNB) [28]. The morphological differences between IT and DT carcinomas can be attributed, at least in part, to differences in CDH1 expression.…”

Section: Discussionmentioning

confidence: 98%

Mixed-type gastric cancer and its association with high-frequency CpG island hypermethylation

et al. 2010

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Gastric carcinoma (GC) is one of the human cancers in which promoter CpG island hypermethylation is frequently found. We used the MethyLight assay to evaluate the methylation status of 16 CpG island loci that are hypermethylated in GC. We analyzed the relationship between CpG island hypermethylation of these 16 genes and the clinicopathological features in 191 advanced GCs. A significant difference was observed between the number of methylated genes in Epstein-Barr virus (EBV)-negative and microsatellite instability (MSI)-negative GCs of different histological types (Lauren classification; P < 0.01). We found that mixed-type (MT) carcinomas, which have both diffuse-type (DT) and intestinal-type (IT) components, had more methylated genes (10.6) than either DT carcinomas (7.6 methylated genes) or IT carcinomas (6.7 methylated genes) (P < 0.001). This trend was also observed when EBV-positive or MSI-positive GCs were excluded from the analysis (9.2, 6.9, and 4.8; P < 0.001). When the IT and DT components were dissected from MT carcinomas and the methylation of these 16 genes was evaluated, both components had a number of methylated genes similar to MT carcinomas, (10.2 and 9.7, respectively), which was significantly higher than was found in IT and DT carcinomas (P < 0.05). These findings indicate that MT carcinoma is distinct from IT and DT carcinomas in its enhanced CpG island hypermethylation status and implicate the enhanced promoter CpG island hypermethylation in the histogenesis of MT carcinoma.

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β‐Catenin (CTNNB1) gene amplification: A new mechanism of protein overexpression in cancer

Cited by 29 publications

References 41 publications

Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer

Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer

Inhibition of Gastric Cancer Invasion and Metastasis by PLA2G2A, a Novel β-Catenin/TCF Target Gene

Mixed-type gastric cancer and its association with high-frequency CpG island hypermethylation

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