Loss of Dickkopf 3 Promotes the Tumorigenesis of Basal Breast Cancer

Lorsy, Eva; Topuz, Aylin Sophie; Geisler, Cordelia; Stahl, S.; Garczyk, Stefan; Stillfried, Saskia von; Hoß, Mareike; Gluz, Oleg; Hartmann, Arndt; Knüchel, Ruth; Dahl, Edgar

doi:10.1371/journal.pone.0160077

Cited by 26 publications

(17 citation statements)

References 47 publications

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“…Probably it is related to REIC/Dkk-3 that regulates the growth and survival of glioma cells by caspase-dependent and -independent mechanisms, via modification of the Wnt signaling pathway. Loss of Dkk-3 expression is particularly observed in some types of cancer; particularly, in in vitro studies was revealed that the impact of Dkk-3 on tumor growth is probably mediated by regulation of apoptosis and accompanied by changes on cell morphology [ 23 ]. In an interesting study it was shown that down-regulation of Dkk-3 is a key event in the progression of gliomas [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Modulation of Dkk-3 and claudin-5 as new therapeutic strategy in the treatment of meningiomas

et al. 2017

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Meningiomas are the most common tumors of the central nervous system, where the incidence is around 25% of all primary brain tumors. The optimal treatment is represented by total resection accompanied by the removal of the dura mater and bone when infiltrated by the tumor. The histological grading is the most important prognostic factor in the outcome. However, recurrences do occur in a significant proportion (10–25%) of cases, representing the most relevant clinical complication. Molecular therapies are providing to give different opportunities in the development of new treatments. The Dickkopf-related family of proteins includes four secretory proteins. The expression of the REIC/Dkk-3 gene is down-regulated in many tumor cell lines and could contribute to the immunomodulatory properties of the tissue microenvironment. An important role in carcinogenesis is played by Dickkopf protein-related protein 3, which is involved in embryonic development through its interaction and modulation of the pathway of the Wnt signal transduction. The mutations of this pathway are of clinical importance, because they lead to the onset of several cancers, including brain tumors, being also involved in tumor angiogenesis. The claudin-5, is an integral membrane protein, which regulate the permeability of the blood-brain barrier. In various pathological processes, including inflammation, trauma and tumor, claudin 5 regulate the change in endothelial or epithelial permeability, therefore, modification in claudin-5 expression may play a role in malignant transformation. The aim of our study is to demonstrate the role of Dkk-3 and claudin-5 in the pathogenesis of meningiomas. A more correct identification of the role of these proteins might suggest interesting and new molecular targets for future therapeutic protocols.

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Section: Discussionmentioning

confidence: 99%

Modulation of Dkk-3 and claudin-5 as new therapeutic strategy in the treatment of meningiomas

et al. 2017

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“…Dkk3 knockout mice exhibit no obvious phenotype during the developmental stages, but do differ in hematologic and immunologic parameters as well as pulmonary ventilation (12). DKK3/ REIC has also been shown to exhibit reduced expression gene in human immortalized cells (13) and its expression is frequently suppressed by promoter hypermethylation in human cancer cells, including the highly aggressive basal breast cancer (14), nonsmall cell lung cancer (15), hepatocellular carcinoma (16), gastric cancers, and colon cancers (17). DKK3 consistently suppressed cancer cell proliferation when ectopically overexpressed in various cancer cell types (14,18).…”

Section: Introductionmentioning

confidence: 99%

p63-Dependent Dickkopf3 Expression Promotes Esophageal Cancer Cell Proliferation via CKAP4

et al. 2018

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Dickkopf3 (DKK3) is a secretory protein that belongs to the DKK family, but exhibits structural divergence from other family members, and its corresponding receptors remain to be identified. Although DKK3 has been shown to have oncogenic functions in certain cancer types, the underlying mechanism by which DKK3 promotes tumorigenesis remains to be clarified. We show here that DKK3 stimulates esophageal cancer cell proliferation via cytoskeleton-associated protein 4 (CKAP4), which acts as a receptor for DKK3. DKK3 was expressed in approximately 50% of tumor lesions of esophageal squamous cell carcinoma (ESCC) cases; simultaneous expression of DKK3 and CKAP4 was associated with poor prognosis. Anti-CKAP4 antibody inhibited both binding of DKK3 to CKAP4 and xenograft tumor formation induced by ESCC cells. p63, a p53-related transcriptional factor frequently amplified in ESCC, bound to the upstream region of the gene. Knockdown of decreased DKK3 expression in ESCC cells, and reexpression of DKK3 partially rescued cell proliferation in -depleted ESCC cells. Expression of ΔNp63α and DKK3 increased the size of tumor-like esophageal organoids, and anti-CKAP4 antibody inhibited growth of esophageal organoids. Taken together, these results suggest that the DKK3-CKAP4 axis might serve as a novel molecular target for ESCC. In esophageal cancer, findings identify DKK3 as a poor prognostic indicator and demonstrate CKAP4 inhibition as an effective therapeutic strategy. .

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“…The role of Dkk3 in mechanisms of cell death and survival is also context-dependent. Dkk3 behaves as an oncosuppressor protein by inducing apoptotic death in a variety of cancers (Hoang et al, 2004 ; Hsieh et al, 2004 ; Ueno et al, 2011 ; Dellinger et al, 2012 ; Veeck and Dahl, 2012 ; Yang et al, 2012 ; Eskander et al, 2016 ; Lorsy et al, 2016 ; Sawahara et al, 2016 ), although it might favor cancer cell spreading by promoting angiogenesis (Untergasser et al, 2008 ; Zitt et al, 2008 ). Dkk3 induces kidney tubular cell death in proteinuric nephrosis (Wong et al, 2016 ), but, in contrast, it supports cell survival in the mouse retina (Nakamura et al, 2007 ).…”

Section: Introductionmentioning

confidence: 99%

Dickkopf-3 Causes Neuroprotection by Inducing Vascular Endothelial Growth Factor

Busceti

Menna

Bianchi

et al. 2018

Front. Cell. Neurosci.

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Dickkopf-3 (Dkk3) is an atypical member of the Dkk family of Wnt inhibitors, which has been implicated in the pathophysiology of neurodegenerative disorders. However, the role of Dkk3 in mechanisms of cell degeneration and protection is unknown. We used Dkk3 knockout mice to examine how endogenous Dkk3 influences ischemic brain damage. In addition, we used primary cultures of astrocytes or mixed cultures of astrocytes and neurons to investigate the action of Dkk3 on cell damage and dissect the underlying molecular mechanisms. In a model of focal brain ischemia induced by permanent middle cerebral artery (MCA) occlusion (MCAO) Dkk3−/− mice showed a significantly greater infarct size with respect to their wild-type counterparts at all time points investigated (1, 3 and 7 days after MCAO). Immunohistochemical analysis showed that Dkk3 expression was enhanced at the borders of the ischemic focus, and was predominantly detected in astrocytes. This raised the possibility that Dkk3 produced by astrocytes acted as a protective molecule. We tested this hypothesis using either primary cultures of cortical astrocytes or mixed cortical cultures containing both neurons and astrocytes. Genetic deletion of Dkk3 was permissive to astrocyte damage induced by either oxidative stress or glucose deprivation. In addition, application of human recombinant Dkk3 (hrDkk3) was highly protective against oxidative stress in cultured astrocytes. We tested the hypothesis that the protective activity of Dkk3 was mediated byvascular endothelial growth factor (VEGF). Interestingly, glucose deprivation up-regulated both Dkk3 and VEGF in cultured astrocytes prepared from wild-type mice. VEGF induction was not observed in astrocytes lacking Dkk3 (i.e., in cultures prepared from Dkk3−/− mice). In mixed cultures of cortical cells, excitotoxic neuronal death induced by a brief pulse with N-methyl-D-aspartate (NMDA) was significantly enhanced when Dkk3 was lacking in astrocytes, whereas post-NMDA addition of hrDkk3 was neuroprotective. Neuroprotection by hrDkk3 was significantly reduced by pharmacological blockade of type-2 VEGF receptors and was mimicked by hrVEGF. These data offer the first evidence that Dkk3 protects both neurons and astrocytes against a variety of toxic insults, and at least in culture, protection involves VEGF induction.

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Loss of Dickkopf 3 Promotes the Tumorigenesis of Basal Breast Cancer

Cited by 26 publications

References 47 publications

Modulation of Dkk-3 and claudin-5 as new therapeutic strategy in the treatment of meningiomas

Modulation of Dkk-3 and claudin-5 as new therapeutic strategy in the treatment of meningiomas

p63-Dependent Dickkopf3 Expression Promotes Esophageal Cancer Cell Proliferation via CKAP4

Dickkopf-3 Causes Neuroprotection by Inducing Vascular Endothelial Growth Factor

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