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Plasma dickkopf-related protein 1, an antagonist of the Wnt pathway, is associated with HIV-associated neurocognitive impairment.

ABSTRACT: Dickkopf-related protein 1 (DKK1) is a soluble antagonist of the Wningless (Wnt) pathway. It binds to and sequesters low-density lipoprotein receptor-related proteins 5/6 away from Wnts. Because the Wnt pathway regulates synaptic transmission and plasticity, we hypothesized that increased DKK1 would increase the risk for neurocognitive impairment (NCI) in HIV-positive (HIV) individuals. We evaluated, here, the relationship between plasma DKK1 and global NCI.Plasma samples and data from 41 HIV to 42 HIV adults were obtained from the University of California, San Diego, California, USA. Concentrations of DKK1 and a comparator protein, monocyte chemoattractant protein-1 (MCP-1), were quantified in plasma by immunoassay. All study participants completed a standardized comprehensive neuropsychological test battery and their performance was summarized using the global deficit score method.A higher DKK1 level was associated with NCI among HIV participants (d?=?0.63, P?=?0.05), particularly among the 26 participants whose plasma HIV RNA level was suppressed (d?=?0.74, P?=?0.08). DKK1 level was not associated with NCI among HIV participants (P?=?0.98). was not associated with NCI in either group. In HIV adults with suppressed plasma HIV RNA, a receiver operator characteristic curve identified that a DKK1 level of at least 735?pg/ml had a positive predictive value of 83.3% for a diagnosis of NCI. This association did not weaken after accounting for the effect of AIDS, nadir CD4 T-cell count, addictive drug use, or demographic characteristics.DKK1 is a specific biomarker for NCI in HIV adults, implicating the Wnt pathway in HIV neuropathogenesis.

SUBMITTER: Yu C

PROVIDER: S-EPMC5472066 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Plasma dickkopf-related protein 1, an antagonist of the Wnt pathway, is associated with HIV-associated neurocognitive impairment.

Yu Chunjiang C Seaton Melanie M Letendre Scott S Heaton Robert R Al-Harthi Lena L

AIDS (London, England) 20170601 10

<h4>Objective</h4>Dickkopf-related protein 1 (DKK1) is a soluble antagonist of the Wningless (Wnt) pathway. It binds to and sequesters low-density lipoprotein receptor-related proteins 5/6 away from Wnts. Because the Wnt pathway regulates synaptic transmission and plasticity, we hypothesized that increased DKK1 would increase the risk for neurocognitive impairment (NCI) in HIV-positive (HIV) individuals. We evaluated, here, the relationship between plasma DKK1 and global NCI.<h4>Methods</h4>Plas ...[more]

PMID: 28358733

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by late diagnosis and treatment resistance. Recurrent genetic alterations in defined genes in association with perturbations of developmental cell signaling pathways have been associated with PDAC development and progression. Here, we show that GATA6 contributes to pancreatic carcinogenesis during the temporal progression of pancreatic intraepithelial neoplasia by virtue of Wnt pathway activation. GATA6 is recurrently amplified by both quantitative-PCR and fluorescent in-situ hybridization in human pancreatic intraepithelial neoplasia and in PDAC tissues, and GATA6 copy number is significantly correlated with overall patient survival. Forced overexpression of GATA6 in cancer cell lines enhanced cell proliferation and colony formation in soft agar in vitro and growth in vivo, as well as increased Wnt signaling. By contrast siRNA mediated knockdown of GATA6 led to corresponding decreases in these same parameters. The effects of GATA6 were found to be due to its ability to bind DNA, as forced overexpression of a DNA-binding mutant of GATA6 had no effects on cell growth in vitro or in vivo, nor did they affect Wnt signaling levels in these same cells. A microarray analysis revealed the Wnt antagonist Dickopf-1 (DKK1) as a dysregulated gene in association with GATA6 knockdown, and direct binding of GATA6 to the DKK1 promoter was confirmed by chromatin immunoprecipitation and electrophoretic mobility shift assays. Transient transfection of GATA6, but not mutant GATA6, into cancer cell lines led to decreased DKK1 mRNA expression and secretion of DKK1 protein into culture media. Forced overexpression of DKK1 antagonized the effects of GATA6 on Wnt signaling in pancreatic cancer cells. These findings illustrate that one mechanism by which GATA6 promotes pancreatic intraepithelial neoplasia is by virtue of its activation of canonical Wnt signaling via regulation of DKK1. AsPC1 and A13A cells were stably transfected with a lentivirus expressing mock shRNA or shRNA to GATA6. Each control/shRNA pair (total 4 samples) was analyzed by two-color microarray and the genes commonly dysregulated in both cell lines identified.

Dataset Information

Plasma dickkopf-related protein 1, an antagonist of the Wnt pathway, is associated with HIV-associated neurocognitive impairment.

Publications

Plasma dickkopf-related protein 1, an antagonist of the Wnt pathway, is associated with HIV-associated neurocognitive impairment.

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