ADAM23, a possible tumor suppressor gene, is frequently silenced in gastric cancers by homozygous deletion or aberrant promoter hypermethylation

Takada, Hisashi; Imoto, Issei; Tsuda, Hitoshi; Nakanishi, Yukihiro; Ichikura, Takashi; Mochizuki, Hidetaka; Mitsufuji, Shoji; Hosoda, Fumie; Hirohashi, Setsuo; Ohki, Masafumi; Inazawa, Johji

doi:10.1038/sj.onc.1208952

Cited by 61 publications

(61 citation statements)

References 33 publications

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“…Quantitative measurement of DNA copy numbers across the genome has revealed various oncogenes (Tanami et al, 2005) or tumour suppressor genes (Takada et al, 2005(Takada et al, , 2006) that had not been detected by earlier techniques. In addition, the higher resolution of array-CGH has allowed precise mapping of the boundaries of the gained and lost regions, thereby helping to elucidate the clonal relationship between multifocal tumours (Shelley Hwang et al, 2004;Wa et al, 2005).…”

Section: Discussionmentioning

confidence: 98%

“…Array-CGH experiments were carried out as described previously (Takada et al, 2005) with minor modifications. Briefly, DpnII-restricted test DNA (tumour DNA) and reference DNA (peripheral blood genomic DNA) were labelled by random priming with Cy3-and Cy5-dCTP (Amersham Biosciences, Tokyo, Japan), precipitated with ethanol in the presence of Cot-1 DNA, redissolved in a hybridisation mixture (50% formamide, 10% dextran sulphate, 2 Â standard saline citrate (SSC), and 4% sodium dodecyl sulphate, pH 7), and denatured at 751C for 8 min.…”

Section: Array-cgh Analysismentioning

confidence: 99%

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Genetic analysis of multifocal superficial urothelial cancers by array-based comparative genomic hybridisation

et al. 2007

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The purpose of this study was to investigate the accumulation of genetic alterations during metachronous and/or synchronous development of multifocal low-grade superficial urothelial tumours in the same patient, by using array-based comparative genomic hybridisation (array-CGH) and FGFR mutation analysis. We analysed 24 tumours (pTa-1 G1-2) from five patients. We had previously identified a clonal relationship among the tumours of each patient by microsatellite analysis. This time, unsupervised hierarchical cluster analysis revealed that the tumours from each patient were clustered together independently of the tumours from the other patients. All of the tumours from a single patient showed a set of 2 -7 identical regional or whole-arm chromosomal changes. In addition, several individual alterations were also found. Cladistic diagrams revealed that the accumulation of genetic alterations could not be explained by a linear model, and the existence of a hypothetical precursor cell was assumed in four patients. In some cases, FGFR mutation seemed to occur later during multifocal tumour development. Taken together, these findings suggest that low-grade superficial urothelial tumours accumulate minor genetic alterations during multifocal development, although these tumours are genetically stable.

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Section: Discussionmentioning

confidence: 98%

Section: Array-cgh Analysismentioning

confidence: 99%

Genetic analysis of multifocal superficial urothelial cancers by array-based comparative genomic hybridisation

et al. 2007

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“…Array-based CGH (array-CGH) technique allows high-throughput and quantitative analyses of copy-number changes at high-resolution throughout the genome, providing many advantages, including the identification of homozygous loss, over conventional methods (Snijders et al, 2001;Inazawa et al, 2004), although the resolution fully depends on the type of array. Indeed, our previous array-CGH studies using inhouse bacterial artificial chromosome-(BAC-)/P1-derived artificial chromosome-(PAC-) based arrays (BAC/ PAC-arrays) have successfully mapped complete genetic losses, allowing the rapid identification of candidate TSGs inactivated mainly by genetic and/or epigenetic mechanisms (Sonoda et al, 2004;Izumi et al, 2005;Takada et al, 2005bTakada et al, , 2006Imoto et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

PRTFDC1, a possible tumor-suppressor gene, is frequently silenced in oral squamous-cell carcinomas by aberrant promoter hypermethylation

et al. 2007

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Array-based comparative genomic hybridization (array-CGH) has good potential for the high-throughput identification of genetic aberrations in cell genomes. In the course of a program to screen a panel of oral squamouscell carcinoma (OSCC), cell lines for genomic copynumber aberrations by array-CGH using our in-house arrays, we identified a 3-Mb homozygous deletion at 10p12 in 1 of 18 cell lines (5.6%). Among seven genes located within this region, expression of PRTFDC1 mRNA was not detected in 50% (9/18) or decreased in 5.6% (1/18) of OSCC cell lines, but detected in normal oral epithelia and restored in gene-silenced OSCC cells without its homozygous loss after treatment with 5-aza-2 0 -deoxycytidine. Among 17 cell lines without a homozygous deletion, the hypermethylation of the PRTFDC1 CpG island, which showed promoter activity, was observed in all nine cell lines with no or reduced PRTFDC1 expression (52.9%). Methylation of this CpG island was also observed in primary OSCC tissues (8/47, 17.0%). In addition, restoration of PRTFDC1 in OSCC cells lacking its expression inhibited cell growth in colony-formation assays, whereas knockdown of PRTFDC1 expression in OSCC cells expressing the gene promoted cell growth. These results suggest that epigenetic silencing of PRTFDC1 by hypermethylation of the CpG island leads to a loss of PRTFDC1 function, which might be involved in squamous cell oral carcinogenesis.

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“…14 In particular, ADAM23 has an inactive metalloprotease domain, which suggests that it is exclusively involved in cell adhesion. ADAM23 has been reported in breast, 12 brain 15 and gastric 16 cancers in association with CpG island promoter hypermethylation. For the promoter region of ADAM23, two CpG islands were identified within 2.0 kb region that includes 1.0 kb upstream from the initiation site, together with the first exon and intron.…”

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confidence: 99%

“…The 3 gastric cancer cell lines were used as controls, SNU-484, SNU-719 as positive controls and MKN1 as negative control. 16 All cell lines were maintained in RPMI1640 media with 10% fetal bovine serum at 37°C and 5% CO 2 .In total, 76 primary colorectal cancer tissues and available 47 corresponding normal tissues were obtained from patients during surgery at Seoul National University Hospital. The normal mucosal tissue specimens were collected from the same cancer patients 10 cm, or more, away from the tumor areas.…”

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confidence: 99%

Promoter hypermethylation of the ADAM23 gene in colorectal cancer cell lines and cancer tissues

Choi

Kim

Jeon

et al. 2008

Intl Journal of Cancer

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Promoter hypermethylation of the ADAM23 gene, which is normally involved in cell-to-cell and cell-to matrix adhesion, has been reported in pancreatic, breast and brain cancer, and recently the role of this gene was examined in gastric cancer. In this study, we analyzed ADAM23 expression in colorectal cancer cell lines and examined its methylation by methylation-specific PCR (MSP) and bisulfate-modified DNA sequencing analysis. Methylated cells were treated with 5-aza-2 0 -deoxycytidine to restore the ADAM23 expression. We then examined ADAM23 methylation status in colorectal cancer tissues and their corresponding normal tissues. We found that ADAM23 was aberrantly silenced or expressed at very low levels in 28 of the 32 (88%) colorectal cancer cell lines. MSP analysis showed that ADAM23 was methylated in 29 of 32 (91%) colorectal cancer cell lines and attenuated expression of ADAM23 was found to be related to hypermethylation in its promoter region. Moreover, the CpG dinucleotide methylation threshold of 70-90% was found to be required for complete silencing. In addition, when some cell lines without ADAM23 expression were treated with 5-aza-2 0 -deoxycytidine, ADAM23 was reexpressed. In colorectal cancer tissues, the promoter region of ADAM23 was hypermethylated in 36 of 76 (47%). These results demonstrated that ADAM23 may be down-regulated by aberrant promoter hypermethylation during the progression of colorectal cancer. ' 2008 Wiley-Liss, Inc.Key words: ADAM23 gene; methylation; methylation-specific PCR (MSP); colorectal cancer; cancer cell lines Colorectal cancer is the third most common cancer in both males and females in the United States, although incidence rates have decreased from 1998 through 2004. 1 In Korea, colorectal cancer is the fourth common cancer in both sexes. 2 Moreover, evidence indicates that most cancers have a genetic component. 3 However, it is also believed that epigenetic mechanisms may also have a significant role in colorectal cancer development, 4 and methylation of the C 5 position of cytosine residues in DNA is one of the most fundamental epigenetic characteristics. This methylation is performed by DNA methyltransferases (DNMTs), which have been implicated in many processes including transcriptional regulation, genomic stability, X-chromosome inactivation and in the silencing of parasitic DNA transposable elements. 5 In a recent study, it was estimated that up to 80% of all CpG dinucleotides in the genome are methylated. 6 Furthermore, unmethylated CpG residues are known to be predominantly located in the promoter regions of active and inducible genes. They are referred to as CpG islands, 7 which consist of regions of more than 500 base pairs with the GC content exceeding 55%. 6 The importance of DNA methylation was highlighted by the finding that many human disease result from abnormal control. 8 Moreover, the aberrant methylation of CpG islands is a characteristic of many human cancers and may be found during early carcinogenesis. 9 This methylation may silence many genes, esp...

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ADAM23, a possible tumor suppressor gene, is frequently silenced in gastric cancers by homozygous deletion or aberrant promoter hypermethylation

Cited by 61 publications

References 33 publications

Genetic analysis of multifocal superficial urothelial cancers by array-based comparative genomic hybridisation

Genetic analysis of multifocal superficial urothelial cancers by array-based comparative genomic hybridisation

PRTFDC1, a possible tumor-suppressor gene, is frequently silenced in oral squamous-cell carcinomas by aberrant promoter hypermethylation

Promoter hypermethylation of the ADAM23 gene in colorectal cancer cell lines and cancer tissues

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