Frequent epigenetic silencing of the bone morphogenetic protein 2 gene through methylation in gastric carcinomas

Xz, Wen; Akiyama, Yoshimitsu; Sb, Baylin; Yuasa, Yasuhito

doi:10.1038/sj.onc.1209297

Cited by 73 publications

(67 citation statements)

References 39 publications

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“…germ cell-, pluripotencyand developmental-specific genes) that are repressed by CpG island methylation in a tissue-and developmental stage-specific manner (Shen et al 2007, Weber et al 2007, Illingworth et al 2008, Straussman et al 2009). Promoter hypermethylation has been shown to suppress PTGS2 and BMP2 expression in cancer cells (Song et al 2001, Wen et al 2006, suggesting that this chromatin modification may contribute to the suppression of labour-associated inflammatory genes in the gestational tissues during pregnancy. Indeed, we found that variable copy proportions of the studied inflammatory genes were densely methylated in both tissues.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory and steroid receptor gene methylation in the human amnion and decidua

Mitchell¹,

Sykes²,

Pan³

et al. 2013

Journal of Molecular Endocrinology

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Correct timing of parturition requires inflammatory gene activation in the gestational tissues at term and repression during pregnancy. Promoter methylation at CpG dinucleotides represses gene activity; therefore, we examined the possibility that DNA methylation is involved in the regulation of labour-associated genes in human pregnancy. Amnion and decidua were collected at 11-17 weeks of gestation and at term following elective Caesarean delivery or spontaneous labour. Methylation of the inflammatory genes PTGS2, BMP2, NAMPT and CXCL2 was analysed using the Methyl-Profiler PCR System and bisulphite sequencing. Methylation of the glucocorticoid, progesterone and oestrogen receptor genes, involved in the hormonal regulation of gestational tissue function, and the expression of the DNA methyltransferases DNMT1, -3A and -3B were also determined. Variable proportions of inflammatory and steroid receptor gene copies, to a maximum of 50.9%, were densely methylated in both tissues consistent with repression. Densely methylated copy proportions were significantly different between genes showing no relationship with varying expression during pregnancy, between tissues and in individuals. Methylated copy proportions of all genes in amnion and most genes in decidua were highly correlated in individuals. DNMT1 and -3A were expressed in both tissues with significantly higher levels in the amnion at 11-17 weeks than at term. We conclude that the unmethylated portion of gene copies is responsible for the full range of regulated expression in the amnion and decidua during normal pregnancy. Dense methylation of individually variable gene copy proportions happens in the first trimester amnion influenced by sequence context and affected strongly by individual circumstances.

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Section: Discussionmentioning

confidence: 99%

Inflammatory and steroid receptor gene methylation in the human amnion and decidua

Mitchell¹,

Sykes²,

Pan³

et al. 2013

Journal of Molecular Endocrinology

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“…All the cell lines were cultured in appropriate medium. For demethylation studies, cells were daily treated with 5 mM 5-aza-2 0 -deoxycytidine (Sigma, St Louis, MO, USA) for 48 h (Wen et al, 2006). A total of 74 primary gastric carcinoma tissue samples and corresponding noncancerous gastric mucosae were obtained as described previously (Wen et al, 2006).…”

Section: Cell Lines and Tissue Samplesmentioning

confidence: 99%

“…Methylation-specific PCR (MSP) and bisulphitesequencing analyses were performed as described previously (Wen et al, 2006). Primer sequences used for all analyses are available upon request.…”

Section: Methylation Analysismentioning

confidence: 99%

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SOX2 is frequently downregulated in gastric cancers and inhibits cell growth through cell-cycle arrest and apoptosis

Otsubo

Akiyama

Yanagihara³

et al. 2008

Br J Cancer

Self Cite

197

173

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SOX transcription factors are essential for embryonic development and play critical roles in cell fate determination, differentiation and proliferation. We previously reported that the SOX2 protein is expressed in normal gastric mucosae but downregulated in some human gastric carcinomas. To clarify the roles of SOX2 in gastric carcinogenesis, we carried out functional characterisation of SOX2 in gastric epithelial cell lines. Exogenous expression of SOX2 suppressed cell proliferation in gastric epithelial cell lines. Flow cytometry analysis revealed that SOX2-overexpressing cells exhibited cell-cycle arrest and apoptosis. We found that SOX2-mediated cell-cycle arrest was associated with decreased levels of cyclin D1 and phosphorylated Rb, and an increased p27Kip1 level. These cells exhibited further characteristics of apoptosis, such as DNA laddering and caspase-3 activation. SOX2 hypermethylation signals were observed in some cultured and primary gastric cancers with no or weak SOX2 expression. Among the 52 patients with advanced gastric cancers, those with cancers showing SOX2 methylation had a significantly shorter survival time than those without this methylation (P ¼ 0.0062). Hence, SOX2 plays important roles in growth inhibition through cell-cycle arrest and apoptosis in gastric epithelial cells, and the loss of SOX2 expression may be related to gastric carcinogenesis and poor prognosis.

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“…Specifically, restoration of silenced BMP expression could be aimed for to inhibit adrenocortical tumour growth. While hypermethylation of BMP-2 promoter regions has been reported to be the cause of diminished BMP-2 expression in prostate and gastric tumours (Horvath et al 2004, Wen et al 2006, this could not be demonstrated in ACC. However, in vitro treatment of NCIh295R cells with the demethylation agent 5-aza-2 0 -deoxycytidin (5-AZA) was followed by a decrease in BMP-2 promoter methylation, which was further associated with re-expression of endogenous BMPs and activation of downstream IDs ( Johnsen et al 2009).…”

Section: Potential Therapeutic Implicationsmentioning

confidence: 62%

Role of bone morphogenetic proteins in adrenal physiology and disease

Johnsen¹,

Beuschlein²

2010

Journal of Molecular Endocrinology

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Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-b superfamily of ligands that impact on a multitude of biological processes including cell type specification, differentiation and organogenesis. Furthermore, a large body of evidence points towards important BMP-dependent mechanisms in tumorigenesis. In accordance with their diverse actions, BMPs have been demonstrated to serve as auto-, para-and endocrine modulators also in a number of hormonal systems. In this review, we highlight novel aspects of BMP-dependent regulatory networks that pertain to adrenal physiology and disease, which have been uncovered during recent years. These aspects include the role of BMP-dependent mechanism during adrenal development, modulating effects on catecholamine synthesis and steroidogenesis and dysregulation of BMP signalling in adrenal tumorigenesis. Furthermore, we summarize potential therapeutic approaches that are based on reconstitution of BMP signalling in adrenocortical tumour cells.

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Frequent epigenetic silencing of the bone morphogenetic protein 2 gene through methylation in gastric carcinomas

Cited by 73 publications

References 39 publications

Inflammatory and steroid receptor gene methylation in the human amnion and decidua

Inflammatory and steroid receptor gene methylation in the human amnion and decidua

SOX2 is frequently downregulated in gastric cancers and inhibits cell growth through cell-cycle arrest and apoptosis

Role of bone morphogenetic proteins in adrenal physiology and disease

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