Regulation of prostate cell growth and morphogenesis by Dickkopf-3

Kawano, Yoshiaki; Kitaoka, Mitsuhiko; Hamada, Yasuyuki; Walker, Marjorie M.; Waxman, Jonathan; Kypta, Robert M.

doi:10.1038/sj.onc.1209661

Cited by 111 publications

(146 citation statements)

References 50 publications

(54 reference statements)

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“…18,19 Cell growth inhibition induced by the ectopic expression of Dkk3 was observed in vitro and in vivo. 15,17,20 These findings collectively indicate that Dkk3 possesses a tumor suppressor property, but the mechanism has not been confirmed.…”

mentioning

confidence: 78%

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

Lee

Rho

et al. 2008

Intl Journal of Cancer

133

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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mentioning

confidence: 78%

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

Lee

Rho

et al. 2008

Intl Journal of Cancer

133

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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“…21 There is evidence that Dkk-3 might influence acinar differentiation and morphogenesis. 22 Apart from its postulated function as a ''tumor suppressor'' in epithelial cell compartments, 17,23 Dkk-3 gene expression has been demonstrated in endothelial cells freshly isolated from advanced colorectal carcinomas by SAGE analysis. 5 However, there is no data on the functional role of Dkk-3, neither in endothelial cell biology nor in tumor-stroma interaction.…”

Section: Discussionmentioning

confidence: 99%

The Dickkopf‐homolog 3 is expressed in tumor endothelial cells and supports capillary formation

Untergasser

Steurer

Zimmermann

et al. 2008

Intl Journal of Cancer

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A critical event in tumor growth and progression is the upregulation of angiogenesis. Thus, targeting angiogenesis has become an attractive treatment modality in cancer medicine. Our study analyzed various solid tumor types for the expression of Dkk-3, a cystein-rich, N-glycosylated secreted member of the dickkopf protein family that has been proposed as a tumor suppressor gene. Tissue microarrays of gliomas (n 5 30), high-grade non-Hodgkin's lymphomas (NHL, n 5 80), colorectal cancer (n 5 35) and melanoma (n 5 30) were immunohistochemically analyzed for Dkk-3 and CD31 expression. Moreover, the effects of Dkk-3 were studied in vitro in primary endothelial colony-forming cells (ECFC) and in vivo in a mouse melanoma model. In comparison to normal tissue, the number of blood vessels expressing Dkk-3 was increased in glioma, high-grade NHL, melanoma and colorectal carcinoma. Confocal laser scanning microscopy revealed that Dkk-3 vesicles localized also in Weibel Palade bodies. In vitro cell proliferation and migration of ECFC was not significantly affected by adenoviral overexpression or siRNA-mediated downregulation of Dkk-3. Interestingly, tube formation in matrigel decreased after downregulation of Dkk-3 and increased after adenoviral overexpression. Stable overexpression of murine Dkk-3 in B16F10 cells significantly increased microvessel density in the C57/BL6 melanoma model. Thus, we postulate a novel function of Dkk-3 in endothelial cells as a differentiation factor involved in remodeling the tumor vasculature. ' 2007 Wiley-Liss, Inc.Key words: angiogenesis; glioma; lymphoma; melanoma; colorectal cancer; Dickkopf-3 Growth, progression and metastasis of solid tumors are strongly dependent on the supply of oxygen and nutrients. 1 Without adequate blood supply tumors become hypoxic, acidotic and necrotic. Therefore, growing tumors induce an angiogenic switch 2 and produce a variety of growth factors that are responsible either for remodeling of the pre-existing vascular network by means of angiogenic sprouting or intus-susceptive growth or for neovascularization by recruiting circulating endothelial cells. 3 Capillaries of the tumor vascular bed show a variety of structural abnormalities, such as the lack of a basement membrane, low numbers of surrounding pericytes, mosaic vessel structure and altered expression patterns of leukocyte adhesion molecules. 4 On the molecular level, tumor endothelial cells show a distinct gene expression profile 5 that differs from that of normal endothelial cells. 6 Thus, markers specifically expressed or overexpressed on tumor endothelial cells or secreted into the perivascular space are potential candidates for vascular targeting. 7 Among the dickkopf family of secreted modulators of wnt signalling, Dkk-3 is the most divergent member with still unknown signal transduction and function. 8 Dkk-1 and Dkk-2 have been shown to bind to Kremen receptors, resulting in down-regulation of the Wnt-coreceptor lipoprotein-related protein from the cell surface. 9-11 Dkk-1 knock-out mice show se...

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Regulation of prostate cell growth and morphogenesis by Dickkopf-3

Cited by 111 publications

References 50 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

The Dickkopf‐homolog 3 is expressed in tumor endothelial cells and supports capillary formation

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