Epigenetic Down-Regulation and Suppressive Role of DCBLD2 in Gastric Cancer Cell Proliferation and Invasion

Abstract

The promoter region of Discoidin, CUB and LCCL domain containing 2 (DCBLD2) was found to be aberrantly methylated in gastric cancer cell lines and in primary gastric cancers, as determined by restriction landmark genomic scanning. DCBLD2 expression was inversely correlated with DCBLD2 methylation in gastric cancer cell lines. Treatment with 5-aza-2 ¶-deoxycytidine and trichostatin A partially reversed DCBLD2 methylation and restored gene expression in DCBLD2-silenced cell lines. In an independent series of 82 paired gastric cancers and adjacent normal tissues, DCBLD2 expression was down-regulated in 79% of gastric cancers as compared with normal tissues as measured by real-time reverse transcription-PCR. Pyrosequencing analysis of the DCBLD2 promoter region revealed abnormal hypermethylation in gastric cancers, and this hypermethylation was significantly correlated with down-regulation of DCBLD2 expression. Furthermore, ectopic expression of DCBLD2 in gastric cancer cell lines inhibited colony formation in both anchorage-dependent and anchorage-independent cultures and also inhibited invasion through the collagen matrix. These data suggest that downregulation of DCBLD2, often associated with promoter hypermethylation, is a frequent event that may be related to the development of gastric cancer. (Mol Cancer Res 2008;6(2):222 -30)

Epigenetic regulation ofmicroRNA-10band targeting of oncogenicMAPRE1in gastric cancer

“…We identified the aberrant methylation of several genes and suggested roles for these genes in gastric carcinogenesis. [23][24][25][26][27] In this study, we applied methylation array technology to detect the aberrant methylation of miRNA genes in gastric cancers and found heavy methylation on promoter CpGs of miR10b, which is a regulator of multiple aspects of cancer biology the methylation status of two miR-10b promoter regions in gastric cancer cells with bisulfate pyrosequencing analysis of six CpG sites (two in Region 1 and four in Region 2; Fig. 1C).…”

MicroRNA-mediated upregulation of integrin-linked kinase promotes Src-induced tumor progression

“…Thus, we further searched for more general targets in more broadly conserved targets predicted by TargetScan. Among the candidates, ILK and DCBLD2 (Discoidin, CUB and LCCL domain containing 2) were identified as targets likely to be involved in tumor growth, based on previous reports (McDonald et al, miR-542-3p controls c-Src-mediated malignancy C Oneyama et al 2008; Kim et al, 2008a). However, as DCBLD2 is downregulated by DNA hypermethylation in human cancers (Kim et al, 2008a), we asked whether ILK might be regulated by miR-542-3p.…”

“…Among the candidates, ILK and DCBLD2 (Discoidin, CUB and LCCL domain containing 2) were identified as targets likely to be involved in tumor growth, based on previous reports (McDonald et al, miR-542-3p controls c-Src-mediated malignancy C Oneyama et al 2008; Kim et al, 2008a). However, as DCBLD2 is downregulated by DNA hypermethylation in human cancers (Kim et al, 2008a), we asked whether ILK might be regulated by miR-542-3p. A luciferase reporter assay in c-Src-transformed cells showed that introduction of miR-542-3p significantly suppressed the expression of the ILK reporter by specifically targeting the predicted miR-542-3p binding sequences in the 3 0 -untranslated region of the ILK mRNA (Figures 2a and b, left panel).…”

Expression of AP-2α, AP-2γ and ESDN in primary melanomas: Correlation with histopathological features and potential prognostic value

“…Low AP-2 expression was associated with disease progression in breast cancer [9]. ESDN was up-regulated in the highly metastatic compared with parental cells in lung cancer [7], whereas a study on gastric cancer correlated loss of ESDN expression with increased tumour proliferation [10]. The mechanism of ESDN expression is still poorly understood.…”