Dataset Information

Wnt Pathway Inhibitor DKK1: A Potential Novel Biomarker for Adiposity.

ABSTRACT: Emerging evidence indicates that ectopic skeletal muscle adiposity may be a risk factor for type 2 diabetes (T2D), especially in persons of African ancestry. In vitro studies suggest that a Wnt pathway inhibitor, Dickkopf-related protein 1 (DKK1), plays a role in adiposity regulation and could be a biomarker for adiposity in humans. The objective of this study was to test whether serum DKK1 levels relate to adiposity measures in a cohort from an African ancestry population at high risk for T2D. Fasting serum DKK1 was measured in a sample of 159 men of African ancestry aged ?40 years (mean age ± SD, 63.5 ± 8.2 years; mean body mass index, 27.8 ± 4.5 kg/m2). Anthropometrics included total-body and trunk adiposity measured by dual-energy x-ray absorptiometry and lower-leg skeletal muscle density measured by CT [which reflects the intramuscular adiposity content (mg/cm3)]. Serum DKK1 was positively correlated with BMI (r = 0.20; P = 0.01), waist circumference (r = 0.15; P = 0.046), DXA total-body adiposity (r = 0.24; P = 0.003), and DXA trunk adiposity (r = 0.21; P = 0.009), independent of age and height. In addition, serum DKK1 was inversely correlated with skeletal muscle density (r = -0.25; P = 0.002), independent of age, BMI, and calf muscle area. No significant correlation was found between serum DKK1 and fasting serum glucose or insulin levels or insulin resistance estimated by homeostasis model assessment. These findings suggest that higher levels of serum DKK1 may be associated with greater overall, central, and ectopic skeletal muscle adiposity. Further studies are needed to unravel the potential role of DKK1 in the regulation of adiposity in humans.

SUBMITTER: Ali H

PROVIDER: S-EPMC6364619 | biostudies-other | 2019 Feb

REPOSITORIES: biostudies-other

ACCESS DATA

Similar Datasets

Project description:ObjectiveAberrant activation of Wnt/β-catenin signaling contributes to the maintenance of cancer stem cells and chemoresistance in colorectal cancer (CRC). Retinoic acid-induced 2 (RAI2) was proved to be a tumor suppressor in CRC in our previous report. In this study, the role of RAI2 in Wnt/β-catenin signaling was further investigated.MethodsAs a transcriptional co-regulator, C-terminal Binding Protein 2 (CtBP2) was reported to be involved in Wnt signaling in multiple and complex ways. The correlation of RAI2 and CtBP2 in CRC was analyzed by TCGA dataset, and the interaction between RAI2 and CtBP2 was explored by co-immunoprecipitation (Co-IP) in CRC cells. The effect of RAI2 on the activity of Wnt signaling and the location of β-catenin was detected by Dual-Luciferase reporter assay and Immunofluorescence respectively. Western blotting analysis was performed to detect the expression of target genes involved in Wnt signaling. Sphere formation assay was employed to detect the effect of RAI2 on stem cell like properties. Cell viability assay was used to detect the chemosensitivity of cells before and after transfection of RAI2.ResultsThe interaction between RAI2 and CtBP2 was confirmed by Co-IP in CRC cells. Besides, the negative correlation of RAI2 and CtBP2 in CRC was found by analyzing the TCGA dataset. Re-expression of RAI2 in human colon cancer cells (HCT116 and LoVo) suppressed the fluorescent activity of Wnt signaling, increased the phosphorylation and inhibited nuclear translocation of β-catenin, with down-regulation of target genes like c-Myc, CyclinD1, ASCL2, and LGR5. In contrast, the mutated RAI2, which can't interact with CtBP2, has no above effects. We observed low expression of RAI2 in 33.89% (101/298) of CRC patients, which was significantly associated with reduced phosphorylation of β-catenin (r=0.8866, P<0.0001), poor 5-year relapse-free survival (RFS) (P = 0.0029) and overall survival (OS) (P = 0.0102). Restoration of RAI2 in HCT116 and LoVo cells inhibited stem cell-like properties of CRC cells and increased chemosensitivity of these cells to oxaliplatin and fluorouracil.ConclusionLow expression of RAI2 can serve as an independent poor prognostic marker. RAI2 inhibits Wnt signaling by interacting with or down-regulating CtBP2, resulting in repression of stem cell-like properties and increased chemosensitivity of CRC cells.

Project description:The deficiency of very low-density lipoprotein receptor resulted in Wnt signaling activation and neovascularization in the retina. The present study sought to determine whether the very low-density lipoprotein receptor extracellular domain (VLN) is responsible for the inhibition of Wnt signaling in ocular tissues.A plasmid expressing the soluble VLN was encapsulated with poly(lactide-co-glycolide acid) to form VLN nanoparticles (VLN-NP). Nanoparticles containing a plasmid expressing the low-density lipoprotein receptor extracellular domain nanoparticle were used as negative control. MTT, modified Boyden chamber, and Matrigel (™) assays were used to evaluate the inhibitory effect of VLN-NP on Wnt3a-stimulated endothelial cell proliferation, migration, and tube formation. Vldlr(-/-) mice, oxygen-induced retinopathy, and alkali burn-induced corneal neovascularization models were used to evaluate the effect of VLN-NP on ocular neovascularization. Wnt reporter mice (BAT-gal), Western blotting, and luciferase assay were used to evaluate Wnt pathway activity. Our results showed that VLN-NP specifically inhibited Wnt3a-induced endothelial cell proliferation, migration, and tube formation. Intravitreal injection of VLN-NP inhibited abnormal neovascularization in Vldlr(-/-), oxygen-induced retinopathy, and alkali burn-induced corneal neovascularization models, compared with low-density lipoprotein receptor extracellular domain nanoparticle. VLN-NP significantly inhibited the phosphorylation of low-density lipoprotein receptor-related protein 6, the accumulation of ?-catenin, and the expression of vascular endothelial growth factor in vivo and in vitro.Taken together, these results suggest that the soluble VLN is a negative regulator of the Wnt pathway and has antiangiogenic activities. Nanoparticle-mediated expression of VLN may thus represent a novel therapeutic approach to treat pathological ocular angiogenesis and potentially other vascular diseases affected by Wnt signaling.

Dataset Information

Wnt Pathway Inhibitor DKK1: A Potential Novel Biomarker for Adiposity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets