Search

Abstract Several novel urinary kidney damage biomarkers predict the progression of kidney disease. However, the relations of these biomarkers to atherosclerosis, a major consequence of kidney disease, are less studied. Urinary levels of several biomarkers, including kidney injury molecule-1 (KIM-1), osteopontin, epidermal growth factor, and Dickkopf-3, were assessed in participants enrolled in the Swedish CArdioPulmonary BioImage Study. The study included 9,628 individuals with a mean age of 57.5 years, of which 52.4% were women. The presence of coronary artery stenosis and the coronary artery calcium score (CACS) were determined using coronary computed tomography angiography. To analyze the associations between coronary atherosclerosis and urinary biomarker levels, an ordered logistic regression model adusting for confounding factors was employed. KIM-1 was the only biomarker associated with both coronary stenosis and CACS after adjusting for established cardiovascular risk factors (odds ratio [95% confidence intervals], 1.23[1.05–1.44] and 1.25[1.07–1.47]). These results were consistent in sensitivity analyses of individuals without hypertension, diabetes, or known cardiovascular disease and with normal kidney function. Urinary KIM-1, a specific marker of proximal tubular damage, was robustly linked to coronary atherosclerosis even in apparently healthy individuals, which suggests that the detrimental interplay between the kidney and cardiovascular system begins before clinically overt kidney disease. Additional studies are warranted to evaluate the urinary KIM-1 to predict kidney and cardiovascular disease.

Background Patients with chronic heart failure (HF) show an increased risk for the occurrence of chronic kidney disease and cardiorenal syndrome. Urinary Dickkopf‐3 (uDKK3), a stress‐induced, tubular profibrotic glycoprotein, may be elevated in HF as early as in New York Heart Association class I HF and may indicate subsequent decline in estimated glomerular filtration rate (eGFR). Methods and Results uDKK3 levels in patients with HF and controls were measured by enzyme‐linked immunosorbent assay. eGFR was determined up to 5 years in HF. Change in eGFR was assessed with respect to baseline uDKK3 using (mixed‐effect) linear and logistic regression models. A total of 488 patients with chronic HF and 45 control patients were included. Patients with HF showed higher median uDKK3 levels than controls (259.6 pg/mg creatinine [interquartile range (IQR), 119.2–509.4 pg/mg creatinine] versus 107.5 pg/mg creatinine [IQR, 60.5–181.2 pg/mg creatinine], P

Rishabh Singh,1 James C Watchorn,2 Alexander Zarbock,3 Lui G Forni4,5 1Department of Surgery, Royal Surrey Hospital, Guildford, Surrey, UK; 2Intensive Care Unit, Royal Berkshire NHS Foundation Trust, Reading, Berkshire, UK; 3Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany; 4Critical Care Unit, Royal Surrey Hospital, Guildford, Surrey, UK; 5School of Medicine, Kate Granger Building, University of Surrey, Guildford, UKCorrespondence: Lui G Forni, Email luiforni@nhs.netAbstract: Acute kidney injury (AKI) is a common complication after surgery and the more complex the surgery, the greater the risk. During surgery, patients are exposed to a combination of factors all of which are associated with the development of AKI. These include hypotension and hypovolaemia, sepsis, systemic inflammation, the use of nephrotoxic agents, tissue injury, the infusion of blood or blood products, ischaemia, oxidative stress and reperfusion injury. Given the risks of AKI, it would seem logical to conclude that early identification of patients at risk of AKI would translate into benefit. The conventional markers of AKI, namely serum creatinine and urine output are the mainstay of defining chronic kidney disease but are less suited to the acute phase. Such concerns are compounded in surgical patients given they often have significantly reduced mobility, suboptimal levels of nutrition and reduced muscle bulk. Many patients may also have misleadingly low serum creatinine and high urine output due to aggressive fluid resuscitation, particularly in intensive care units. Over the last two decades, considerable information has accrued with regard to the performance of what was termed “novel” biomarkers of AKI, and here, we discuss the most examined molecules and performance in surgical settings. We also discuss the application of biomarkers to guide patients’ postoperative care.Plain Language Summary: Kidney damage is common after major surgery with a recent study showing almost 1 in 5 patients suffer kidney damage. The usual tests for measuring kidney function are excellent in the outpatient but not so good in acute scenario’s. Therefore, there has been a lot of interest in new markers of kidney damage (so-called novel biomarkers) which perform well acutely and allow earlier detection of damage allowing treatment to be started earlier. This article summarises the currently available biomarkers for use post-operatively and points out the different information that can be achieved by using them routinely.Keywords: acute kidney injury, biomarkers, DKK-3, dickkopf-3, suPAR, soluble urokinase plasminogen activator receptor, IGFBP-7, insulin growth factor binding protein-7 and TIMP-2, tissue inhibitor of metalloproteinases-2, PENK, proenkephalin A 119-159, NGAL, neutrophil gelatinase-associated lipocalin, KIM-1, kidney injury molecule-1, CCL14, chemokine 14

Prostate cancer (PCa) is considered one of the most common cancers worldwide. Despite advances in patient diagnosis, management, and risk stratification, 10%–20% of patients progress to castration-resistant disease. Our previous report highlighted a protective role of Dickkopf-3 (DKK3) in PCa stroma. This role was proposed to be mediated through opposing extracellular matrix protein 1 (ECM-1) and TGF-β signalling activity. However, a detailed analysis of the prognostic value of DKK3, ECM-1 and members of the TGF-β signalling pathway in PCa was not thoroughly investigated. In this study, we explored the prognostic value of DKK3, ECM-1 and TGFB1 using a bioinformatical approach through analysis of large publicly available datasets from The Cancer Genome Atlas Program (TGCA) and Pan-Cancer Atlas databases. Our results showed a significant gradual loss of DKK3 expression with PCa progression (p < 0.0001) associated with increased DNA methylation in its promoter region (p < 1.63E-12). In contrast, patients with metastatic lesions showed significantly higher levels of TGFB1 expression compared to primary tumours (p < 0.00001). Our results also showed a marginal association between more advanced tumour stage presented as positive lymph node involvement and low DKK3 mRNA expression (p = 0.082). However, while ECM1 showed no association with tumour stage (p = 0.773), high TGFB1 expression showed a significant association with more advanced stage presented as advanced T3 stage compared to patients with low TGFB1 mRNA expression (p < 0.001). Interestingly, while ECM1 showed no significant association with patient outcome, patients with high DKK3 mRNA expression showed a significant association with favourable outcomes presented as prolonged disease-specific (p = 0.0266), progression-free survival (p = 0.047) and disease-free (p = 0.05). In contrast, high TGFB1 mRNA expression showed a significant association with poor patient outcomes presented as shortened progression-free (p = 0.00032) and disease-free survival (p = 0.0433). Moreover, DKK3, TGFB1 and ECM1 have acted as immune-associated genes in the PCa tumour microenvironment. In conclusion, our findings showed a distinct prognostic value for this three-gene signature in PCa. While both DKK3 and TGFB1 showed a potential role as a clinical marker for PCa stratification, ECM1 showed no significant association with the majority of clinicopathological parameters, which reduce its clinical significance as a reliable prognostic marker.

Abstract Purpose We previously reported that expression of dickkopf-3 (DKK3), which is involved in the Wnt/β-catenin pathway, is significantly associated with prognosis in patients with glioblastoma multiforme (GBM). The aim of this study was to compare the association of DKK3 with other Wnt/β-catenin pathway-related genes and immune responses between lower grade glioma (LGG) and GBM. Methods We obtained the clinicopathological data of 515 patients with LGG (World Health Organization [WHO] grade II and III glioma) and 525 patients with GBM from the Cancer Genome Atlas (TCGA) database. We performed Pearson’s correlation analysis to investigate the relationships between Wnt/β-catenin-related gene expression in LGG and GBM. Linear regression analysis was performed to identify the association between DKK3 expression and immune cell fractions in all grade II to IV gliomas. Results A total of 1,040 patients with WHO grade II to IV gliomas were included in the study. As the grade of glioma increased, DKK3 showed a tendency to be more strongly positively correlated with the expression of other Wnt/β-catenin pathway-related genes. DKK3 was not associated with immunosuppression in LGG but was associated with downregulation of immune responses in GBM. We hypothesized that the role of DKK3 in the Wnt/β-catenin pathway might be different between LGG and GBM. Conclusion According to our findings, DKK3 expression had a weak effect on LGG but a significant effect on immunosuppression and poor prognosis in GBM. Therefore, DKK3 expression seems to play different roles, through the Wnt/β-catenin pathway, between LGG and GBM.

Purpose: We previously reported that expression of dickkopf-3 (DKK3), which is involved in the Wnt/β-catenin pathway, is significantly associated with prognosis in patients with glioblastoma multiforme (GBM). The aim of this study was to compare the association of DKK3 with other Wnt/β-catenin pathway-related genes and immune responses between lower grade glioma (LGG) and GBM. Methods: We obtained the clinicopathological data of 515 patients with LGG (World Health Organization [WHO] grade II and III glioma) and 525 patients with GBM from the Cancer Genome Atlas (TCGA) database. We performed Pearson's correlation analysis to investigate the relationships between Wnt/β-catenin-related gene expression in LGG and GBM. Linear regression analysis was performed to identify the association between DKK3 expression and immune cell fractions in all grade II to IV gliomas. Results: A total of 1,040 patients with WHO grade II to IV gliomas were included in the study. As the grade of glioma increased, DKK3 showed a tendency to be more strongly positively correlated with the expression of other Wnt/β-catenin pathway-related genes. DKK3 was not associated with immunosuppression in LGG but was associated with downregulation of immune responses in GBM. We hypothesized that the role of DKK3 in the Wnt/β-catenin pathway might be different between LGG and GBM. Conclusion: According to our findings, DKK3 expression had a weak effect on LGG but a significant effect on immunosuppression and poor prognosis in GBM. Therefore, DKK3 expression seems to play different roles, through the Wnt/β-catenin pathway, between LGG and GBM. [ABSTRACT FROM AUTHOR]

Patients with resistant hypertension (HTN) demonstrate an increased risk of chronic kidney disease and progression to end-stage renal disease; however, the individual course of progression is hard to predict. Assessing the stress-induced, urinary glycoprotein Dickkopf-3 (uDKK3) may indicate ongoing renal damage and consecutive estimated glomerular filtration rate (eGFR) decline. The present study aimed to determine the association between uDKK3 levels and further eGFR changes in patients with resistant HTN. In total, 31 patients with resistant HTN were included. Blood pressure and renal function were measured at baseline and up to 24 months after (at months 12 and 24). uDKK3 levels were determined exclusively from the first available spot urine sample at baseline or up to a period of 6 months after, using a commercial ELISA kit. Distinctions between different patient groups were analyzed using the unpaired t-test or Mann–Whitney test. Correlation analysis was performed using Spearman's correlation. The median uDKK3 level was 303 (interquartile range (IQR) 150–865) pg/mg creatinine. Patients were divided into those with high and low eGFR loss (≥3 vs. <3 mL/min/1.73 m²/year). Patients with high eGFR loss showed a significantly higher median baseline uDKK3 level (646 (IQR 249–2555) (n = 13) vs. 180 (IQR 123–365) pg/mg creatinine (n = 18), p = 0.0412 (Mann–Whitney U)). Alternatively, patients could be classified into those with high and low uDKK3 levels (≥400 vs. <400 pg/mg creatinine). Patients with high uDKK3 levels showed significantly higher eGFR loss (−6.4 ± 4.7 (n = 11) vs. 0.0 ± 7.6 mL/min/1.73 m2/year (n = 20), p = 0.0172 (2-sided, independent t-test)). Within the entire cohort, there was a significant correlation between the uDKK3 levels and change in eGFR at the latest follow-up (Spearman's r = −0.3714, p = 0.0397). In patients with resistant HTN, high levels of uDKK3 are associated with higher eGFR loss up to 24 months later. [ABSTRACT FROM AUTHOR]

• TH reduce myocardial infarction size, myocardial injury, inflammatory response. • TH inhibite DKK3/Wnt/β-catenin pathway. • TH alleviate myocardial I/R injury. The impact and mechanisms of therapeutic hypothermia (TH) on myocardial ischemia–reperfusion (I/R) injury are still unknown. Sprague-Dawley (SD) rat model and primary cardiomyocytes were applied in our study. TTC staining evaluated myocardial infarction, while H&E staining assessed myocardial injury. ELISA quantified lactate dehydrogenase (LDH), IL-1β, IL-6, and TNF-α. Blood serum concentrations of CK, CK-MB, and cTnT were detected using a biochemical assay. TUNEL assay, flow cytometry and western blot were used to detect cell apoptosis. EdU assay was applied to examine cell proliferation. The expression of DKK3 and β-catenin protein was analyzed using Realtime PCR and Western blot. TH alleviated myocardial infarction size and injury in rat models of I/R, and reduced serum levels of myocardial injury markers and inflammatory factors in animal and cell models. In addition, TH inhibited the increased apoptosis and β-catenin expression as well as decreased DKK3 expression caused by I/R in I/R cell models, while si-DKK3 reversed the changes brought by TH, and XAV939 inhibited the effects of si-DKK3. TH may reduce myocardial infarction size, myocardial injury, inflammatory response and apoptosis through DKK3/Wnt/β-catenin pathway, thereby alleviating myocardial I/R injury. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma multiforme (GBM) is an aggressive malignant primary brain tumor. Wnt/β-catenin is known to be related to GBM stemness. Cancer stem cells induce immunosuppressive and treatment resistance in GBM. We hypothesized that Wnt/β-catenin-related genes with immunosuppression could be related to the prognosis in patients with GBM. Methods: We obtained the clinicopathological data of 525 patients with GBM from the brain cancer gene database. The fraction of tumor-infiltrating immune cells was evaluated using in silico flow cytometry. Among gene sets of Wnt/β-catenin pathway, Dickkopf-3 (DKK3) gene related to the immunosuppressive response was found using machine learning. We performed gene set enrichment analysis (GSEA), network-based analysis, survival analysis and in vitro drug screening assays based on Dickkopf-3 (DKK3) expression. Results: In analyses of 31 genes related to Wnt/β-catenin signaling, high DKK3 expression was negatively correlated with increased antitumoral immunity, especially CD8 + and CD4 + T cells, in patients with GBM. High DKK3 expression was correlated with poor survival and disease progression in patients with GBM. In pathway-based network analysis, DKK3 was directly linked to the THY1 gene, a tumor suppressor gene. Through in vitro drug screening, we identified navitoclax as an agent with potent activity against GBM cell lines with high DKK3 expression. Conclusions: These results suggest that high DKK3 expression could be a therapeutic target in GBM. The results of the present study could contribute to the design of future experimental research and drug development programs for GBM. [ABSTRACT FROM AUTHOR]

Background: Patients with chronic heart failure (HF) show an increased risk for the occurrence of chronic kidney disease and cardiorenal syndrome. Urinary Dickkopf-3 (uDKK3), a stress-induced, tubular profibrotic glycoprotein, may be elevated in HF as early as in New York Heart Association class I HF and may indicate subsequent decline in estimated glomerular filtration rate (eGFR)., Methods and Results: uDKK3 levels in patients with HF and controls were measured by enzyme-linked immunosorbent assay. eGFR was determined up to 5 years in HF. Change in eGFR was assessed with respect to baseline uDKK3 using (mixed-effect) linear and logistic regression models. A total of 488 patients with chronic HF and 45 control patients were included. Patients with HF showed higher median uDKK3 levels than controls (259.6 pg/mg creatinine [interquartile range (IQR), 119.2-509.4 pg/mg creatinine] versus 107.5 pg/mg creatinine [IQR, 60.5-181.2 pg/mg creatinine], P <0.001). Regression models demonstrated a significant association between log uDKK3 and the decline in eGFR during a median of 13 months (IQR, 12-59 months) (estimated higher eGFR loss, 0.8039 mL/min per 1.73 m 2 /year [95% CI, 0.002-1.606 mL/min per 1.73 m 2 /year], P =0.049; odds ratio, 1.345 [95% CI, 1.049-1.741], P =0.021). uDKK3 levels ≥354 pg/mg creatinine were associated with a significantly higher risk for eGFR decline at 1-year follow-up (estimated higher eGFR loss, 4.538 mL/min per 1.73 m 2 [95% CI, 1.482-9.593 mL/min per 1.73 m 2 ]), P =0.004). Even patients with HF without chronic kidney disease (n=334) had higher uDKK3 levels compared with controls (233.4 [IQR, 109.0-436.9 pg/mg creatinine] versus 107.5 [IQR, 60.5-181.2 pg/mg creatinine], P <0.001)., Conclusions: The present findings indicate that uDKK3 is a promising prognostic biomarker for subsequent eGFR decline in patients with HF, irrespective of the presence of chronic kidney disease and even in the early stages of HF. This potential allows for early intervention to mitigate the deterioration of kidney function. Further investigation is warranted to validate its clinical utility.

Introduction: Urinary dickkopf-3 (DKK3), which is a kidney tubular stress marker has been suggested recently for preoperative identification of patients at risk of acute kidney injury. We aimed to assess the predictive role of urinary DKK3/creatinine (Cr) ratio in contrast-induced nephropathy (CIN) in patients undergoing percutaneous coronary intervention (PCI). Methods: This prospective observational study included patients undergoing elective PCI. The association between the ratio of precontrast urinary concentrations of DKK3/Cr and post contrast CIN was evaluated. The serum Cr, urinary DKK3 and Cr levels of the patients were measured before and after contrast media administration, and the sensitivity of urinary DKK3/Cr ratio in diagnosing CIN in the early stage was assessed by the area under receiver operating characteristic curve. Results: A total of 44 patients (33 males) undergoing PCI were enrolled and mean age of the patients was 61.5 ± 10.0 years. 22.7% of the patients developed CIN, none of them received hemodialysis during hospitalization. The mean urinary DKK3/Cr ratio was 950 ± 491 pg/mg in the CIN patients versus 386 ± 272 pg/mg in the non-CIN patients before contrast media administration (p=0.001). The mean urinary DKK3/Cr ratio was 1266 ± 738 pg/mg in the CIN patients versus 305 ± 192 pg/mg in the non- CIN patients at 12th hour after contrast media infusion (p<0.001). The roc-curve for the urinary DKK3/Cr ratio before contrast administration (AUC=0.835, p=0.001). Conclusions: Pre-contrast urinary DKK3/Cr ratio is a predictor for CIN. Urinary DKK3/Cr ratio may help in the identification of patients who are at risk of CIN. [ABSTRACT FROM AUTHOR]

Abstract 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.

Cervical cancer is a common gynecological malignant tumor with high morbidity and mortality. DKK3 (dickkopf-3) is an antagonist of the classic Wnt signaling pathway and a tumor suppressor gene discovered in recent years. DKK3 exerts its anti-tumor function by regulating β-catenin signal transduction pathway, reversing epithelial-mesenchymal transition, inhibiting tumor angiogenesis and other pathways. It is a potential target in tumor therapy. Epigenetic modification of genes, especially promoter methylation, plays a very important role in the occurrence and development of a variety of malignant tumors. Hypermethylation in the promoter region of DKK3 gene is an important reason for the inactivation of DKK3 protein, which makes the Wnt signaling pathway abnormally activated, leading to the occurrence of tumors. The expression of DKK3 is often down-regulated in cervical cancer tissues, and the silencing of DKK3 expression caused by the methylation of the gene promoter is a frequent event in cervical cancer. The methylation level and expression level of DKK3 are significantly correlated to the prognosis of patients with cervical cancer, and it has a good predictive effect. Therefore, in -depth study on the relationship between DKK3 and cervical cancer may provide new ideas for the mechanism research, targeted therapy and prognosis judgment of cervical cancer. [ABSTRACT FROM AUTHOR]

Cervical cancer is one of the malignant tumors in women, and the pathogenesis and related pathway molecules have been studied more and more deeply. Among them, the research on Wnt/β-catenin signaling pathway has attracted great attention. The Wnt/β-catenin signaling pathway involves a wide range of physiological and pathological processes, including cell growth, differentiation, ontogeny, migration, genetic stability, apoptosis, stem cell self-renewal, and maintenance of adult tissue homeostasis. Stable β-catenin is accumulated in the cytoplasm and transferred to the nucleus, which activates the Wnt/ β-catenin signaling pathway and is one of the inducing factors of multiple cancers. The accumulation of β-catenin occupies a core position in the Wnt/β-catenin signaling pathway. β-catenin drives target genes through Wnt/β-catenin signaling pathway and participates in the multi -step occurrence and development of cervical cancer. DKK3 may inhibit the Wnt/β -catenin signaling pathway by degrading β-catenin, blocking the nuclear transport of β-catenin, and thus become a potential key role in the inhibition of cervical cancer. Therefore, it is particularly important to study the relationship between DKK3, Wnt/β-catenin signaling pathway and cervical cancer. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a global public health problem accompanied by substantial comorbidities and reduced life expectancy. In this respect, progressive CKD leading to uraemia can be seen as a systemic disease with a critical impact on virtually all organ systems. Therefore, it is of particular importance to identify patients with ongoing CKD progression, which is challenging, because the individual course of CKD is difficult to predict. Patterns of progression in CKD patients include linear and non-linear trajectories of GFR loss, but kidney function can also remain stable for years. Moreover, a substantial GFR decline may occur in the absence of higher-grade albuminuria (non-proteinuric CKD), rendering the measurement of albuminuria less reliable for progression prediction in such individuals. In the present review, we focus on the recently identified glycoprotein Dickkopf-3 (DKK3) as a stress-induced, renal tubular epithelial cell-derived, pro-fibrotic molecule. In experimental CKD models, DKK3 promoted renal tubulointerstitial fibrosis through modulation of the canonical Wnt/β-catenin signalling pathway. In clinical studies, increased urinary DKK3 levels identified patients at high risk for short-term CKD progression, regardless of the cause of kidney disease, baseline kidney function and albuminuria. Moreover, increased urinary DKK3 levels are associated with a high risk for acute kidney injury and the subsequent loss of kidney function after cardiac surgery. These findings highlight DKK3 as a mediator of renal tubular cell damage in kidney injury and short-term progression of kidney disease, with potential therapeutic implications. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is considered one of the most common cancers worldwide. Despite advances in patient diagnosis, management, and risk stratification, 10%-20% of patients progress to castration-resistant disease. Our previous report highlighted a protective role of Dickkopf-3 (DKK3) in PCa stroma. This role was proposed to be mediated through opposing extracellular matrix protein 1 (ECM-1) and TGF-β signalling activity. However, a detailed analysis of the prognostic value of DKK3, ECM-1 and members of the TGF-β signalling pathway in PCa was not thoroughly investigated. In this study, we explored the prognostic value of DKK3, ECM-1 and TGFB1 using a bioinformatical approach through analysis of large publicly available datasets from The Cancer Genome Atlas Program (TGCA) and Pan-Cancer Atlas databases. Our results showed a significant gradual loss of DKK3 expression with PCa progression ( p < 0.0001) associated with increased DNA methylation in its promoter region ( p < 1.63E-12). In contrast, patients with metastatic lesions showed significantly higher levels of TGFB1 expression compared to primary tumours ( p < 0.00001). Our results also showed a marginal association between more advanced tumour stage presented as positive lymph node involvement and low DKK3 mRNA expression ( p = 0.082). However, while ECM1 showed no association with tumour stage ( p = 0.773), high TGFB1 expression showed a significant association with more advanced stage presented as advanced T3 stage compared to patients with low TGFB1 mRNA expression ( p < 0.001). Interestingly, while ECM1 showed no significant association with patient outcome, patients with high DKK3 mRNA expression showed a significant association with favourable outcomes presented as prolonged disease-specific ( p = 0.0266), progression-free survival ( p = 0.047) and disease-free ( p = 0.05). In contrast, high TGFB1 mRNA expression showed a significant association with poor patient outcomes presented as shortened progression-free ( p = 0.00032) and disease-free survival ( p = 0.0433). Moreover, DKK3, TGFB1 and ECM1 have acted as immune-associated genes in the PCa tumour microenvironment. In conclusion, our findings showed a distinct prognostic value for this three-gene signature in PCa. While both DKK3 and TGFB1 showed a potential role as a clinical marker for PCa stratification, ECM1 showed no significant association with the majority of clinicopathological parameters, which reduce its clinical significance as a reliable prognostic marker., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Al Shareef, Hachim, Bouzid, Talaat, Al-Rawi, Hamoudi and Hachim.)

Objective: To explore the value of serum Dickkopf-3 (sDKK3) in predicting Early Neurological Deterioration (END) and in-hospital adverse outcomes in acute ischemic stroke (AIS) patients., Methods: AIS patients (n = 200) were included and assessed by the National Institutes of Health Stroke Rating Scale. Serum Dkk3 levels were assessed by ELISA. END was defined as an increase of ≥ 4 points in NIHSS score within 72h. The biological threshold of sDKK3 level and END occurrence were predicted based on X-tile software. Primary outcomes were END and all-cause death, and the secondary outcome was ICU admission during hospitalization. The logistic regression model and Cox risk regression model were applied to evaluate the relationship between DKK3 level and END incidence, all-cause in-hospital mortality, and in-hospital adverse outcomes (ICU admission)., Results: During hospitalization, the incidence of END in patients with AIS was 13.0 %, and the mortality rate within 7 days after END was 11.54 % (3/26). In patients below the serum DKK3 cutoff (93.0 pg/mL), the incidence of END was 43.5 % (20/48). Patients with lower sDKK3 levels were associated with a 1.188-fold increased risk of developing END (OR = 1.188, 95 % CI 1.055‒1.369, p < 0.0001). However, there was no significant association with admission to the ICU. sDKK3 below the threshold (93.0 pg/mL) was a risk factor for death., Conclusion: Predictive threshold levels of serum DKK3 based on X-tile software may be a potential predictive biomarker of in-hospital END in patients with AIS, and low levels of DKK3 are independently associated with increased in-hospital mortality., Competing Interests: Declaration of competing interest The authors declare conflicts of interest., (Copyright © 2024. Published by Elsevier España, S.L.U.)

Cisplatin is widely employed in combating renal cancers. However, a major challenge is the resistance of cisplatin by renal cancer cells. Increased miR-222 expression is known to promote this resistance and so ways of downregulating the expression of miR-222 is widely sought after as a means of combating the resistance. The study was performed to explore the effects of miR-222 on cisplatin resistance of renal cancer cell strains and related mechanisms. The expression of miR-222 and Dickkopf-3 (DKK3) was regulated to explore the effects of miR-222 and DKK3 on cisplatin chemotherapy in renal cancer cisplatin-resistant cell strains, and to figure out the regulatory relationship between miR-222 and DKK3. In renal cancer tissues and cell lines, miR-222 was highly expressed and DKK3 was lowly expressed. Renal cancer cisplatin-resistant cells had markedly higher miR-222 expression and lower DKK3 expression than normal renal cancer cells, suggesting a potential involvement of miR-222 and DKK3 in the cisplatin resistance in renal cancer cells. Down-regulated miR-222 expression led to stronger inhibition of the renal cancer cell growth by cisplatin and markedly higher DKK3 expression. Dual-luciferase reporter assay results showed that miR-222 had a targeted inhibition on DKK3. Co-transfection of miR-222 mimic and shDKK3, together with the up-regulation of miR-222 and DKK3 expressions, resulted in a higher sensitivity of renal cancer cells to cisplatin chemotherapy than the up-regulation of miR-222 expression alone. Down-regulated miR-222 expression can remove the inhibition of DKK3 expression and increase the sensitivity of renal cancer cells to cisplatin chemotherapy. [ABSTRACT FROM AUTHOR]

In chronic kidney disease (CKD), kidneys develop injured over time and don’t work properly as in the kidneys for healthy people. At what time the kidneys cannot blood clean, further liquids stay and wastes in the body and which leads to many problems in health, such as high blood pressure (BP) and cardiovascular disease (CVD). In current study, we attempt to examine the association of asprosin (APN) and dickkopf-3 (DKK-3) with kidney injury molecule-1 (KIM-1), N-terminal pro-brain natriuretic peptide (NTpro-BNP), growth differentiation factor 15 (GDF- 15) and copeptin (CPP) among male Iraqi with CKD. Methods: serum APN, DKK-3, KIM-1, NTpro-BNP, GDF-15 and CPP were determined by ELISA technique in 40 healthy controls (HCs) and 44 male patients with CKD, from the Al-Fallujah teaching hospital were recorded in this paper, serum concentrations of urea, creatinine and estimated glomerular filtration rate (eGFR) were measured by colorimetric methods Results: serum APN and DKK-3 were importantly greater in CKD males than in HCs (P<0.0001) and they positively associated with KIM- 1, NTpro-BNP, GDF-15 and CPP (P<0.01), also serum concentration of ANP was positively associated DKK-3 (P<01). Studied variables presented the following descending order of area under the receiver operating characteristic (AUROC) curve urea, creatinine and e GFR (1for all, P<0.0001), KIM-1(0.9896), APN (0.939), CPP (0.8966), DKK-3 (0.893), NTpro-BNP (0.8558) and GDF-15 (0.8375) respectively (P<0.0001for all). Conclusion: serum levels APN, DKK3 KIM-1, NTpro-BNP, GDF-15 and CPP may be a biomarker of renal damage in CKD development in Iraqi males. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Objectives: Urinary levels of dickkopf-3 (DKK-3) are associated with poor renal survival in patients with non-dialytic chronic kidney disease. However, it remains unknown whether urinary DKK-3 levels can predict residual renal function (RRF) decline in patients undergoing peritoneal dialysis (PD). Therefore, we investigated the correlation between urinary levels of DKK-3 and the subsequent rate of RRF decline in PD patients. Materials and Methods: This study included 36 PD patients who underwent multiple peritoneal equivalent tests during 2011–2021. The relationship between baseline clinical characteristics and the subsequent annual rate of Kt/V decline was investigated. Results: The annual rate of renal Kt/V decline was 0.29 (range: 0.05–0.48), which correlated with renal Kt/V (r = 0.55, p = 0.0005) and 24 h urinary DKK-3 excretion (r = 0.61, p < 0.0001). Similarly, 24 h urinary DKK-3 excretion (β = 0.44, p = 0.0015) and renal Kt/V (β = 0.38, p = 0.0059) were independently associated with the annual rate of renal Kt/V decline in multivariate analyses. Conclusions: Urinary DKK-3 assessment may help identify PD patients at a high risk of RRF decline.

The Wnt/β-catenin signaling pathway is one of the highly conserved signaling pathway widely reported to play essential roles in the development of various tumors and human cancers, thus serving as a potential target for anticancer therapy. However, the specific effects of the related proteins in the Wnt/β-catenin signaling pathway in nasopharyngeal carcinoma (NPC) still remain elusive. Thus, this study was performed to uncover the correlation between the Wnt/β-catenin signaling pathway-related proteins and the clinical characteristics and prognosis of NPC. NPC tissues were revealed to present high expression of β-catenin and v-myc myelocytomatosis viral oncogene homolog (c-MYC) but low expression of Dickkopf-3 (DKK-3). Immunohistochemical staining revealed that DKK-3 was positively linked to but β-catenin and c-MYC were negatively linked to differentiation, tumor-node-metastasis (TNM) stage and lymph node metastasis of patients with NPC. In addition, c-MYC was identified to be positively correlated to DKK-3 in NPC tissues. The positive expression of β-catenin and c-MYC had negative relations with and that of DKK-3 had positive relations with survival rate of patients with NPC, which was analyzed by Kaplan-Meier method. Moreover, it was shown that later TNM stage and positive expression of β-catenin were risk factors for NPC-related death. These findings provide evidence that the proteins related to the Wnt/β-catenin signaling pathway (DKK-3, β-catenin, and c-MYC) participate in the development of NPC and positive expression of DKK-3 and negative expression of β-catenin, and c-MYC can serve as essential prognostic biomarkers, shedding new light on the prognosis and treatment of NPC. [ABSTRACT FROM AUTHOR]

[Display omitted] [ABSTRACT FROM AUTHOR]

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.

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. [ABSTRACT FROM AUTHOR]

BackgroundDickkopf‐3 (DKK3) is a negative regulator of the Wnt/β‐catenin signaling pathway, which is involved in inflammation. However, little is known about the relationship between DKK3 expression and the progression of atherosclerosis. The aim of the present study was to define the role of DKK3 and its potential mechanism in the development of atherosclerosis. Methods and ResultsImmunofluorescence analysis showed that DKK3 was strongly expressed in macrophages of atherosclerotic plaques from patients with coronary heart disease and in hyperlipidemic mice. The expression level was significantly increased in atherogenesis. DKK3−/−ApoE−/− mice exhibited a significant decrease in atherosclerotic lesions in the entire aorta, aortic sinus, and brachiocephalic arteries. Transplantation of bone marrow from DKK3−/−ApoE−/− mice into lethally irradiated ApoE−/− recipients resulted in a reduction of atherosclerotic lesions, compared with the lesions in recipients transplanted with ApoE−/− donor cells, suggesting that the effect of DKK3 deficiency was largely mediated by bone marrow–derived cells. A reduction in the necrotic core size, accompanied by increased collagen content and smooth muscle cells and decreased accumulation of macrophages and lipids, contributed to the stability of plaques in DKK3−/−ApoE−/− mice. Furthermore, multiple proinflammatory cytokines exhibited marked decreases in DKK3−/−ApoE−/− mice. Finally, we observed that DKK3 ablation increased β‐catenin expression in the nuclei of macrophages both in vivo and in vitro. ConclusionsDKK3 expression in macrophages is involved in the pathogenesis of atherosclerosis through modulation of inflammation and inactivation of the Wnt/β‐catenin pathway.

Background and Aim Reduced expression in immortalized cells (REIC)/dickkopf-3 (Dkk-3) is a tumor suppressor gene that is downregulated in various cancers. In our previous study of prostate cancer, the REIC/Dkk-3-expressing adenoviral vector (Ad-REIC) was found to induce cancer-selective apoptosis. This study recently developed a novel super gene expression (SGE) system and used this system to re-construct an Ad-REIC vector, termed the Ad-SGE-REIC, to achieve more effective therapeutic outcomes. In this study, the therapeutic effects of Ad-SGE-REIC on hepatocellular carcinoma (HCC) was assessed. Methods Human HCC cell lines (HLE, Huh7, HepG2, HLF, SK-Hep1, and PLC), human HCC tissues, and mouse HCC cell line (Hepa1-6) were used in this study. REIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry. The relative cell viability and the apoptotic effect were examined in vitro, and the anti-tumor effects of Ad-SGE-REIC treatment were analyzed in the mouse xenograft model. This study additionally assessed anti-tumor immunological effects on the immunocompetent mice. Results REIC/Dkk-3 expression was decreased in HCC cell lines and HCC tissues. Ad-SGE-REIC reduced cell viability and induced apoptosis in HCC cell lines (HLE and Huh7), inhibited tumor growth in the mouse xenograft model, and demonstrated in vivo anti-cancer immunostimulatory effects on the HCC cell line (Hepa1-6). Conclusions Ad-SGE-REIC treatment not only enhanced cell killing effects in vitro but also elicited significant therapeutic effects, with tumor growth suppression, in vivo. REIC/Dkk-3 gene therapy using Ad-SGE-REIC potentially represents an innovative new therapeutic tool for HCC. [ABSTRACT FROM AUTHOR]

Dkk-3 is a member of the dickkopf protein family of secreted inhibitors of the Wnt pathway, which has been shown to enhance angiogenesis. The mechanism underlying this effect is currently unknown. Here, we used cultured HUVECs to study the involvement of the TGF-b and VEGF on the angiogenic effect of Dkk-3. Addition of hrDkk-3 peptide (1 or 10 ng/ml) to HUVECs for 6 or 12 h enhanced the intracellular and extracellular VEGF protein levels, as assessed by RTPCR, immunoblotting, immunocytochemistry and ELISA. The increase in the extracellular VEGF levels was associated to the VEGFR2 activation. Pharmacological blockade of VEGFR2 abrogated Dkk-3-induced endothelial cell tubes formation, indicating that VEGF is a molecular player of the angiogenic effects of Dkk-3. Moreover, Dkk-3 enhanced Smad1/5/8 phosphorylation and recruited Smad4 to the VEGF gene promoter, suggesting that Dkk-3 activated ALK1 receptor leading to a transcriptional activation of VEGF. This mechanism was instrumental to the increased VEGF expression and endothelial cell tubes formation mediated by Dkk-3, because both effects were abolished by siRNA-mediated ALK1 knockdown. In summary, we have found that Dkk-3 activates ALK1 to stimulate VEGF production and induce angiogenesis in HUVECs. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are known to limit immune responses in vivo by multiple soluble factors. Dickkopf-3 (DKK3), a secreted glycoprotein, has recently been identified as a novel immune modulator. Since DKK3 has been reported to be produced by MSCs we investigated whether DKK3 contributes to the immune suppression of anti-tumor responses by MSCs. Whereas wild-type MSCs inhibited immune responses against two different transplantation tumors, DKK3-deficient MSCs did not affect the rejection process. Increased CD8+ T cell and reduced M2-type macrophages infiltration was observed in tumors inoculated together with DKK3-deficient MSCs. Thus, DKK3 could alter the composition of the tumor stroma, thereby supporting the MSCs-mediated suppression of immune responses against these tumor transplants.

The adaptive immune system protects organisms from harmful environmental insults. In parallel, regulatory mechanisms control immune responses in order to assure preservation of organ integrity. Yet, molecules involved in the control of T cell responses in peripheral tissues are poorly characterized. Here, we investigated the function of Dickkopf-3 in the modulation of local T cell reactivity. Dkk3 is a secreted, mainly tissue derived protein with highest expression in organs considered as immune privileged such as the eye, embryo, placenta and brain. While T cell development and activation status in naïve Dkk3 deficient mice was comparable to littermate controls, we found that Dkk3 contributes to the immunosuppressive microenvironment that protects transplanted, class-I mismatched embryoid bodies from T cell mediated rejection. Moreover, genetic deletion or antibody mediated neutralization of Dkk3 led to an exacerbated experimental autoimmune encephalomyelitis (EAE). This phenotype was accompanied by a change of T cell polarization displayed by an increase of IFNγ producing T cells within in the CNS. In the wild type situation, Dkk3 expression in the brain was up-regulated during the course of EAE in an IFNγ dependent manner. In turn, Dkk3 decreased IFNγ activity and served as part of a negative feedback mechanism. Thus, our findings suggest that Dkk3 functions as a tissue-derived modulator of local CD4+ and CD8+ T cell responses.

Dickkopf-related protein 3 (Dkk-3) is a potential tumor suppressor reported in various cancer entities. However, we found that Dkk-3 was exceptionally upregulated in bladder cancer T24 cells. To validate the biological role of Dkk-3 other than a tumor suppressor, we examined the function of Dkk-3 in T24 cells. Gene silencing of Dkk-3 inhibited cell growth through inducing G0/G1 cell-cycle arrest. Furthermore, Dkk-3 knock-down caused macropinocytosis accompanied by autophagy, which were canceled in part by their inhibitors 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and 3-methyladenine (3-MA). The macropinocytosis was induced by the Dkk-3 knock-down when there were sufficient extracellular nutrients. On the other hand, when the nutritional condition was poor, the autophagy was mainly induced by the Dkk-3 knock-down. These data indicated that Dkk-3 has a role in modulating macropinocytotic and autophagic pathways, a distinct function other than a Wnt antagonist. [ABSTRACT FROM AUTHOR]

Background & Aims Dickkopf-3 (DKK3), a protein belonging to the DKK family, has been extensively investigated in the context of cancer, including liver cancer. However, the role of DKK3 in hepatic steatosis and related metabolic disorders remains largely unexplored. Methods We detected the expression of DKK3 in the fatty livers of NAFLD patients and of obese mice and investigated the function of DKK3 in hepatic steatosis and related metabolic disorders by using hepatocyte-specific DKK3 deficiency or overexpression obese mice induced by high fat diet (HFD) or genetic defect ( ob/ob ). The molecular mechanisms underlying DKK3-regulated hepatic steatosis were further explored and verified in mice. Results DKK3 expression was significantly decreased in the livers of NAFLD patients and of obese mice as well as in cultured hepatocytes stimulated with palmitate. Further investigation indicated that specific overexpression of DKK3 in hepatocytes enhanced insulin sensitivity and glucose tolerance, reduced the inflammatory response, and ameliorated the imbalance of lipid metabolism in response to HFD or genetic defects. In contrast, DKK3 deficiency in hepatocytes led to an almost complete reversal of these pathologies. Mechanistically, DKK3 combined with Apoptosis signal-regulating kinase 1 (ASK1) under palmitate stimulation, and thus inhibited the activation of the downstream P38/JNK pathway. Importantly, dominant-negative ASK1 blocked the accelerated effects of DKK3 deficiency, while the constitutively active form of ASK1 overcame the inhibitory effects of DKK3 overexpression on HFD-induced metabolic disorders in vivo . Conclusion DKK3 functions as a negative regulator of insulin resistance, hepatic steatosis, and associated inflammatory responses, which depends on its inhibitory regulation of ASK1 activity. Lay summary DKK3 expression is decreased in the non-alcoholic fatty liver of humans and mice. Adding DKK3 expression alleviates fatty liver in mice by inhibiting ASK1 activity. [ABSTRACT FROM AUTHOR]

To explore how uterine innervations affect expression of Dickkopf-3 (DKK-3) during peri-implantation, we first examined the consequence of uterine neurectomy on embryo implantation events. We observed that amputation of autonomic nerves innervating the uterus led to the failure of on-time implantation in rats. We then analyzed the effect of neurectomy on expression of DKK-3 further using immunohistochemistry and quantitative real-time reverse transcription polymerase chain reaction. We observed that disconnection of autonomic nerve innervation significantly increased DKK-3 expression in the endometrium before and during invasion of the blastocyst. We also observed high levels of DKK-3 immunoreactivity in the vasculature of the uterus during peri-implantation. Thus, we speculate that DKK-3 may relate to implantation. Besides, our findings provide a new line of evidence that DKK-3 may be regulated by the autonomic nervous system. [ABSTRACT FROM AUTHOR]

The adaptive immune system protects organisms from harmful environmental insults. In parallel, regulatory mechanisms control immune responses in order to assure preservation of organ integrity. Yet, molecules involved in the control of T-cell responses in peripheral tissues are poorly characterized. Here, we investigated the function of Dickkopf-3 in the modulation of local T-cell reactivity. Dkk3 is a secreted, mainly tissue-derived protein with highest expression in organs considered as immune-privileged such as the eye, embryo, placenta, and brain. While T-cell development and activation status in naïve Dkk3-deficient micewas comparable to littermate controls,we found that Dkk3 contributes to the immunosuppressive microenvironment that protects transplanted, class-I mismatched embryoid bodies from T-cell-mediated rejection. Moreover, genetic deletion or antibody-mediated neutralization of Dkk3 led to an exacerbated experimental autoimmune encephalomyelitis (EAE). This phenotype was accompanied by a change of T-cell polarization displayed by an increase of IFNγ-producing T cells within the central nervous system. In the wildtype situation, Dkk3 expression in the brain was up-regulated during the course of EAE in an IFNγ-dependent manner. In turn, Dkk3 decreased IFNγ activity and served as part of a negative feedback mechanism. Thus, our findings suggest that Dkk3 functions as a tissue-derived modulator of local CD4+ and CD8+ T-cell responses. [ABSTRACT FROM AUTHOR]

Introduction: Dickkopf-3 (Dkk3) has been proposed as tumor suppressor gene and a marker for tumor blood vessels and has pro-angiogenic properties. Dkk3 is expressed in platelets and megakaryocytes from healthy controls and patients with BCR-ABL1-negative myeloproliferative neoplasms (MPN). The aim of this study is, to find out whether patients with MPN have higher Dkk3 serum levels than normal controls. Material & methods: We analyzed Dkk3 serum levels with ELISA in patients with newly diagnosed and untreated MPN, including 10 essential thrombocythemia (ET), 10 polycythemia vera (PV), 10 primary meylofibrosis (PMF) and 10 healthy blood donors and correlated these findings with biological and clinical key data and the JAK2-V617F status. Dkk3 levels were corrected to platelet count, Dkk3c, as patients with MPN have higher platelet counts than controls. Results: As expected, patients with MPN have higher platelet counts than normal controls. Dkk3 serum levels of patients with MPN (5.4±6.1ng/ml) showed no significant difference compared to normal controls (4.4±3.8ng/ml). Regarding Dkk3c, a significant difference to controls was found in PV (8.5±8.7ng/ml; p=0.04), but not in ET and PMF (5.7±3.8ng/ml; p=0.07 and 2.7±3.6ng/ml; p=0.9; respectively. Dkk3c correlated with the JAK2-V617F mutational burden (p=0.014, Rho=0.445). Conclusion: Dkk3 levels corrected to platelet count showed higher levels in PV than normal controls. Elevated Dkk3c level could possibly correlate to platelet activation in PV patients and increased Dkk3 release. Whether this remains a surrogate marker of platelet release or it contributes to the thrombophilic state through its pro-angiogenic properties remains to be shown. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Emerging evidence implicates the Wnt antagonist Dickkopf-3 (Dkk3) as a tumor suppressor and potential biomarker in solid tumors. We investigated whether Dkk3 plays an important role in the carcinogenesis of endometrial cancer (EC). Methods: We analyzed Dkk3 mRNA expression via real-time RT-PCR in twenty-seven human primary EC tissues, and six matched normal endometrial controls. Dkk3 levels were correlated with various clinicopathologic characteristics. Additionally, enforced Dkk3 expression was examined in proliferation and tumorigenesis in vitro and in vivo, using MTT, soft agar assay, invasion assay, a xenograft mouse model, and a β-catenin-responsive SuperTopFlash luciferase assay. Results: Compared with matched normal endometrial cases, Dkk3 was down-regulated in EC (p<0.0001). Among cancer cases, Dkk3 expression was significantly reduced in patients with higher stage (p=0.002), positive pelvic lymph nodes (p=0.0004), non-endometrioid histology (p=0.02), and cytology-positive ECs (p=0.02). Enforced expression of Dkk3 in EC cell lines showed reduced proliferation (p<0.0001), anchorage-independent growth (p=0.005), invasion (p=0.02), and reduced TCF activity (p=0.04), confirming Dkk3 as a negative regulator of the β-catenin/Wnt signaling pathway. Tumor growth in Dkk3-injected mice was not statistically different, though did plateau towards the end, and was associated with increased lymphoid infiltration and tumor necrosis. Conclusion: Dkk3 gene expression is frequently downregulated in endometrial cancer, and is associated with poor prognostic clinicopathologic markers. The results also identify a role for Dkk3 as a tumor suppressor in EC, affecting both proliferation and invasiveness. These findings may prove to be important in the design of novel biomarkers and treatment modalities for advanced EC. [Copyright &y& Elsevier]

Dickkopf-3 (Dkk-3) may act as a tumor suppressor as it is downregulated in various types of cancer. Moreover, a putative role in tumor neovascularization is discussed. Here, we investigated the expression of Dkk-3 protein in gastric cancer and its potential value as a prognostic marker. Dkk-3 expression was analyzed by immunohistochemistry in 136 tumor samples and was correlated with microvessel density (MVD), tumor stage, and grading as well as the clinical outcome of the patients. Dkk-3 expression was detected in endothelial cells of the tumor vessels in 129/136 (94.9%) and in tumor cells in 85/136 (62.5%) samples. MVD was high and low in 57 (42.9%) and 76 (57.1%) specimens respectively. In tumor cells, overexpression of Dkk-3 was found in 41 (30.1%) of all cases and was correlated significantly to pT-stage (p < 0.05) and UICC stage (p < 0.05). Survival analysis regarding Dkk-3 expression in tumor endothelial cells showed that Dkk-3 is an independent predictor of disease-free survival (p < 0.05). Dkk-3 expression in tumor vessels of patients with gastric cancer identifies a population of patients with relatively favorable prognosis. [ABSTRACT FROM AUTHOR]