Aberrant methylation and histone deacetylation of cyclooxygenase 2 in gastric cancer

Kikuchi, Takefumi; Itoh, Fumio; Toyota, Minoru; Suzuki, Hiromu; Yamamoto, Hiroyuki; Fujita, Masahiro; Hosokawa, Masao; Imai, Kohzoh

doi:10.1002/ijc.1612

Cited by 68 publications

(63 citation statements)

References 29 publications

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“…We also sought to analyse the methylation in RCC of other well-known tumor-associated genes that are frequently methylated in other cancers (Herman et al, 1996(Herman et al, , 1998Katzenellenbogen et al, 1999;Toyota et al, 1999aToyota et al, , c, 2003Esteller et al, 2000;Baylin et al, 2001;Sato et al, 2001;Ogi et al, 2002;Kikuchi et al, 2002;Herman and Baylin, 2003;Satoh et al, 2003;Okami et al, 2004;Terasawa et al, 2004) to clarify whether the frequent inactivation of HOXB13 in primary RCC is significant. We could not detect the methylation of p14ARF, p15INK4B, p16INK4A, BNIP3, hMLH1, DCC, and MINT2, and only low methylation frequencies (o18%) in CHFR, CACNA1G, TMS1, DAPK, COX-2, and MINT1 were detected, suggesting that these genes are not the main targets for methylation in RCC.…”

Section: Discussionmentioning

confidence: 99%

“…The restriction enzyme used for HOXB13 was BstUI (New England Biolabs). The primer sequences, PCR parameters, and the restriction enzymes used for the COBRA of other genes (p14ARF, p15INK4B, p16INK4A, CHFR, CACNA1G, TMS1, BNIP3, COX-2, hMLH1, DAPK, DCC, MINT1, and MINT2) have been described previously (Kikuchi et al, 2002;Ogi et al, 2002;Satoh et al, 2003;Terasawa et al, 2004). The resultant DNA fragments were electrophoresed in 2.5% agarose gels and stained with ethidium bromide.…”

Section: Cobramentioning

confidence: 99%

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Epigenetic inactivation of the candidate tumor suppressor gene HOXB13 in human renal cell carcinoma

Okuda¹,

Toyota

Ishida

et al. 2005

Oncogene

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Epigenetic alterations like DNA methylation and the resulting inactivation of cancer-related genes often contribute to the development of various cancers. To identify the genes that are silenced by aberrant methylation in renal cell carcinoma (RCC), we subjected two RCC lines to methylated CpG island amplification/representational difference analysis. This identified 27 CpG islands. Combined bisulfite restriction analysis of these CpG islands in primary RCC cases revealed that four were methylated in a tumor-specific manner. One of these was identified as the human homeo-box gene B13 (HOXB13) gene, but the remaining three CpG islands were not associated with known genes. The methylation frequencies of HOXB13 in primary RCC samples and lines were 30 and 73%, respectively. The methylation status of HOXB13 correlated with the loss of its expression both in RCC lines and primary tumors, and methyltransferase inhibitor treatment induced the recovery of its expression. Exogenous expression of HOXB13 in RCC cells that lacked endogenous HOXB13 expression suppressed colony formation and induced apoptotic features. Furthermore, HOXB13 methylation correlated positively with tumor grade and microvessel invasion. These results suggest that HOXB13 is a novel candidate tumor suppressor gene in RCC and that its inactivation may play an important role in both RCC tumorigenesis and progression.

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Section: Discussionmentioning

confidence: 99%

Section: Cobramentioning

confidence: 99%

Epigenetic inactivation of the candidate tumor suppressor gene HOXB13 in human renal cell carcinoma

Okuda¹,

Toyota

Ishida

et al. 2005

Oncogene

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“…However, it is increasingly recognised that promoter hypermethylation can also be detected in genes other than tumour-suppressor genes. One example is the methylation of cyclooxygenase-2 (COX-2) in gastric and colorectal cancer (Toyota et al, 2000;Kikuchi et al, 2002). COX-2 is generally considered to promote cancer development, and suppression of COX-2 activity may have an antiproliferative effect on tumour.…”

Section: Discussionmentioning

confidence: 99%

“…COX-2 is generally considered to promote cancer development, and suppression of COX-2 activity may have an antiproliferative effect on tumour. Several groups of investigators (Toyota et al, 2000;Kikuchi et al, 2002) indicated that the promoter of COX-2 gene is methylated in a proportion of gastric cancer but not in normal gastric tissues. Their findings raise the possibility that a subgroup of gastric or colorectal cancers may not be responsive to the growth inhibitory effect of COX-2 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Absence of cyclin D2 expression is associated with promoter hypermethylation in gastric cancer

Leung

Ebert

et al. 2003

Br J Cancer

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Expression of cyclin D2 is absent in 30 -70% of gastric cancers. We investigated the role of promoter hypermethylation in the transcriptional silencing of cyclin D2 in five gastric cell lines and 47 primary gastric carcinomas. CpG island methylation status of the cyclin D2 gene was studied by methylation-specific polymerase chain reaction and bisulphite sequencing. RNA and protein expression was analysed by reverse transcription -PCR and Western blot, respectively. Dense methylation of cyclin D2 was detected in three cell lines (KATOIII, AGS and NCI-N87), which also lacked cyclin D2 mRNA and protein expression. Bisulphite DNA sequencing revealed that loss of cyclin D2 expression was closely associated with the density of methylation in the promoter region. Treatment with DNA methyltransferase inhibitor, 5-aza-2 0 -deoxycytidine, restored the cyclin D2 expression level in methylated gastric cells. Among the 47 primary gastric cancers, cyclin D2 hypermethylation was detected in 23 (48.9%) cases. None of the 23 normal gastric biopsies from noncancer patients showed hypermethylation. Hypermethylation was associated with loss of mRNA (Po0.001) and protein (P ¼ 0.006) expressions. Our study showed that cyclin D2 hypermethylation is associated with loss of cyclin D2 expression in a subset of gastric cancers, which may suggest an alternative gastric carcinogenesis pathway in the absence of cyclin D2 expression.

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“…Although several reports have been published about methylation of various genes in gastric carcinoma, [5][6][7][8][9][10][11][12][13][14][15] in most of these studies, the methylation status was investigated for just a single gene and no reports have described an association between DNA methylation pattern and CIMP status or histological classification. Kang et al 16) studied DNA methylation of multiple genes and reported that EpsteinBarr virus (EBV)-positive gastric carcinoma frequently shows aberrant methylation; however, they did not investigate whether any association exists between DNA hypermethylation and CIMP status or histological classification.…”

Section: Ink4amentioning

confidence: 99%

DNA methylation of multiple genes in gastric carcinoma: Association with histological type and CpG island methylator phenotype

et al. 2003

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Hypermethylation of CpG islands is associated with silencing of various tumor suppressor genes. Recent studies on colorectal and gastric cancer have identified a CpG island methylator phenotype (CIMP), which involves the targeting of multiple genes by promoter hypermethylation. For determination of association between DNA methylation pattern or histological type and CIMP status in gastric carcinoma, CpG islands in the promoters of hMLH1 and CDH1 genes, CpG islands overlapping exon 1 of MGMT and p16INK4a genes, and a non-CpG island in exon 1 of the RAR-β β β β gene were studied. The presence of the CIMP was determined by monitoring five methylated in tumor (MINT) loci in 103 gastric carcinomas. Among the 103 gastric carcinomas, DNA hypermethylation was detected in the following frequencies: 14 (14%) for hMLH1, 26 (25%) for MGMT, 26 (25%) for p16 INK4a , 54 (52%) for CDH1, and 53 (52%) for RAR-β β β β. Forty-two (41%) of 103 gastric carcinomas were positive for the CIMP. CIMP and hypermethylation of p16INK4a gene were found more frequently in intestinal and diffuse-adherent types than in diffuse-scattered type (P = = = =0.013 and 0.017, respectively). In contrast, hypermethylation of the CDH1 and RAR-β β β β genes was more common in the diffusescattered type than in the other types (P = = = =0.008 and 0.007, respectively). In intestinal-and diffuse-adherent-type gastric carcinomas, we found significant associations between the presence of the CIMP and hypermethylation of several genes: hMLH1 (P = = = =0.006), p16 INK4a(P = = = =0.018), CDH1 (P = = = =0.024), and RAR-β β β β (P = = = =0.044). Our overall results suggest that in some intestinal-and diffuse-adherent-type gastric carcinomas, DNA hypermethylation affects non-specific gene promoters concordantly, at least in part, whereas in diffuse-scattered-type gastric carcinoma, DNA hypermethylation affects specific genes such as CDH1 and RAR-β β β β. lterations in DNA methylation patterns, such as hypermethylation of CpG islands, are common changes in human cancers. Hypermethylation of CpG islands in promoters is associated with silencing of various tumor suppressor genes.

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Aberrant methylation and histone deacetylation of cyclooxygenase 2 in gastric cancer

Cited by 68 publications

References 29 publications

Epigenetic inactivation of the candidate tumor suppressor gene HOXB13 in human renal cell carcinoma

Epigenetic inactivation of the candidate tumor suppressor gene HOXB13 in human renal cell carcinoma

Absence of cyclin D2 expression is associated with promoter hypermethylation in gastric cancer

DNA methylation of multiple genes in gastric carcinoma: Association with histological type and CpG island methylator phenotype

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