Dickkopf3 overexpression inhibits pancreatic cancer cell growth<i>in vitro</i>

Gu, Yumei

doi:10.3748/wjg.v17.i33.3810

Cited by 29 publications

(26 citation statements)

References 43 publications

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“…There are reports on DKK3 both enhancing and repressing the Wnt signalling pathway 30, 31. Recently, DKK3 was also reported as playing distinct roles in different human pancreatic cancer cells, but not much is known about the detailed mechanism 20, 32.…”

Section: Discussionmentioning

confidence: 99%

DKK3 blocked translocation of β‐catenin/EMT induced by hypoxia and improved gemcitabine therapeutic effect in pancreatic cancer Bxpc‐3 cell

Guo

Qin

2015

J Cellular Molecular Medi

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The Wnt/β‐catenin signalling pathway is activated in pancreatic cancer initiation and progression. Dickkopf‐related protein 3 (DKK3) is a member of the human Dickkopf family and an antagonist of Wnt ligand activity. However, the function of DKK3 in this pathway in pancreatic cancer is rarely known. We examined the expression of DKK3 in six human pancreatic cancer cell lines, 75 pancreatic cancer and 75 adjacent non‐cancerous tissues. Dickkopf‐related protein 3 was frequently silenced and methylation in pancreatic cancer cell lines (3/6). The expression of DKK3 was significantly lower in pancreatic cancer tissues than in adjacent normal pancreas tissues. Further, ectopic expression of DKK3 inhibits nuclear translocation of β‐catenin induced by hypoxia in pancreatic cancer Bxpc‐3 cell. The forced expression of DKK3 markedly suppressed migration and the stem cell‐like phenotype of pancreatic cancer Bxpc‐3 cell in hypoxic conditions through reversing epithelial–mesenchymal transition (EMT). The stable expression of DKK3 sensitizes pancreatic cancer Bxpc‐3 cell to gemcitabine, delays tumour growth and augments gemcitabine therapeutic effect in pancreatic cancer xenotransplantation model. Thus, we conclude from our finding that DKK3 is a tumour suppressor and improved gemcitabine therapeutic effect through inducing apoptosis and regulating β‐catenin/EMT signalling in pancreatic cancer Bxpc‐3 cell.

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Section: Discussionmentioning

confidence: 99%

DKK3 blocked translocation of β‐catenin/EMT induced by hypoxia and improved gemcitabine therapeutic effect in pancreatic cancer Bxpc‐3 cell

Guo

Qin

2015

J Cellular Molecular Medi

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“…However, Dkk-3 is a secreted protein and the relevance of these interactions, which take place in the cytoplasm, to the function of endogenous Dkk-3 remains unclear. In addition, ectopic expression of Dkk-3 affects the activities of several kinases, including JNK, p38, and Erk (Abarzua et al, 2005;Gu et al, 2011;Hsu et al, 2011), but it is not known if secreted Dkk-3 has similar effects. Studies performed in Xenopus and zebrafish embryos highlight a functional link between Dkk-3 and TGF-b signalling.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Dickkopf-3 disrupts prostate acinar morphogenesis through TGF-β/Smad signaling

Romero

Kawano

Bengoa³

et al. 2013

Journal of Cell Science

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SummaryLoss of tissue organization is a hallmark of the early stages of cancer, and there is considerable interest in proteins that maintain normal tissue architecture. Prostate epithelial cells cultured in Matrigel form three-dimensional acini that mimic aspects of prostate gland development. The organization of these structures requires the tumor suppressor Dickkopf-3 (Dkk-3), a divergent member of the Dkk family of secreted Wnt signalling antagonists that is frequently downregulated in prostate cancer. To gain further insight into the function of Dkk-3 in the prostate, we compared the prostates of Dkk3-null mice with those of control littermates. We found increased proliferation of prostate epithelial cells in the mutant mice and changes in prostate tissue organization. Consistent with these observations, cell proliferation was elevated in acini formed by human prostate epithelial cells stably silenced for Dkk-3. Silencing of Dkk-3 increased TGF-b/Smad signalling, and inhibitors of TGF-b/Smad signalling rescued the defective acinar phenotype caused by loss of Dkk-3. These findings suggest that Dkk-3 maintains the structural integrity of the prostate gland by limiting TGF-b/Smad signalling.

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“…Immunofluorescence H9c2 cells cultured as described previously 3 were seeded onto 24-well plates containing round cover slides. The slides were first incubated with anti-β-catenin Ab (1:200; Abcam) overnight at 4°C.…”

Section: Dkk3-ko Cell Linementioning

confidence: 99%

“…Dkk3 is abundant in the liver and brain, but is absent in the spleen and peripheral blood mononuclear cells. 1 Dkk3 mediates potent antitumor effects, including reducing cell proliferation, anchorage-independent, growth and metastasis, [2][3][4][5][6][7] or inducing cancer cell apoptosis both in vitro and in murine tumor models. [8][9][10] Furthermore, Dkk3 is upregulated during a series of disease and situation, including Alzheimer's disease, 11 endochondral bone formation, 12 retinal degeneration, 13 and cellular senescence in prostate basal epithelial cells.…”

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confidence: 99%

Dkk3 prevents familial dilated cardiomyopathy development through Wnt pathway

Bao

Dong

et al. 2016

Laboratory Investigation

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To date, the role of Dickkopf 3 (Dkk3) on the pathogenesis of familial dilated cardiomyopathy (FDCM), and whether and how Dkk3 interferes with Wnt signaling in heart tissues remains unknown. Here, we demonstrate that strong Dkk3 expression was markedly downregulated in adult hearts from WT mice, and Dkk3 expression was upregulated suddenly in hearts from DCM mouse models. Using Dkk3 transgenic and knockout mice, as well as cTnT R141W transgenic mice, which manifests progressive chamber dilation and contractile dysfunction and has pathologic phenotypes similar to human DCM patients, we determined that transgenic expression of Dkk3 increased survival rate, improved cardiac morphology breakage and dysfunction, and ameliorated cardiac pathological changes in the cTnT R141W mice. In contrast, Dkk3 knockout reduced the survival rate and aggravated the pathological phenotypes of the cTnT R141W mice. The protective effects of Dkk3 appeared clearly at 3 months of age, peaked at 6 months of age, and decreased at 10 months of age in the cTnT R141W mice. Furthermore, we determined that Dkk3 upregulated Dvl1 (Dishevelled 1) and key proteins of the canonical Wnt pathway (cytoplasmic and nuclear β-catenin, c-Myc, and Axin2) and downregulated key proteins of the noncanonical Wnt pathway (c-Jun N-terminal kinase (JNK), Ca 2+ /calmodulin-dependent protein kinase II (CAMKII), and histone deacetylase 4 (HDAC4)). In contrast, Dkk3 knockout reversed these changes in the cTnT R141W mice. In summary, Dkk3 could prevent FDCM development in mice, especially in the compensatory stage, and probably through activation of the canonical and inhibition of the noncanonical Wnt pathway, which suggested that Dkk3 could serve as a therapeutic target for the treatment of cardiomyopathy and heart failure.

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Dickkopf3 overexpression inhibits pancreatic cancer cell growthin vitro

Abstract: Our findings, for the first time, implicate Dkk3 as a tumor suppressor in human pancreatic cancer, through the downregulation of β-catenin expression via the ERK-mediated pathway.

Cited by 29 publications

References 43 publications

DKK3 blocked translocation of β‐catenin/EMT induced by hypoxia and improved gemcitabine therapeutic effect in pancreatic cancer Bxpc‐3 cell

DKK3 blocked translocation of β‐catenin/EMT induced by hypoxia and improved gemcitabine therapeutic effect in pancreatic cancer Bxpc‐3 cell

Downregulation of Dickkopf-3 disrupts prostate acinar morphogenesis through TGF-β/Smad signaling

Dkk3 prevents familial dilated cardiomyopathy development through Wnt pathway

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