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.

The Wnt signaling pathway regulates crucial aspects such as cell fate determination, cell polarity and organogenesis during embryonic development. Wnt pathway deregulation is a hallmark of several cancers such as lung, gastric and liver cancer, and has been reported to be altered in others. Despite the general agreement reached by the scientific community on the oncogenic potential of the central components of the pathway, the role of the antagonist proteins remains less clear. Deregulation of the pathway may be caused by overexpression or downregulation of a wide range of antagonist proteins. Although there is growing information related to function and regulation of Dickkopf (DKK) proteins, their pharmacological potential as cancer therapeutics still has not been fully developed. This review provides an update on the role of DKK proteins in cancer and possible potential as therapeutic targets for the treatment of cancer; available compounds in pre-clinical or clinical trials are also reviewed.

In this review, we summarize the role of Wnt proteins in cardiomyogenesis. More specifically, we focus on how the development of cardiomyocytes from precursor cells involves a complex interplay between Wnt canonical β-catenin signaling pathways and Wnt noncanonical signaling pathways involving PCP and JNK. We also describe recent literature which suggests that endogenous Wnt inhibitors such as the Sfrp and DKK proteins play important roles in regulating the cardiomyocyte differentiation.

Since 1967, it is known that the loss of GLI3 causes very severe defects in murine eye development. GLI3 is able to act as a transcriptional activator (GLI3-A) or as a transcriptional repressor (GLI3-R). Soon after the discovery of these GLI3 isoforms, the question arose which of the different isoforms is involved in eye formation - GLI3-A, GLI3-R or even both. For several years, this question remained elusive. By analysing the eye morphogenesis of Gli3XtJ/XtJ mouse embryos that lack GLI3-A and GLI3-R and of Gli3Δ699/Δ699 mouse embryos in which only GLI3-A is missing, we revealed that GLI3-A is dispensable in vertebrate eye formation. Remarkably, our study shows that GLI3-R is sufficient for the creation of morphologically normal eyes although the molecular setup deviates substantially from normality. In depth-investigations elucidated that GLI3-R controls numerous key players in eye development and governs lens and retina development at least partially via regulating WNT/β-CATENIN signalling.

Wnt proteins, a group of secreted glycoproteins, mainly combine with receptors Frizzled (FZD) and/or low-density-lipoprotein receptor-related proteins 5/6 (LRP5/6), initiating β-catenin-dependent and -independent signaling pathways. These pathways, which can be regulated by some secreted antagonists such as secreted Frizzled-related proteins (SFRP) and dickkopf-related protein (DKK), play a critical role in embryo development and adult homeostasis. Overactivation of Wnt signaling has been implicated in some human diseases including cancer. Wnt transgenic mice provide convincing evidence that Wnt signaling is involved in breast cancer initiation and progression, which is further strengthened by observations on human clinical breast cancer patients and studies on in vitro cultured human breast cancer cells. This review focuses on the roles of Wnt ligands, receptors and antagonists in breast cancer development instead of molecules or signaling transactivating β-catenin independent on Wnt upstream components.

Neural crest progenitors are specified through the modulation of several signaling pathways, among which the activation of Wnt/β-catenin signaling by Wnt8 is especially critical. Glycoproteins of the Dickkopf (Dkk) family are important modulators of Wnt signaling acting primarily as Wnt antagonists. Here we report that Dkk2 is required for neural crest specification functioning as a positive regulator of Wnt/β-catenin signaling. Dkk2 depletion in Xenopus embryos causes a loss of neural crest progenitors, a phenotype that is rescued by expression of Lrp6 or β-catenin. Dkk2 overexpression expands the neural crest territory in a pattern reminiscent of Wnt8, Lrp6 and β-catenin gain-of-function phenotypes. Mechanistically, we show that Dkk2 mediates its neural crest-inducing activity through Lrp6 and β-catenin, however unlike Wnt8, in a GSK3β independent manner. These findings suggest that Wnt8 and Dkk2 converge on β-catenin using distinct transduction pathways both independently required to activate Wnt/β-catenin signaling and induce neural crest cells.

OBJECTIVE: To investigate the association between the genetic variants of DKK4 (rs2073664), DKK3 (rs2291599, rs3206824 and rs7391689) and DKK2 (rs447372, rs419558 and rs17037102) and lung cancer predisposition in north Indians.
METHODS: A total of 600 subjects were genotyped using PCR restriction fragment length polymorphism technique. Association analysis was carried out using logistic regression approach.
RESULTS: DKK3 rs7396187 showed a protective effect (p = 0.01). Subjects with heterozygous genotype of DKK2 rs17037102 and rs419558 showed an increased risk. The variant genotype of the genotypic combination, DKK3 rs3206824 and DKK2 rs419558 showed a twofold increased risk (p = 0.008). Lung cancer risk increased four-times in subjects with variant genotype of all the three DKK2 variants.
CONCLUSIONS: DKK2 is certainly playing a crucial role in modulating cancer susceptibility.

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide. There are multiple etiologic factors including viral and environmental influences that can lead to HCC. Successful screening for early HCC is challenging due to the lack of well characterized and specific biomarkers. However, achieving successful screening is critically important as early diagnosis can potentially provide curative opportunities. Once HCC is advanced, there are multiple therapeutic venues, but most eventually fail, therefore developing new targeted therapies may provide greater chance for effective therapies. Along these lines, the Wnt pathway has been identified as contributing to the development and progression of HCC. Wnts can modify HCC growth and invasive ability. A key factor in the Wnt pathway is the dickkopf (DKK) family of Wnt inhibitors. DKKs have also been shown to modulate HCC progression. Additionally, several studies have suggested that DKK expression in tissue and serum has diagnostic and prognostic value.

Dkk3 is a member of Dkk family proteins, regulating Wnt signaling. Dkk3 plays different roles in human and mouse tumors. Dkk3 predominantly act as a tumor suppressor, however several reports revealed that Dkk3 could accelerate cancer cell proliferation. Herein, we aimed at launching an in silico study to determine Dkk3 structure and its interactions with Kremen and LRP as Wnt signaling receptors as well as EGF receptor. Using various softwares a model was built for Dkk3 molecule. Different protein modeling approaches along with model refinement processes were employed to arrive at the final model. To achieve the final complex of Dkk3 with Kremen, LRP and EGFR molecules protein-protein docking servers were employed. Model assessment softwares indicated the high quality of the finally refined Dkk3 3D structure, indicating the accuracy of modeling and refinement process. Our results revealed that Dkk3 is capable of interacting with Kremen, LRP and EGFR with comparable binding energies. Dkk3 efficiently interacts with LRP, Kremen and EGF receptor and may be a promising protein in cancer therapy by blocking Wnt and EGFR downstream signaling.

Canonical Wnt signaling plays crucial roles during development and disease. How Wnt signaling is modulated in different in vivo contexts is currently not well understood. Here, we investigate the modulation of Wnt signaling in the posterior lateral line primordium (pLLP), a cohort of ~100 cells that collectively migrate along the trunk of the zebrafish embryo. The pLLP comprises proliferative progenitor cells and organized epithelial cells that will form the mechanosensory organs of the posterior lateral line. Wnt signaling is active in the leading progenitor zone of the pLLP and restricted from the trailing zone through expression of the secreted Wnt inhibitors dkk1b and dkk2. We have identified a zebrafish strain, krm1(nl10), which carries a mutation in the kremen1 gene, a non-obligate co-receptor for the Dkk family of proteins. Previous studies have shown that Kremen1 inhibits Wnt signaling by facilitating internalization of the Kremen1-Dkk-Lrp5/6 complex. Surprisingly, we found that disruption of Kremen1 in the pLLP exhibited molecular and cellular phenotypes associated with a decrease rather than overactivation of Wnt signaling. Transplantation of wild-type cells into the mutant primordia failed to rescue the krm1(nl10) phenotype, thus revealing that the effects of Kremen1 loss are non-cell-autonomous. Finally, ectopic expression of Dkk1b-mTangerine protein revealed larger spread of the fusion protein in the mutant primordia compared with the wild type. Based on our data, we propose a novel mechanism in which Kremen1 modulates Wnt activity by restricting the range of secreted Dkk proteins during collective cell migration in the pLLP.