Frequent loss of the AXIN1 locus but absence of AXIN1 gene mutations in adenocarcinomas of the gastro-oesophageal junction with nuclear β-catenin expression

Koppert, Linetta B.; Velden, Alike W van der; Wetering, M van de; Abbou, Mustaffa; Ouweland, Ans M.W. van den; Tilanus, Hugo W.; Wijnhoven, Bas P. L.; Dinjens, Winand N.M.

doi:10.1038/sj.bjc.6601589

Cited by 27 publications

(17 citation statements)

References 53 publications

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“…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%

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: Discussionmentioning

confidence: 99%

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

et al. 2007

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“…Mutational analysis of some of the Wnt components including Axin, APC and b-catenin so far have identified very few genetic abnormalities in esophageal cancer, indicating that mechanisms other than mutations are responsible for activation of this pathway in esophageal cancer. [29][30][31] Figure 5 E-cadherin nuclear translocation was also found in primary colorectal cancer and metastasis. E-cadherin nuclear translocation was detected in primary colorectal cancers and in some areas of the corresponding liver metastasis of a colorectal tumor with nuclear E-cadherin (a).…”

Section: Discussionmentioning

confidence: 99%

Frequent accumulation of nuclear E-cadherin and alterations in the Wnt signaling pathway in esophageal squamous cell carcinomas

et al. 2008

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Esophageal squamous cell carcinoma is frequently associated with poor prognosis, as a result of high levels of lymph node metastasis. So far, very few genetic abnormalities have been associated with this disease, and its molecular etiology remains largely unknown. To assess whether the Wnt pathway contributes to esophageal squamous cell carcinoma, we characterized the expression and subcellular localization of the key Wnt signaling components in all 30 cases of esophageal squamous cell carcinomas analyzed. We found abnormal expression and/or localization in glycogen synthase kinase-3 a/b (34%), Axin2 (48%), a-catenin (31%), MYC (73%) and cyclin D1 in 46% of cases. Only 13% of tumors showed nuclear accumulation of b-catenin. By contrast, 60% showed nuclear expression of E-cadherin using an antibody that recognizes the cytoplasmic domain of E-cadherin. When the same tumors were stained with antibody raised against the extracellular domain of E-cadherin, the expression was lost. A direct correlation was found between nuclear E-cadherin and the increased nuclear cyclin D1, one of the AP-1 target genes in these tumors. By transfection experiments, the cytoplasmic portion of E-cadherin was found to activate the AP-1 transcription factor pathway and induced cyclin D1 promoter activity, but b-catenin/Tcf transcription activity was unaffected. Nuclear expression of E-cadherin was also detected in tumors other than squamous cell carcinoma, including pancreatic and colon cancers, albeit at lower frequency. Nuclear accumulation of a portion of E-cadherin in esophageal squamous cell carcinoma and the other types of tumors indicates that, in addition to the previously implicated tumor suppressor activity of E-cadherin, modified forms of this glycoprotein might also play a role in growth promotion. Keywords: Wnt signaling; esophageal squamous cell carcinomas; pancreatic cancer; colon cancer; E-cadherin Esophageal cancer is one of the deadliest but least studied forms of cancer and the sixth ranking cause of death from cancer in North America. It shows a varied geographical distribution and very poor survival rates. 1 Esophageal cancer accounts for 5% of all gastrointestinal cancers, and the overall number of new cases each year is steadily increasing. 2 Esophageal cancer can be divided into squamous cell carcinomas and adenocarcinomas. So far, very few genetic abnormalities have directly been linked to esophageal carcinogenesis. In this study, we sought to examine the expression and localization of the key components of the Wnt signaling pathway that have previously been shown to play important roles in colorectal, breast, stomach and prostate cancer. Wnt signaling regulates cell growth, motility and differentiation. Upon binding to their receptor, specific Wnt ligands trigger phosphorylation of LRP5/6 (low density lipoprotein) by glycogen synthase kinase-3 (GSK3a/b) and casein kinase-1 (CK1g), which distances Axin (Axin1 and Axin2) from the b-catenin destruction-complex. [3][4][5][6] As a result, the b-catenin is stabilized a...

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“…detected (Gonzalez et al, 1997;Bian et al, 2000;Koppert et al, 2004). The mechanism of Wnt pathway activation in EAC in BE remains unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in CTNNB1 and Axin have not, and in APC rarely been detected in Barrett's-associated EAC (Gonzalez et al, 1997;Bian et al, 2000;Koppert et al, 2004), and therefore the mechanism of Wnt pathway activation remains unclear in this cancer. In this study, we investigated whether activation of Wnt and Frizzled proteins and/or silencing of APC, and/or downregulation of Wnt antagonists through promoter methylation, are responsible for the activation of the Wnt pathway in the development of EAC in BE.…”

Section: Introductionmentioning

confidence: 99%

Alterations of the Wnt signaling pathway during the neoplastic progression of Barrett's esophagus

et al. 2006

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Aberrant activation of the Wnt signaling pathway has been reported during neoplastic progression in Barrett's esophagus (BE). However, mutations in APC and CTNNB1 genes were rarely observed. In this study, expression pattern of Wnt ligands, Frizzled receptors and APC, as well as the methylation status of the APC, SFRP1 and SFRP2 promoter genes were investigated in normal esophageal mucosa and in preneoplastic and neoplastic lesions of BE patients. Promoter methylation of APC was found in all BE samples and in 95% of esophageal adenocarcinomas (EAC). Full methylation of APC correlated with lack of expression. In EAC, nuclear translocation of b-catenin was observed regardless of the expression of APC. WNT2 expression was higher in dysplasia and EAC than in BE, with 20/26 (77%) of the EAC showing high expression of WNT2. SFRP1 methylation occurred in all BE samples and in 96% of EAC, while SFRP2 was methylated in 73% of the normal squamous esophageal mucosa samples. In conclusion, (1) alterations of key regulators of the Wnt signaling are frequent in the pathogenesis of BE; (2) the APC and SFRP1 genes are inactivated by promoter methylation in BE; (3) the WNT2 gene is upregulated along the progression from low-grade dysplasia to EAC.

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Frequent loss of the AXIN1 locus but absence of AXIN1 gene mutations in adenocarcinomas of the gastro-oesophageal junction with nuclear β-catenin expression

Cited by 27 publications

References 53 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

Frequent accumulation of nuclear E-cadherin and alterations in the Wnt signaling pathway in esophageal squamous cell carcinomas

Alterations of the Wnt signaling pathway during the neoplastic progression of Barrett's esophagus

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