The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas

Chan, Stephen L.; Cui, Yan; Hasselt, Andrew van; Li, Hongyu; Srivastava, Gopesh; Jin, Hongchuan; Ng, Ka Man; Wang, Yajun; Lee, Kwan Y.; Tsao, George S.W.; Zhong, Sheng; Robertson, Keith D.; Rha, Sun Young; Chan, Anthony T.C.; Tao, Qian

doi:10.1038/labinvest.3700547

Cited by 92 publications

(84 citation statements)

References 36 publications

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“…To our best knowledge, no study about Wnt-antagonist genes promoter methylation and mRNA expression in GCA had been reported, however, there were some studies about the correlation of promoter hypermethylation of Wnt-antagonist genes with gastric cancer and esophageal carcinoma [17][18][19]. In their studies, the hypermethylation of Wnt-antagonist genes were founded, and may contribute to the pathogenesis of gastric and esophageal cancer, which was consistent with our results.…”

Section: Discussionsupporting

confidence: 81%

“…Thus, the functional loss of Wnt antagonists can contribute to activation of the Wnt pathway and induced ectopic expression of ß-catenin. Up to now, downregulation of Wnt-antagonist genes have been identified in a variety of malignancies, including bladder [8,11,12], lung [13,14], breast [15], and chronic lymphocytic leukemia [16], and even the gastric carcinoma [17,18]and esophageal carcinoma [19]. Inactivation caused by promoter hypermethylation seems to be one of the mechanisms underlying down-regulation of the Wnt antagonists, which strongly suggests Wnt-antagonist genes function as tumor suppressor genes may play important role in tumorigenesis.…”

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confidence: 99%

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Hypermethylation and aberrant expression of Wnt-antagonist family genes in gastric cardia adenocarcinoma

Guo

Guo²,

Chen³

et al. 2011

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The canonical Wnt signalling pathway plays a key role during embryogenesis and pathogenesis of various types of tumors. Recently, several studies have shown that the promoter hypermethylation of Wnt-antagonist genes, including sFRP-1, , have been certified to contribute to the tumorigenesis of several cancers.The aim of this study was to investigate the promoter methylation of Wnt-antagonist genes in gastric cardia adenocarcinoma (GCA) and corresponding adjacent non-cancerous tissues, and to establish the possible relationship between DNA methylation status and the pathogenesis of GCA.MSP, RT-PCR methods were applied respectively to examine the CpG methylation of the Wnt-antagonist genes and its mRNA expression in tumors and corresponding non-cancerous tissues, and immunohistochemistry method was used to determine protein expression of β-catenin(the key factor of the Wnt signalling pathway) and cyclin D1(the target gene of this pathway).The frequency of promoter methylation of sFRP-1, sFRP-2, sFRP-4, sFRP-5, Wif-1 and Dkk-3 genes in GCA tumor tissues were 78.7%(74/94), 76.6%(72/94), 70.2%(66/94), 77.1%(73/94), 61.7%(58/94) and 21.3%(20/94), respectively, which were significantly higher than those in adjacent non-cancerous tissues. Furthermore, the frequencies of silenced mRNA expression of these six genes in GCA tumor tissues were significantly higher than those in adjacent non-cancerous tissues. Methylation levels of these six genes were all correlated with loss of mRNA expression. The ectopic expression of β-catenin and cyclin D1 was significantly more frequent in GCA tumor tissues than that in adjacent non-cancerous tissues and correlated with each Wnt-antagonist genes hypermethylation status.Epigenetic silencing of Wnt-antagonist genes expression by promoter hypermethylation may play an important role in gastric cardia adenocarcinoma.

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Section: Discussionsupporting

confidence: 81%

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confidence: 99%

Hypermethylation and aberrant expression of Wnt-antagonist family genes in gastric cardia adenocarcinoma

Guo

Guo²,

Chen³

et al. 2011

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“…From the downregulated genes, only a single gene (WIF-1) was seen as down-regulated in data from all three anatomic sites. Silencing of WIF-1 expression due to promoter hypermethylation is known to be an important mechanism underlying the activation of the Wnt signaling pathway in several solid tumors, including nasopharyngeal (NPC) and esophageal squamous cell (ESCC) carcinomas [20,21].…”

Section: Discussionmentioning

confidence: 99%

Site-Specific Molecular Signatures Predict Aggressive Disease in HNSCC

Belbin

Smith

Adrien

et al. 2008

Head and Neck Pathol

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It is known that head and neck squamous cell carcinomas (HNSCC) originating from different anatomic locations can exhibit varying behavior that is not predictable by histopathology of the primary tumor. Using a microarray containing 27,323 cDNA clones, we generated sets of gene expression profiles for 36 HNSCC primary tumors (12 oral cavity, 12 oropharynx, and 12 larynx/ hypopharynx). From these datasets, we ranked genes according to their ability to differentiate between patients whose disease progressed within a 24 month period (aggressive phenotype) and those that did not (nonaggressive phenotype) based on levels of gene expression. A merging of datasets from the three sites revealed that only a fraction of identified genes were shared between any two sites. This contrasted greatly with the significant overlap (approximately 50%) in down-regulated genes identified in tumor/normal comparisons using cases both from oropharynx and larynx/hypopharynx. From these data, we conclude that HNSCC tumors originating from different anatomic sites share consistent changes in gene expression when comparing primary tumors to normal adjacent mucosa; these common changes most likely reflect alterations required for tumor development. In contrast, once a tumor has developed, tumor-host interactions at the different anatomic sites are likely responsible for the site-specific signatures associated with aggressive versus non-aggressive disease. Predictions of outcome based on gene expression profiling are therefore heavily influenced by the anatomic site of the primary tumor.

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“…for 3 days. Primary tumor and normal nasopharyngeal tissue samples have been described previously (25)(26)(27)(28)(29). Genomic DNA and total RNA were extracted with Tri Reagent (Molecular Research Center, Inc.).…”

Section: Methodsmentioning

confidence: 99%

The Tumor Suppressor UCHL1 Forms a Complex with p53/MDM2/ARF to Promote p53 Signaling and Is Frequently Silenced in Nasopharyngeal Carcinoma

Tao

Jin

et al. 2010

Clinical Cancer Research

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139

135

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Purpose: Nasopharyngeal carcinoma is prevalent in southern China and Southeast Asia, with distinct geographic and ethnic distribution. One candidate susceptibility locus has been identified at 4p11-14, with the associated candidate gene(s) not identified yet. This study investigated the role of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) in nasopharyngeal carcinoma pathogenesis.Experimental Design: UCHL1 expression and methylation were examined in nasopharyngeal carcinoma. Furthermore, the mechanism of its tumor-suppressive function was elucidated in nasopharyngeal carcinoma cells.Results: Through genomewide expression profiling, we identified UCHL1, a 4p14 gene normally expressed in normal upper respiratory tract tissues, being silenced in all nasopharyngeal carcinoma cell lines. Its silencing is mediated by CpG methylation because UCHL1 promoter methylation was detected in all silenced cell lines, and pharmacologic demethylation reactivated UCHL1 expression along with concomitant promoter demethylation. UCHL1 methylation was also frequently detected in primary tumors but only weakly detected in few normal nasopharyngeal tissues, indicating that the methylation-mediated silencing of UCHL1 is important in nasopharyngeal carcinoma pathogenesis. Ectopic UCHL1 expression dramatically inhibited the growth of nasopharyngeal carcinoma cells through promoting tumor cell apoptosis. We further found that UCHL1 formed a complex with p53/p14 ARF /Mdm2 p53 binding protein homolog (mouse), MDM2 and activated the p53 signaling pathway. UCHL1 expression extended p53 and p14ARF protein half-life and shortened MDM2 protein half-life. Conclusions:These results indicate that UCHL1 could deubiquitinate p53 and p14 ARF and ubiquitinate MDM2 for p53 stabilization to promote p53 signaling, thus involved in nasopharyngeal carcinoma pathogenesis, whereas it is frequently silenced in this tumor.

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The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas

Cited by 92 publications

References 36 publications

Hypermethylation and aberrant expression of Wnt-antagonist family genes in gastric cardia adenocarcinoma

Hypermethylation and aberrant expression of Wnt-antagonist family genes in gastric cardia adenocarcinoma

Site-Specific Molecular Signatures Predict Aggressive Disease in HNSCC

The Tumor Suppressor UCHL1 Forms a Complex with p53/MDM2/ARF to Promote p53 Signaling and Is Frequently Silenced in Nasopharyngeal Carcinoma

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