Metastatic suppressor genes inactivated by aberrant methylation in gastric cancer

Wang, Jianfeng; Dai, Dong‐Qiu

doi:10.3748/wjg.v13.i43.5692

Cited by 22 publications

(12 citation statements)

References 22 publications

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“…Promoter hypermethylation was detected in NPC cell lines and demethylation restored PTPRG gene expression. PTPRG promoter hypermethylation was reported for T-cell lymphomas (18), gastric cancer (25), and melanoma cell lines (26), suggesting promoter hypermethylation is an important mechanism to silence PTPRG expression. The homozygous pattern of the chromosome 3p microsatellite markers in NPC cell lines suggests that besides promoter hypermethylation, allelic loss is another important mechanism for PTPRG inactivation.…”

Section: Resultsmentioning

confidence: 98%

Functional Analysis of a Cell Cycle–Associated, Tumor-Suppressive Gene, Protein Tyrosine Phosphatase Receptor Type G, in Nasopharyngeal Carcinoma

et al. 2008

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Functional studies to identify the potential role of a chromosome 3p14-21 gene, protein tyrosine phosphatase receptor type G (PTPRG), were performed. PTPRG was identified as a candidate tumor suppressor gene (TSG) in nasopharyngeal carcinoma (NPC) by differential gene profiling of tumorigenic and nontumorigenic NPC chromosome 3 microcell hybrids (MCH). Down-regulation of this gene was found in tumor segregants when compared with their corresponding tumor-suppressive MCHs, as well as in NPC cell lines and tumor biopsies. Promoter hypermethylation and loss of heterozygosity were found to be important mechanisms contributing to PTPRG silencing. PTPRG overexpression in NPC cell lines induces growth suppression and reduced anchorage-independent growth in vitro. This is the first study to use a tetracycline-responsive vector expression system to study PTPRG stable transfectants. Results indicate its ability to induce significant tumor growth suppression in nude mice under conditions activating transgene expression. These studies now provide functional evidence indicating critical interactions of PTPRG in the extracellular matrix milieu induce cell arrest and changes in cell cycle status. This is associated with inhibition of pRB phosphorylation through down-regulation of cyclin D1. These novel findings enhance our current understanding of how PTPRG may contribute to tumorigenesis.

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Section: Resultsmentioning

confidence: 98%

Functional Analysis of a Cell Cycle–Associated, Tumor-Suppressive Gene, Protein Tyrosine Phosphatase Receptor Type G, in Nasopharyngeal Carcinoma

et al. 2008

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“…These abnormalities can also define biological characteristics of gastric cancer, which can play a role in therapy (3,4). Although genetic abnormalities which include gene mutation and deletion are remarkable in causing oncogene activation and tumor suppressor gene inactivation, epigenetic silence of tumor suppressor genes through aberrant promoter hypermethylation have also been confirmed to be frequent in gastric carcinoma (5,6). Gene silencing by promoter hypermethylation has been affirmed in several genes in gastric cancer, including CDH1, which is involved in cell adhesion, and hMLH1, which is associated with DNA mismatch repair and the cell cycle regulator p16.…”

Section: Introductionmentioning

confidence: 99%

Frequent silencing of protocadherin 8 by promoter methylation, a candidate tumor suppressor for human gastric cancer

et al. 2012

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The cadherins are a family of cell surface glycoproteins responsible for cell adhesion which play an important role in cell morphology, contact inhibition and signal transduction during tumorigenesis. Protocadherin 8 (PCDH8), a member of the cadherin family, has been reported to act as a tumor suppressor involved in oncogenesis in breast cancer. In this study, we aimed to investigate the epigenetic inactivation of PCDH8 and its tumor suppressor function in gastric cancer. The expression of PCDH8 was markedly reduced or silenced in gastric cancer cell lines compared with normal gastric cells or tissues. Methylation of the PCDH8 gene promoter was observed in 100% (4/4) of cell lines and 55.38% (36/65) of the primary gastric cancer by methylation-specific PCR, but not in normal gastric mucosa (0/10). Methylated PCDH8 was significantly associated with lymph node metastasis in a logistic regression analysis. The demethylation reagent 5-aza-2'-deoxycytidine was able to restore or upregulate PCDH8 expression in gastric cancer cell lines. Ectopic expression of PCDH8 in silenced gastric cancer cells significantly inhibited cell migration and induced apoptosis. For the first time, our study demonstrates the epigenetic inactivation of PCDH8 by promoter methylation and its tumor suppressor function in human gastric cancer. Thus, PCDH8 could be identified as a candidate tumor suppressor in human gastric cancer.

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“…[39][40][41] Transcriptional downregulation was shown to be associated with PTPRG promoter methylation in the cutaneous T-cell lymphomas study. 39 This study used a similar microarray for identification of differential methylation as the present study.…”

Section: Discussionmentioning

confidence: 90%

Tumour-specific methylation of PTPRG intron 1 locus in sporadic and Lynch syndrome colorectal cancer

et al. 2010

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DNA methylation is a hallmark in a subset of right-sided colorectal cancers. Methylation-based screening may improve prevention and survival rate for this type of cancer, which is often clinically asymptomatic in the early stages. We aimed to discover prognostic or diagnostic biomarkers for colon cancer by comparing DNA methylation profiles of right-sided colon tumours and paired normal colon mucosa using an 8.5 k CpG island microarray. We identified a diagnostic CpG-rich region, located in the first intron of the protein-tyrosine phosphatase gamma gene (PTPRG) gene, with altered methylation already in the adenoma stage, that is, before the carcinoma transition. Validation of this region in an additional cohort of 103 sporadic colorectal tumours and 58 paired normal mucosa tissue samples showed 94% sensitivity and 96% specificity. Interestingly, comparable results were obtained when screening a cohort of Lynch syndrome-associated cancers. Functional studies showed that PTPRG intron 1 methylation did not directly affect PTPRG expression, however, the methylated region overlapped with a binding site of the insulator protein CTCF. Chromatin immunoprecipitation (ChIP) showed that methylation of the locus was associated with absence of CTCF binding. Methylation-associated changes in CTCF binding to PTPRG intron 1 could have implications on tumour gene expression by enhancer blocking, chromosome loop formation or abrogation of its insulator function. The high sensitivity and specificity for the PTPRG intron 1 methylation in both sporadic and hereditary colon cancers support biomarker potential for early detection of colon cancer.

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Metastatic suppressor genes inactivated by aberrant methylation in gastric cancer

Cited by 22 publications

References 22 publications

Functional Analysis of a Cell Cycle–Associated, Tumor-Suppressive Gene, Protein Tyrosine Phosphatase Receptor Type G, in Nasopharyngeal Carcinoma

Functional Analysis of a Cell Cycle–Associated, Tumor-Suppressive Gene, Protein Tyrosine Phosphatase Receptor Type G, in Nasopharyngeal Carcinoma

Frequent silencing of protocadherin 8 by promoter methylation, a candidate tumor suppressor for human gastric cancer

Tumour-specific methylation of PTPRG intron 1 locus in sporadic and Lynch syndrome colorectal cancer

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