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

Yu, Jun; Leung, Wai K.; Ebert, Matthias P.; Leong, Rupert W.; Tse, Pete C.H.; Chan, Michael W.Y.; Bai, Alfa H.C.; To, Ka‐Fai; Malfertheiner, Peter; Sung, Joseph J.Y.

doi:10.1038/sj.bjc.6600940

Cited by 40 publications

(37 citation statements)

References 26 publications

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“…As such, and being positively correlated with the metastatic potential of the tumour (this study), cyclin D2 expression may serve as an early marker for colon tumorigenesis and for prediction of clinical prognosis of colon cancer. It has been suggested that hypermethylation of the CpG islands in the cyclin D2 promoter is related to the lack of cyclin D2 protein expression in breast cancer (Evron et al, 2001), prostate cancer (Padar et al, 2003) and gastric cancer (Yu et al, 2003), while hypomethylation of the CpG islands is related to the elevated expression of cyclin D2 in gastric cancer (Oshimo et al, 2003). It is possible that the overexpression of cyclin D2 in colon cancer is also related to promoter hypomethylation.…”

Section: Discussionmentioning

confidence: 99%

Expression of D-type cyclins in colon cancer and in cell lines from colon carcinomas

et al. 2005

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Cyclins D1, D2 and D3 play important roles in cell proliferation and differentiation. Although their abnormal expression has been linked to cancer development and progression in a number of tissues, the expression of cyclin D2 and D3 proteins in colon cancer has not yet been characterised. In this study, we examined cyclin D1, D2 and D3 protein expression by Western blot analysis in tumour and adjacent normal colon tissues of 57 patients. In addition, we examined D-type cyclins protein expression in HT29 and LoVo39 cell lines from colon carcinomas, as a function of induced proliferation and differentiation. In both cell lines, the expression of the three D-type cyclins increased as a result of induced proliferation, whereas the expression of cyclin D3 increased as a result of induced differentiation. In colon tumours, cyclin D1 was overexpressed in 44%, cyclin D2 was overexpressed in 53% and cyclin D3 was overexpressed in 35% of the cases. We also found that in 16% of the cases, cyclin D3 protein expression was reduced in the tumour, as compared to the adjacent normal tissue. Examination of D-type cyclin protein overexpression in relation to the TNM stage of the tumours revealed that overexpression of cyclins D1 and/or D2, but not cyclin D3, is linked to colon carcinogenesis and that overexpression of cyclin D2 may be related to a higher TNM stage of the tumour.

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Section: Discussionmentioning

confidence: 99%

Expression of D-type cyclins in colon cancer and in cell lines from colon carcinomas

et al. 2005

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“…Epigenetic silencing of tumour-related genes due to CpG island hypermethylation has emerged as one of the most important alternations in gastric cancer development Yu et al, 2003). We have previously shown that tumour-related genes including E-cadherin, p15, and p16 were frequently methylated in gastric cancer as well as in pre-malignant gastric lesions (Leung et al, 2006), suggesting dysregulation in CpG-island methylation is likely to be involved in the early gastric carcinogenesis process.…”

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confidence: 99%

Frequent epigenetic inactivation of secreted frizzled-related protein 2 (SFRP2) by promoter methylation in human gastric cancer

et al. 2007

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The role of secreted frizzled-related protein (SFRP) genes in gastric cancer remains largely unknown. We determined the frequency and functional significance of SFRPs hypermethylation in human gastric cancer. The expression and methylation status of four SFRP members (SFRP1, 2, 4, and 5) in primary gastric cancer samples was screened. The biological effects of SFRP were analysed by flow cytometry, cell viability assay and in vivo tumour growth in nude mice. Among the four SFRPs, only SFRP2 was significantly downregulated in gastric cancer as compared to adjacent non-cancer samples (Po0.01). Promoter hypermethylation of SFRP2 was detected in 73.3% primary gastric cancer tissues, 37.5% of samples showing intestinal metaplasia and 20% adjacent normal gastric tissues. Bisulphite DNA sequencing confirmed the densely methylated SFRP2 promoter region. Demethylation treatment restored the expression of SFRP2 in gastric cancer cell lines. Forced expression of SFRP2 induced cell apoptosis, inhibited proliferation of gastric cancer cells and suppressed tumour growth in vivo. Moreover, methylated SFRP2 was detected in 66.7% of serum samples from cancer patients but not in normal controls. In conclusion, epigenetic inactivation of SFRP2 is a common and early event contributing to gastric carcinogenesis and may be a potential biomarker for gastric cancer.

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“…6,58 Whereas, loss of cyclin D2 expression by hypermethylation of its promoter region was found to be associated with tumor development in breast, lung, gastric, and pancreatic cancer, indicating that cyclin D2 might be involved in a vital tumor suppressor function in a cancer-type dependent manner. 10,[58][59][60] Our results also showed aberrant methylation of the cyclin D2 gene in all three breast cancer cell lines and correlated with silencing of the gene expression. When the cells were exposed to As 2 O 3 , the cyclin D2 promoter was partially demethylated, and cyclin D2 mRNA expression was restored.…”

Section: Tp53mentioning

confidence: 65%

Demethylation and alterations in the expression level of the cell cycle–related genes as possible mechanisms in arsenic trioxide–induced cell cycle arrest in human breast cancer cells

et al. 2017

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Arsenic trioxide (As 2 O 3 ) has been used clinically as an anti-tumor agent. Its mechanisms are mostly considered to be the induction of apoptosis and cell cycle arrest. However, the detailed molecular mechanisms of its anti-cancer action through cell cycle arrest are poorly known. Furthermore, As 2 O 3 has been shown to be a potential DNA methylation inhibitor, inducing DNA hypomethylation. We hypothesize that As 2 O 3 may affect the expression of cell cycle regulatory genes by interfering with DNA methylation patterns. To explore this, we examined promoter methylation status of 24 cell cycle genes in breast cancer cell lines and in a normal breast tissue sample by methylation-specific polymerase chain reaction and/or restriction enzyme-based methods. Gene expression level and cell cycle distribution were quantified by real-time polymerase chain reaction and flow cytometric analyses, respectively. Our methylation analysis indicates that only promoters of RBL1 (p107), RASSF1A, and cyclin D2 were aberrantly methylated in studied breast cancer cell lines. As 2 O 3 induced CpG island demethylation in promoter regions of these genes and restores their expression correlated with DNA methyltransferase inhibition. As 2 O 3 also induced alterations in messenger RNA expression of several cell cycle-related genes independent of demethylation. Flow cytometric analysis revealed that the cell cycle arrest induced by As 2 O 3 varied depending on cell lines, MCF-7 at G1 phase and both MDA-MB-231 and MDA-MB-468 cells at G2/M phase. These changes at transcriptional level of the cell cycle genes by the molecular mechanisms dependent and independent of demethylation are likely to represent the mechanisms of cell cycle redistribution in breast cancer cells, in response to As 2 O 3 treatment.

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

Cited by 40 publications

References 26 publications

Expression of D-type cyclins in colon cancer and in cell lines from colon carcinomas

Expression of D-type cyclins in colon cancer and in cell lines from colon carcinomas

Frequent epigenetic inactivation of secreted frizzled-related protein 2 (SFRP2) by promoter methylation in human gastric cancer

Demethylation and alterations in the expression level of the cell cycle–related genes as possible mechanisms in arsenic trioxide–induced cell cycle arrest in human breast cancer cells

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