Reduced expression of the REIC/Dkk-3 gene by promoter-hypermethylation in human tumor cells

Kobayashi, Kazuya; Ouchida, Mamoru; Tsuji, Toshiya; Hanafusa, Hiroko; Miyazaki, Masahiro; Namba, Masayoshi; Shimizu, Nobuyoshi; Shimizu, Kenji

doi:10.1016/s0378-1119(01)00838-1

Cited by 114 publications

(108 citation statements)

References 13 publications

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“…The same findings were made in paired normal tissue specimens of 22 cancer samples, which indicate that the nucleotide change is a genetic polymorphism (data not shown). However, the genotype frequency of the polymorphism did not differ from that noted in the healthy population, 14 meaning that this single nucleotide polymorphism is not contributing factor to develop cervical cancer.…”

Section: Single-nucleotide Polymorphism In Codon 335 Of Dkk3mentioning

confidence: 58%

“…We then performed PCR with 3 pairs of primers designed for the promoter regions of the Dkk3 gene. 14 The PCR amplification band from the HpaII-cleaved DNA shows the methylation status. We also used MspI-cleaved DNA as a negative control for detecting incomplete restriction and noncleaved DNA as a positive control.…”

Section: Methylation At the Promoter Region Of Dkk3 With Transcriptiomentioning

confidence: 99%

“…Indeed, Dkk3 is downregulated in some cancer cell lines and cancer tissues including cancers of the liver, kidney, lung and prostate as well as in melanoma, and the transcriptional silencing is partly due to the aberrant hypermethylation of the Dkk3 promoter. [13][14][15][16][17][18] The Dkk3 protein was found to inhibit the invasion and motility of osteosarcoma cells and melanoma. 18,19 Cell growth inhibition induced by the ectopic expression of Dkk3 was observed in vitro and in vivo.…”

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confidence: 99%

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Dkk3, downregulated in cervical cancer, functions as a negative regulator of β‐catenin

Lee

Rho

et al. 2008

Intl Journal of Cancer

132

136

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The Wnt/b-catenin signaling pathway is activated during the malignant transformation of keratinocytes that originate from the human uterine cervix. Dkk1, 2 and 4 have been shown to modulate the Wnt-induced stabilization of the b-catenin signaling pathway. However, the function of Dkk3 in this pathway is unknown. Comparison of the Dkk3 gene expression profiles in cervical cancer and normal cervical tissue by cDNA microarray and subsequent real-time PCR revealed that the Dkk3 gene is frequently downregulated in the cancer. Methylation studies showed that the promoter of Dkk3 was methylated in cervical cancer cell lines and 22 (31.4%) of 70 cervical cancer tissue specimens. This promoter methylation was associated with reduced expression of Dkk3 mRNA in the paired normal and tumor tissue samples. Further, the reintroduction of Dkk3 into HeLa cervical cancer cells resulted in reduced colony formation and retarded cell growth. The forced expression of Dkk3 markedly attenuated b-catenin-responsive luciferase activity in a dose-dependent manner and decreased the b-catenin levels. By utilizing a yeast two-hybrid screen, bTrCP, a negative regulator of b-catenin was identified as a novel Dkk3-interacting partner. Coexpression with bTrCP synergistically enhanced the inhibitory function of Dkk3 on b-catenin. The stable expression of Dkk3 blocks the nuclear translocation of b-catenin, resulting in downregulation of its downstream targets (VEGF and cylcin D), whereas knockdown of Dkk3 abrogates this blocking. We conclude from our finding that Dkk3 is a negative regulator of b-catenin and its downregulation contribute to an activation of the b-catenin signaling pathway.

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Section: Single-nucleotide Polymorphism In Codon 335 Of Dkk3mentioning

confidence: 58%

Section: Methylation At the Promoter Region Of Dkk3 With Transcriptiomentioning

confidence: 99%

mentioning

confidence: 99%

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Dkk3, downregulated in cervical cancer, functions as a negative regulator of β‐catenin

Lee

Rho

et al. 2008

Intl Journal of Cancer

132

136

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“…Reduced levels of DKK-3 were found in prostate [15], lung cancers [16], renal clear cell carcinoma [17]. Overexpression of DKK-1 or DKK-3 resulted in inhibition of cell tumorigenicity, cell motility and invasiveness.…”

Section: Discussionmentioning

confidence: 99%

Dickkopf-1 activates cell death in MDA-MB435 melanoma cells

Mikheev

Mikheeva

Rostomily

et al. 2007

Biochemical and Biophysical Research Communications

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SummaryDickkopf-1 (DKK-1) is known inhibitor of the canonical Wnt pathway. Recent studies strongly suggested that activation of DKK-1 expression results in inhibition of cell tumorigenicity. Reduced levels of DKK-1 in melanomas were recently shown. However it is not known if DKK-1 activation in melanoma cells will inhibit cell tumorigenicity. In the present study we overexpressed DKK-1 in melanoma cell line MDA-MB435. We show that while DKK-1 did not affect cell growth in soft agar, weak but significant inhibition of tumorigenicity in nude mice in vivo was observed. Analysis of resulting tumors revealed activation of cell death. In tumors originating from cells transduced with DKK-1 tumor mass was permeated with areas of necrosis. In tumors, originated from control cells, areas of necrosis were limited to the central region, a common feature of large tumors growing in nude mice. TUNEL assay revealed that in tumors originating from cells transduced with DKK-1 apoptotic cells were detected along the border of necrotic and viable areas of the tumors indicating significant increase in apoptotic process. Thus, our results indicate that activation of DKK-1 in melanoma cells leads to activation of apoptosis in vivo and, thus, is incompatible with tumor growth in mice.

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“…For lymphoblastic leukemia (Roman-Gomez et al, 2004), non small lung cancer, gastric cancer, hepatoma and cervical cancer (Kobayashi et al, 2002) previously promoter hypermethylation was described. Obviously, the DKK-1 and -3 gene expression is regulated by transcriptional regulators in malignant melanoma.…”

Section: Discussionmentioning

confidence: 99%

Expression of Dickkopf genes is strongly reduced in malignant melanoma

et al. 2006

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The Dickkopf (DKK) genes were originally identified as factors inducing head formation in Xenopus. The genes code for inhibitors that are involved in Wnt signaling. We speculate that loss of DKK expression plays a role in development or progression of malignant melanoma. Thus, we evaluated melanoma cell lines and tissue samples of malignant melanoma for loss of DKK, especially DKK-3 transcription. We found that DKK-1, -2 and -3 were downregulated or lost in all cell lines and in most of the tumor samples analysed. Reduced DKK-3 expression occurred as early as in primary tumors detected by both immunohistochemical and reverse transcription-polymerase chain reaction RT-PCR analysis. Functional assays with stable DKK-3 transfected cell lines revealed that DKK-3 expression increased cell-cell adhesion and decreased cell migration. Further, downregulation of fibronectin, snail-1 and re-expression of E-cadherin was found in the DKK-3 expressing cell clones supporting a role of DKK-3 in tumor progression. Our studies thus indicate that loss of DKK-3 expression may contribute to melanoma progression.

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Reduced expression of the REIC/Dkk-3 gene by promoter-hypermethylation in human tumor cells

Cited by 114 publications

References 13 publications

Dkk3, downregulated in cervical cancer, functions as a negative regulator of β‐catenin

Dkk3, downregulated in cervical cancer, functions as a negative regulator of β‐catenin

Dickkopf-1 activates cell death in MDA-MB435 melanoma cells

Expression of Dickkopf genes is strongly reduced in malignant melanoma

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