Dickkopf-3 (DKK-3) obstructs VEGFR-2/Akt/mTOR signaling cascade by interacting of β2-microglobulin (β2M) in ovarian tumorigenesis

Kim, Boh-Ram; Lee, Eun‐Ju; Seo, Seung Hee; Lee, Seung‐Hoon; Rho, Seung Bae

doi:10.1016/j.cellsig.2015.08.008

Cited by 14 publications

(10 citation statements)

References 81 publications

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“…p values were based on the likelihood ratio test Dkk-3 has been demonstrated to be closely involved in the development and progression of cardiovascular disease [8,9]. Several studies showed that Dkk-3 overexpression could suppress endothelial cell growth and angiogenesis [19,20]. High expression of Dkk-3 in human coronary artery plaques could accelerate the atherosclerotic process and promoted plaque accumulation, while reduction of Dkk-3 attenuated the atherosclerotic lesion burden through decreasing the size of atherosclerotic lesions and increasing the stability of plaques [8].…”

Section: Discussionmentioning

confidence: 99%

“…As an antagonist of Wnt/β-catenin pathway [6,7,27], the overexpression of Dkk-3 could accelerate the atherosclerotic process and resulted in detrimental outcomes of atherosclerosis through inhibiting this pathway [8]. The high expression of Dkk-3 also appears to downregulate the level of vascular endothelial growth factor [7,20] and then suppresses endothelial cell growth and angiogenesis [19,20]. On the other hand, besides the adverse effects of Dkk-3 overexpression, it is necessary to maintain a certain level of Dkk-3 in tissues or blood in normal physiological process [10].…”

Section: Discussionmentioning

confidence: 99%

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Serum dickkopf-3 is associated with death and vascular events after ischemic stroke: an observational study from CATIS

Zhu

Guo

Zhong

et al. 2020

J Neuroinflammation

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Background: Dickkopf-3 (Dkk-3) is implicated in the progression of atherosclerosis. This study aimed to investigate the association between serum Dkk-3 and the prognosis of ischemic stroke. Methods: We measured serum Dkk-3 levels in 3344 ischemic stroke patients from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). The primary outcome was a combination of death and vascular events within 3 months after ischemic stroke. Results: During 3 months of follow-up, the cumulative incidence rates of primary outcome among ischemic stroke patients in five quintiles of serum Dkk-3 (from low to high) were 4.49%, 3.74%, 2.54%, 5.23%, and 6.73%, respectively (log-rank p = 0.004). Multivariable Cox proportional hazards regression analyses showed that compared with the third quintile of serum Dkk-3, the adjusted hazard ratios (95% confidence intervals) associated with the first and fifth quintile were 3.49 (1.46-8.34) and 4.23 (1.86-9.64) for primary outcome, 3.47 (1.06-11.36) and 5.30 (1.81-15.51) for death, and 2.66 (1.01-7.01) and 3.35 (1.33-8.40) for vascular events, respectively. Multivariable-adjusted Cox proportional hazards regression model with restricted cubic splines showed a U-shaped association between serum Dkk-3 and the risk of primary outcome (p for nonlinearity = 0.030). Moreover, adding serum Dkk-3 to conventional risk factors could improve the predictive power for primary outcome (net reclassification improvement 28.44%, p < 0.001; integrated discrimination improvement 0.48%, p = 0.001). Conclusions: Both low and high serum Dkk-3 levels are associated with increased risks of death and vascular events within 3 months after ischemic stroke, indicating that serum Dkk-3 may have a special effect on the prognosis of ischemic stroke. We also found that serum Dkk-3 might be a prognostic biomarker for ischemic stroke. Further studies are needed to replicate our findings and to determine the optimal levels of serum Dkk-3.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Serum dickkopf-3 is associated with death and vascular events after ischemic stroke: an observational study from CATIS

Zhu

Guo

Zhong

et al. 2020

J Neuroinflammation

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“…DKK3 upregulation in CRC tissue compared to normal adjacent tissue correlated with increased microvessel formation [108]. DKK3 interaction with β2-microglobulin (β2M) inhibits VEGFR-2/Akt/mTOR signaling activation in ovarian cancer and inhibits angiogenesis [109]. DKK3 also modulates the Wnt/β-catenin signaling pathway and could be a diagnostic and prognostic biomarker in the serum of CRC patients [110].…”

Section: Pro-angiogenic Mirnas In Crcmentioning

confidence: 99%

Angioregulatory microRNAs in Colorectal Cancer

Soheilifar

Grusch

Neghab

et al. 2019

Cancers

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Colorectal cancer (CRC) is one of the leading causes of cancer mortality. Angiogenesis is a rate-determining step in CRC development and metastasis. The balance of angiogenic and antiangiogenic factors is crucial in this process. Angiogenesis-related genes can be regulated post-transcriptionally by microRNAs (miRNAs) and some miRNAs have been shown to shuttle between tumor cells and the tumor microenvironment (TME). MiRNAs have context-dependent actions and can promote or suppress angiogenesis dependent on the type of cancer. On the one hand, miRNAs downregulate anti-angiogenic targets and lead to angiogenesis induction. Tumor suppressor miRNAs, on the other hand, enhance anti-angiogenic response by targeting pro-angiogenic factors. Understanding the interaction between these miRNAs and their target mRNAs will help to unravel molecular mechanisms involved in CRC progression. The aim of this article is to review the current literature on angioregulatory miRNAs in CRC.

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“…DKK3, on the other hand, has been shown to act as a pro-survival signal by positively modulating the Wnt pathway ( Nakamura and Hackam, 2010 ). DKK3 also has been described as a cytokine capable of inducing stem cell differentiation ( Wang et al, 2015 ), as a tumor suppressor ( Veeck and Dahl, 2012 ) and as an inhibitor of VEGFR2/Akt/mTOR signaling ( Kim et al, 2015 ). Recently, DKK3 was found to be a tubular epithelia-derived mediator of kidney fibrosis with decreased tubular atrophy and interstitial matrix accumulation after blockade of DKK3 in different mouse models of kidney fibrosis ( Federico et al, 2016 ).…”

Section: Agonists Of Notch and Wnt Pathways In The Secretomementioning

confidence: 99%

Fibrogenic Secretome of Sirtuin 1-Deficient Endothelial Cells: Wnt, Notch and Glycocalyx Rheostat

et al. 2018

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Sirtuins (SIRT) are ubiquitous histone and protein deacetylases and a member of this family, SIRT1, is the best-studied one. Its functions in endothelial cells encompass branching angiogenesis, activation of endothelial nitric oxide synthase, regulation of proapoptotic and proinflammatory pathways, among others. Defective SIRT1 activity has been described in various cardiovascular, renal diseases and in aging-associated conditions. Therefore, understanding of SIRT1-deficient, endothelial dysfunctional phenotype has much to offer clinically. Here, we summarize recent studies by several investigative teams of the characteristics of models of global endothelial SIRT1 deficiency, the causes of facilitative development of fibrosis in these conditions, dissect the protein composition of the aberrant secretome of SIRT1-deficient endothelial cells and present several components of this aberrant secretome that are involved in fibrogenesis via activation of fibroblasts to myofibroblasts. These include ligands of Wnt and Notch pathways, as well as proteolytic fragments of glycocalyx core protein, syndecan-4. The latter finding is crucial for understanding the degradation of glycocalyx that accompanies SIRT1 deficiency. This spectrum of abnormalities associated with SIRT1 deficiency in endothelial cells is essential for understanding the origins and features of endothelial dysfunction in a host of cardiovascular and renal diseases.

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Dickkopf-3 (DKK-3) obstructs VEGFR-2/Akt/mTOR signaling cascade by interacting of β2-microglobulin (β2M) in ovarian tumorigenesis

Cited by 14 publications

References 81 publications

Serum dickkopf-3 is associated with death and vascular events after ischemic stroke: an observational study from CATIS

Serum dickkopf-3 is associated with death and vascular events after ischemic stroke: an observational study from CATIS

Angioregulatory microRNAs in Colorectal Cancer

Fibrogenic Secretome of Sirtuin 1-Deficient Endothelial Cells: Wnt, Notch and Glycocalyx Rheostat

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