Combination of Wnt/β-Catenin Targets S100A4 and DKK1 Improves Prognosis of Human Colorectal Cancer

Metastasis is directly linked to colorectal cancer (CRC) patient survival. Wnt signaling through β-catenin plays a key role. Metastasis-inducing S100A4 is a Wnt/β-catenin target gene and a prognostic biomarker for CRC and other cancer types. We aimed to identify S100A4-dependent expression alterations to better understand CRC progression and metastasis for improved patient survival. S100A4-induced transcriptome arrays, confirmatory studies in isogenic CRC cell lines with defined β-catenin genotypes, and functional metastasis studies were performed. S100A4-regulated transcriptome examination revealed the transcriptional cross-regulation of metastasis-inducing S100A4 with Wnt pathway antagonist Dickkopf-1 (DKK1). S100A4 overexpression down-regulated DKK1, S100A4 knock-down increased DKK1. Recombinant DKK1 reduced S100A4 expression and S100A4-mediated cell migration. In xenografted mice, systemic S100A4-shRNA application increased intratumoral DKK1. The inverse correlation of S100A4 and DKK1 was confirmed in five independent publicly available CRC expression datasets. Combinatorial analysis of S100A4 and DKK1 in two additional independent CRC patient cohorts improved prognosis of overall and metastasis-free survival. The newly discovered transcriptional cross-regulation of Wnt target S100A4 and Wnt antagonist DKK1 is predominated by an S100A4-induced Wnt signaling feedback loop, increasing cell motility and metastasis risk. S100A4 and DKK1 combination improves the identification of CRC patients at high risk.

Serum Dickkopf-1 as a potential prognostic marker in patients with rheumatoid arthritis

Background Rheumatoid arthritis (RA) is a disease of an autoimmune nature that involves all types of joints structures and manifested by chronic joints inflammations and thus their erosions and damage. Dickkopf-1 (DKK-1) is a molecule that has an inhibitory regulation of wingless/integrated genes (Wnt) pathway and has a major role in models of animals with arthritis or joint destruction. Increased DKK-1 levels are implicated in higher resorption of the bone in cases of rheumatoid arthritis and thus with higher probability for joint deformities, while low levels associated with formation of new bone by osteoblasts, we aimed to study the prognostic role of circulating Dickkopf-1 in rheumatoid arthritis. Results The present study revealed that the DKK-1 levels were significantly increased in RA patients in relation to the control group (P=0.001). We found a significant positive correlation between DKK-1 level and ESR (P=0.001), Disease Activity Score (DAS 28) (P=0.001), the disease duration (P=0.001), and the presence of bone erosions in plain X-ray of hands (P =0.001). Moreover, we revealed that, at cutoff value 2150, the DKK-1 in RA has 90% sensitivity and 85% specificity. Conclusions DKK-l serum level can be used as a potential prognostic biomarker for monitoring of joint erosions and destruction in RA patients. Furthermore, it could be a possible target molecule in the future therapy to control the process of joint destruction.

Dickkopf-1 Inhibition Reactivates Wnt/β-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo

The Wnt/β-catenin signaling pathway plays a pivotal role during embryogenesis and its deregulation is a key mechanism in the origin and progression of several tumors. Wnt antagonists have been described as key modulators of Wnt/β-catenin signaling in cancer, with Dickkopf-1 (DKK-1) being the most studied member of the DKK family. Although the therapeutic potential of DKK-1 inhibition has been evaluated in several diseases and malignancies, little is known in pediatric tumors. Only a few works have studied the genetic inhibition and function of DKK-1 in rhabdomyosarcoma. Here, for the first time, we report the analysis of the therapeutic potential of DKK-1 pharmaceutical inhibition in rhabdomyosarcoma, the most common soft tissue sarcoma in children. We performed DKK-1 inhibition via shRNA technology and via the chemical inhibitor WAY-2626211. Its inhibition led to β-catenin activation and the modulation of focal adhesion kinase (FAK), with positive effects on in vitro expression of myogenic markers and a reduction in proliferation and invasion. In addition, WAY-262611 was able to impair survival of tumor cells in vivo. Therefore, DKK-1 could constitute a molecular target, which could lead to novel therapeutic strategies in RMS, especially in those patients with high DKK-1 expression.

Pan-Cancer Analyses Reveal Oncogenic and Immunological Role of Dickkopf-1 (DKK1)

WNT signaling pathway inhibitor Dickkopf-1 (DKK1) is related to cancer progression; however, its diagnostic and prognostic potential have not been investigated in a pan-cancer perspective. In this study, multiple bioinformatic analyses were conducted to evaluate therapeutic value of DKK1 in human cancers. The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project served as data resources. The Wilcoxon rank test was performed to evaluate the expression difference of DKK1 between cancer tissues and normal tissues. A Kaplan-Meier curve and Cox regression were used for prognosis evaluation. Single-sample gene set enrichment analysis (ssGSEA) was used to evaluate the association of DKK1 expression with the immune cell infiltration. The potential function of DKK1 was explored by STRING and clusterProfiler. We found that the expression level of DKK1 is significantly different in different cancer types. Importantly, we demonstrated that DKK1 is an independent risk factor in ESCA, LUAD, MESO, and STAD. Further analysis revealed that DKK1 had a large effect on the immune cell infiltration and markers of certain immune cells, such as Th1 and Th2 cells. PPI network analysis and further pathway enrichment analysis indicated that DKK1 was mainly involved in the WNT signaling pathway. Our findings suggested that DKK1 might serve as a marker of prognosis for certain cancers by affecting the WNT signaling pathway and tumor immune microenvironment.

Comparison of Maternal Serum Levels and Placental mRNA Levels of Dickkopf-1 in Preeclamptic and Normal Pregnant Women at Delivery

Background Preeclampsia remains a major cause of perinatal and maternal mortality and morbidity worldwide. Wnt/β-catenin signaling is known to be critically involved in placenta development processes. Dickkopf-1 (DKK1) is a key regulator of this transduction pathway. The aim of this study is to compare maternal serum DKK1 levels and placental mRNA levels of DKK1 and β-catenin in preeclamptic and normal pregnant women at delivery. Methods The present study included 30 women with preeclampsia and 30 women with normal pregnancy. Maternal serum DKK1 levels were measured by ELISA. Placental mRNA levels of DKK1 and β-catenin were detected using RT-PCR. Results Decreased maternal serum DKK1 levels were associated with worse maternal and fetal complications including HELLP syndrome, determination of one or more pathological symptom and IUGR diagnosis. No significant difference in maternal serum DKK1 levels was reported between preeclamptic women and women with normal pregnancy. Placental mRNA DKK1 levels were lower in preeclamptic women compared with normal pregnant women. Placental mRNA β-catenin levels showed no significant difference between two groups. Conclusions Our findings reported the aberrant placental mRNA DKK1 levels in patients with preeclampsia. In addition, worse preeclampsia features were associated with decreased maternal serum DKK1 levels. Hence, aberrant Wnt/β-catenin signaling might present a plausible mechanism in preeclampsia pathogenicity. Dysregulated expression of DKK1 at gene level in the placenta but not at protein level in the maternal serum might confirm the notion that preeclampsia is a type of placenta-derived disease.