Zonal expression of dickkopf-3 and components of the Wnt signalling pathways in the human adrenal cortex

Suwa, Tetsuya; Chen, M; Hawks, CL; Hornsby, PJ

doi:10.1677/joe.0.1780149

Cited by 50 publications

(39 citation statements)

References 45 publications

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“…The zonal distribution of DKK3 expression in the adrenal gland suggests that DKK3 is involved in zonal differentiation or growth (29). DKK3 was identified as a gene which is down-regulated upon immortalization of primary human cells (30).…”

Section: Discussionmentioning

confidence: 99%

Functional Epigenomics Identifies Genes Frequently Silenced in Prostate Cancer

Lodygin

Epanchintsev²,

Menssen³

et al. 2005

Cancer Research

263

223

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In many cases, silencing of gene expression by CpG methylation is causally involved in carcinogenesis. Furthermore, cancer-specific CpG methylation may serve as a tumor marker. In order to identify candidate genes for inactivation by CpG methylation in prostate cancer, the prostate cancer cell lines LNCaP, PC3, and Du-145 were treated with 5-aza-2V deoxycytidine and trichostatin A, which leads to reversion of epigenetic silencing. By microarray analysis of 18,400 individual transcripts, several hundred genes were found to be induced when compared with cells treated with trichostatin A. Fifty re-expressed genes were selected for further analysis based on their known function, which implied a possible involvement in tumor suppression. Twelve of these genes showed a significant degree of CpG methylation in their promoters. Six genes were silenced by CpG methylation in the majority of five analyzed prostate cancer cell lines, although they displayed robust mRNA expression in normal prostate epithelial cells obtained from four different donors. In primary prostate cancer samples derived from 41 patients, the frequencies of CpG methylation detected in the promoter regions of these genes were: GPX3, 93%; SFRP1, 83%; COX2, 78%; DKK3, 68%; GSTM1, 58%; and KIP2/p57, 56%. Ectopic expression of SFRP1 or DKK3 resulted in decreased proliferation. The expression of DKK3 was accompanied by attenuation of the mitogen-activated protein kinase pathway. The high frequency of CpG methylation detected in the promoters of the identified genes suggests a potential causal involvement in prostate cancer and may prove useful for diagnostic purposes. (Cancer Res 2005; 65(10): 4218-27)

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Section: Discussionmentioning

confidence: 99%

Functional Epigenomics Identifies Genes Frequently Silenced in Prostate Cancer

Lodygin

Epanchintsev²,

Menssen³

et al. 2005

Cancer Research

263

223

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“…Indeed DKK3 is well expressed in adult human adrenal medulla. 50 MYCN is highly expressed in migrating neural crest cells 51 and the suppression of DKK3 by MYCN may stimulate Wnt11-induced neural crest migration. In this hypothesis, the suppression of DKK3 by MYCN in neuroblastoma cells may reflect the normal physiology during the migratory stage of neural crest derived cells.…”

Section: Discussionmentioning

confidence: 99%

Dickkopf‐3 expression is a marker for neuroblastic tumor maturation and is down‐regulated by MYCN

Koppen

Ait-Aissa

Koster

et al. 2008

Intl Journal of Cancer

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Neuroblastoma and ganglioneuroma are neuroblastic tumors originating from the developing sympathetic peripheral nervous system. Ganglioneuromas are usually benign, while neuroblastomas have a variable prognosis and include very aggressive tumors. Examples exist of neuroblastomas regressing to ganglioneuromas and ganglioneuromas progressing to neuroblastomas. Little is known of the molecular differences between the tumor types. Here we report that Dickkopf-3 (DKK3), a putative extra cellular inhibitor of the Wnt/b-catenin pathway, showed a strongly differential expression between neuroblastoma and ganglioneuroma. Microarray analyses of 109 neuroblastic tumors revealed that DKK3 is strongly expressed in ganglioneuroma but only weakly in neuroblastoma. Low DKK3 expression in neuroblastoma correlated with a poor prognosis. The expression of DKK3 in the tumor series and in neuroblastoma cell lines was inversely correlated with the expression of the MYCN oncogene. Analysis of 2 neuroblastoma cell lines with inducible activity of MYCN showed that DKK3 is down-regulated by MYCN. We subsequently generated cell lines with inducible expression of DKK3, which revealed an inhibitory effect of DKK3 on proliferation. High DKK3 expression in the benign ganglioneuromas and down-regulation of DKK3 by MYCN in neuroblastoma might contribute to the strongly different clinical behavior of both neuroblastic tumor types. ' 2007 Wiley-Liss, Inc.

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“…It has been demonstrated that DKKs, including DKK3, display regionalized expression and control cell fate during development in vertebrates (Monaghan et al 1999, Suwa et al 2003, Ang et al 2004, Diep et al 2004, Fjeld et al 2005, Nie 2005). DKK1, DKK2, and DKK4, antagonists of Wnt signaling (Krupnik et al 1999, Veeck & Dahl 2012, interact with Wnt coreceptors, LDL receptor-related protein 5/6 (LRP5/6) and kremen proteins (Davidson et al 2002, Mao et al 2002.…”

Section: Introductionmentioning

confidence: 99%

DKK3 is a potential tumor suppressor gene in papillary thyroid carcinoma

Yin¹,

Wu²,

Li³

et al. 2013

Endocrine-Related Cancer

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The expression of the Dickkopf homolog 3 (DKK3) gene is downregulated in some human cancers, suggesting a possible tumor suppressor role of this gene. The role and regulation of DKK3 in thyroid cancer have not been examined. In this study, we explored the relationship of promoter methylation with the inactivation of DKK3 and tumor behaviors in papillary thyroid carcinoma (PTC). We used methylation-specific PCR and RT-PCR to examine the promoter methylation and expression of DKK3 and tumor characteristics. We found mRNA expression of DKK3 in 44.9% of the PTC tissue samples vs 100% of the matched normal thyroid tissue samples (P!0.01). In contrast, an opposite distribution pattern of DKK3 gene methylation was observed; specifically, 38.8% of the PTC tissue samples vs 0% of the matched normal thyroid tissue samples harbored DKK3 methylation. An inverse correlation between the promoter methylation and mRNA expression of DKK3 in PTC tissue samples was also observed. Moreover, we also found an inverse correlation between DKK3 expression and some aggressive pathological characteristics of PTC, including high TNM stages and lymph node metastasis, but a positive correlation between DKK3 promoter hypermethylation and pathological aggressiveness of the tumor. Treatment of the PTC cell line TPC-1 with the demethylating agent 5-azaC reduced DKK3 promoter methylation and enhanced its expression, establishing functionally the impact of DKK3 methylation on its expression. Our data thus for the first time demonstrate that the DKK3 gene is a potential tumor suppressor gene in thyroid cancer and that aberrant promoter methylation is an important mechanism for its downregulation, which may play a role in the tumorigenesis and aggressiveness of PTC.

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Zonal expression of dickkopf-3 and components of the Wnt signalling pathways in the human adrenal cortex

Cited by 50 publications

References 45 publications

Functional Epigenomics Identifies Genes Frequently Silenced in Prostate Cancer

Functional Epigenomics Identifies Genes Frequently Silenced in Prostate Cancer

Dickkopf‐3 expression is a marker for neuroblastic tumor maturation and is down‐regulated by MYCN

DKK3 is a potential tumor suppressor gene in papillary thyroid carcinoma

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