Analysis of genes upregulated by the demethylating agent 5‐aza‐2′‐deoxycytidine in gastric cancer cell lines

Mikata, Rintaro; Yokosuka, Osamu; Fukai, Kenichi; Imazeki, Fumio; Arai, Makoto; Tada, Motohisa; Kurihara, Tomoko; Zhang, Kaiyu; Saisho, Hiromitsu

doi:10.1002/ijc.21968

Cited by 27 publications

(31 citation statements)

References 23 publications

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“…The cell membrane is thus depleted of LRP receptors, and Wnt signaling is inhibited to a greater extent and for longer (27). Previous studies have shown that the expression of Dkk1 is downregulated in human colon cancer, gastric cancer and melanoma tissues, indicating that Dkk1 may act as a tumor suppressor in these types of cancer and not as an antagonist of Wnt signaling (13,14,28,29). However, Dkk1 has been found to be overexpressed in hepatoblastoma and hepatocellular carcinoma, indicating that Dkk1 may be regulated by a feedback loop activated by the Wnt signaling pathway.…”

Section: A B C Dmentioning

confidence: 99%

Decreased expression of Dkk1 and Dkk3 in human clear cell renal cell carcinoma

Guo

Zhang

Yang

et al. 2014

Molecular Medicine Reports

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Abstract. The expression patterns of the Dickkopf (Dkk) family of proteins varies in different cancers. In the present study, the expression levels of Dkk1 and Dkk3 were investigated in clear cell renal cell carcinoma (ccRCC) tissues. Dkk1 and Dkk3 serum levels were also examined in patients with ccRCC, and the association between clinicopathological features and Dkk levels was investigated. Serum Dkk1 and Dkk3 were quantified using ELISA in 64 patients with ccRCC and in 30 healthy individuals (controls). The expression levels of Dkk1 and Dkk3 were analyzed in tumor and adjacent normal tissues obtained from patients with ccRCC (n=20) using quantitative polymerase chain reaction (qPCR), western blot analysis and immunohistochemistry. The mean serum levels of Dkk1 and Dkk3 in the patients with ccRCC were significantly lower than those in the healthy controls. Furthermore, the serum Dkk1 levels were significantly lower at higher tumor-node-metastasis stages and tumor grades. qPCR, western blot analysis and immunohistochemistry revealed a significant decrease in the Dkk1 and Dkk3 mRNA and protein levels in the tumor tissues compared with the adjacent normal tissues. Consequently, Dkk1 and Dkk3 may present a novel molecular target for the diagnosis and therapeutic treatment of ccRCC.

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Section: A B C Dmentioning

confidence: 99%

Decreased expression of Dkk1 and Dkk3 in human clear cell renal cell carcinoma

Guo

Zhang

Yang

et al. 2014

Molecular Medicine Reports

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“…In colon cancer, Gonzalez-Sancho et al (2005) reported that the loss of DKK1 expression may open the door to cancer by removing the inhibitory effect on the Wnt/b-catenin pathway. Dickkopf-1 epigenetic inactivation may be a consequence of CpG methylation (Aguilera et al, 2006;Mikata et al, 2006). However, hypermethylation has been observed in only 17% of colon cancer clinical specimens, which indicates that this phenomenon is real but cannot be generalised (Aguilera et al, 2006).…”

Section: A B C E Dmentioning

confidence: 99%

The Wnt pathway regulator DKK1 is preferentially expressed in hormone-resistant breast tumours and in some common cancer types

et al. 2007

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In addition to new tumour antigens, new prognostic and diagnostic markers are needed for common cancers. In this study, we report the expression of Dickkopf-1 (DKK1) in multiple common cancers. This constitutes a comprehensive analysis of the DKK1 expression profile. Dickkopf-1 expression was evaluated by classical and quantitative reverse transcriptase -polymerase chain reaction (RT -PCR) and enzyme-linked immunosorbant assay for protein determination, in cancer lines and clinical specimens of several cancer origins. For breast cancer, expression was correlated with clinicopathological parameters. Dickkopf-1 expression was confirmed in several cancer cell lines derived from breast and other common cancers. Dickkopf-1 protein secretion was documented in breast, prostate and lung cancer lines, but was negligible in melanoma. Analysis of DKK1 expression in human cancer specimens revealed DKK1 expression in breast (21 out of 73), lung (11 out of 23) and kidney cancers (six out of 20). Interestingly, DKK1 was preferentially expressed in oestrogen and progesterone receptor-negative tumours (ER À /PR À ; P ¼ 0.005) and in tumours from women with a family history of breast cancer (P ¼ 0.024). Importantly, DKK1 protein production was confirmed in multiple breast cancer specimens that were positive by RT -PCR. This work establishes DKK1 as a potential prognostic and diagnostic marker for cohorts of breast cancer patients with poor prognosis. Dickkopf-1 may also become a relevant candidate target for immunotherapy of different cancers.

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“…In our previous study using cDNA microarray and real-time PCR, five genes were identified to be up-regulated by DAC treatment in gastric cancer cell lines (7). Of these, BCL2L10 was hypermethylated in 4 of 5 gastric cancer cell lines, and its CpG island became demethylated with the restoration of its expression after DAC treatment.…”

Section: Discussionmentioning

confidence: 98%

“…We previously analyzed the genes induced by the demethylating agent 5-aza-2'-deoxycytidine (DAC) in gastric cancer cell lines using a cDNA microarray containing 30,000 genes. We found that BCL2L10, which belongs to the proapoptotic Bcl-2 family, was transcriptionally repressed by promoter hypermethylation (7). BCL2L10 (also called Diva) has been reported to directly interact with Apaf-1 and to displace Bcl-X L , suggesting it inhibits Bcl-X L function and promotes apoptosis (8).…”

Section: Introductionmentioning

confidence: 92%

“…The previous observations that BCL2L10 was associated with either the anti-apoptotic proteins Bcl-2 and Bcl-X L or with the proapoptotic protein Bax (10) suggest that BCL2L10 could exert different effects on cells under certain circumstances depending on the cellular context. Previously, we demonstrated that overexpression of BCL2L10 caused apoptosis and growth inhibition of gastric cancer cells (7). Gastric carcinogenesis is thought to consist of a multi-step process composed of genetic and epigenetic disorders.…”

Section: Introductionmentioning

confidence: 98%

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BCL2L10 is frequently silenced by promoter hypermethylation in gastric cancer

Mikata

Fukai²,

Imazeki³

et al. 2010

Oncol Rep

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Abstract. In gastric cancer, several tumor suppressor and tumor-related genes are silenced by aberrant methylation. Previously, we demonstrated that BCL2L10, which belongs to the pro-apoptotic Bcl-2 family, was transcriptionally repressed by promoter hypermethylation and that its overexpression caused apoptosis and growth inhibition of gastric cancer cells. In this study, we investigated the methylation status of BCL2L10 and its expression in 21 gastric cancer tissues and corresponding non-neoplastic mucosae along with the methylation status of p16, RUNX3, and hMLH1 genes by using methylation specific PCR. In addition, we examined the association between the methylation status of each gene and the expression of EZH2, which was associated with DNA methylation of its target genes. As a result, aberrant methylation of BCL2L10 was detected in 38% of gastric cancer and in 24% of corresponding non-neoplastic mucosae and correlated with low expression of BCL2L10. Methylation of p16, RUNX3, and hMLH1 was found in gastric cancer and in corresponding non-neoplastic mucosae at almost similar frequencies as previous reports. Expression of EZH2 was detected more frequently in tumors (48%) as compared to corresponding non-neoplastic mucosae (10%) (p=0.006), however, no significant difference was found between expression of EZH2 and the methylation frequency of each gene. In conclusion, our data suggest that silencing of BCL2L10 by aberrant methylation is a common feature in gastric cancer and its inactivation may be involved in the early steps of gastric carcinogenesis.

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Analysis of genes upregulated by the demethylating agent 5‐aza‐2′‐deoxycytidine in gastric cancer cell lines

Cited by 27 publications

References 23 publications

Decreased expression of Dkk1 and Dkk3 in human clear cell renal cell carcinoma

Decreased expression of Dkk1 and Dkk3 in human clear cell renal cell carcinoma

The Wnt pathway regulator DKK1 is preferentially expressed in hormone-resistant breast tumours and in some common cancer types

BCL2L10 is frequently silenced by promoter hypermethylation in gastric cancer

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