Leukocyte Beta-Catenin Expression Is Disturbed in Systemic Lupus Erythematosus

Orme, Jacob J.; Du, Yong; Vanarsa, Kamala; Wu, Tianfu; Satterthwaite, Anne B.; Mohan, Chandra

doi:10.1371/journal.pone.0161682

Cited by 10 publications

(8 citation statements)

References 43 publications

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“…Numerous studies have shown that the Wnt/β-catenin signaling pathway is involved in the occurrence and development of a variety of human cancers, such as colorectal, breast, prostate, and liver cancers (31)(32)(33)(34). Abnormalities in dendritic cells, B cells, CD4 + T cells, and other immune cells in the pathogenesis of SLE are also related to abnormal Wnt/β-catenin signaling (35)(36)(37). Furthermore, the JAK-STAT signaling pathway has been shown to play an important role in the occurrence and development of many types of hematological and solid tumors (38).…”

Section: Discussionmentioning

confidence: 99%

A ceRNA regulatory network in systemic lupus erythematosus and its molecular interplay with cancer

Lin¹,

Fan²,

Li³

et al. 2022

Ann Transl Med

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Background: Systemic lupus erythematosus (SLE) is an autoimmune disease defined by the production of autoantibodies and involves multiple organs and systems. Although there are reports on SLE, data on its pathogenesis is limited.Methods: Using R language software, we constructed a competing endogenous RNA (ceRNA) network.We then utilized the Search Tool for Recurring Instances of Neighbouring Genes (STRING) and cytoHubba databases to generate a protein-protein interaction (PPI) network, which led to the identification of hub genes. The top two hub genes with the highest Maximal Clique Centrality (MCC) score in the PPI network were further validated via quantitative real-time polymerase chain reaction (qRT-PCR) using inhouse clinical samples. Also, weighted gene co-expression network analysis (WGCNA) with genes from the Gene Expression Omnibus Series (GSE)121239 dataset identified hub modules that were associated with clinical indicators. In addition, the genes contained in key modules as obtained by WGCNA were enriched and analyzed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tool. The top hub gene, X-linked apoptosis inhibitory protein-associated factor (XAF1), was then identified by intersection of the PPI and WGCNA outcomes, and a pan-cancer analysis of this hub gene was subsequently performed.Results: We comprehensively profiled the expression of Circular RNAs (circRNAs), MicroRNAs (miRNAs), and messenger RNAs (mRNAs) in SLE. We identified a hub gene, XAF1, based on evidence from the ceRNA network, WGCNA key module genes, and PPI network analyses. Moreover, qRT-PCR analysis demonstrated that the expression of XAF1 was significantly upregulated in SLE. Through the pan-cancer analysis, we demonstrated the common molecular roles of XAF1 in the pathogenesis of SLE and tumors, especially cutaneous melanoma.Conclusions: XAF1 is a key molecular biomarker in SLE. The pan-cancer analysis in this study provided shared genomic characteristics in SLE and cancers, especially for skin cutaneous melanoma (SKCM).

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Section: Discussionmentioning

confidence: 99%

A ceRNA regulatory network in systemic lupus erythematosus and its molecular interplay with cancer

Lin¹,

Fan²,

Li³

et al. 2022

Ann Transl Med

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“…Both human and LN MRL/lpr mouse studies indicated that the DKK-1 protein was significantly higher in the sera of SLE patients compared with control subjects, and the LN MRL/lpr mice exhibited a phenotype with an enhanced Wnt/ β -catenin activity, accompanied by an increased level of DKK-1 in the renal tissues and sera and an increased frequency of apoptotic cells of the renal tubular and renal interstitial tissues [ 30 ]. Notably, the beta-catenin transcriptional activity in leukocytes of lupus-prone mice and SLE patients was diminished, particularly in myeloid cells [ 31 ]. Such an activated Wnt signaling was further evidenced in human renal tissues of patients with LN by accessing β -catenin at both transcriptional and translational levels using assays including immunohistochemistry staining, qRT-PCR, and western blotting, suggesting that a dysregulated Wnt/ β -catenin signaling was related to the pathogenesis of LN and might play a role in the renal fibrosis [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Dickkopf-1 Is a Biomarker for Systemic Lupus Erythematosus and Active Lupus Nephritis

Xue

Yang

et al. 2017

Journal of Immunology Research

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An early diagnosis of lupus nephritis (LN) has an important clinical implication in guiding treatments of systemic lupus erythematosus (SLE) in clinical settings. In this study, the concentrations of Wnt-3A, Frizzled-8 (FZD-8), and Dickkopf-1 (DKK-1) of Wnt signaling, as well as their diagnostic values for accessing LN, were evaluated by ELISA in sera and urine of 111 SLE patients (31 with LN and 80 without LN) and 70 healthy cohorts. Significantly more abundances of DKK-1 protein were determined in both of sera and urine of SLE patients compared to healthy cohorts (p < 0.0001); in particular the serum DKK-1 concentration was even higher in LN-SLE patients relative to non-LN SLE subjects (p < 0.0001). Intriguingly, concentrations of above examined proteins in SLE patients showed no correlation between serum and urine. Moreover, a combination of DKK-1 with anti-dsDNA and/or levels of complement C3 and C4 could not increase the specificity and/or sensitivity for identification of patients with LN diseases, but both ROC curve and multiple-factor nonconditional logistic regression analysis showed that serum DKK-1 was considered better positive biomarker for identification of LN in SLE patients. These results imply that serum and/or urine DKK-1 may be a valuable and independent biomarker for identification of SLE patients with LN.

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“…The level of β-catenin in PBMCs isolated from patients with acute uveitis was also reduced. Decreased β-catenin activity has previously been reported in leukocytes from lupus-prone mice and patients with systemic lupus erythematosus [ 37 ]. We also observed that decreased β-catenin activity inhibited the expression of Wnt-associated genes, such as Sox9 , Axin2 , Tcf1 , and Lef1 .…”

Section: Discussionmentioning

confidence: 99%

Pertussis toxin-induced inhibition of Wnt/β-catenin signaling in dendritic cells promotes an autoimmune response in experimental autoimmune uveitis

Zhang

Chen

et al. 2023

J Neuroinflammation

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Background Previous reports have indicated that disrupting the Wnt/β-catenin pathway in dendritic cells (DCs) may affect the progression of autoimmune inflammation; however, the factors and timing that regulate Wnt/β-catenin signaling have not been clearly understood. Methods Experimental autoimmune uveitis (EAU) mice and Vogt–Koyanagi–Harada disease (VKH) patient samples were used to detect the expression of Wnt/β-catenin pathway genes. Western blot, real-time PCR, flow cytometry, and ELISA were performed to examine the expression of components of the Wnt/β-catenin pathway and inflammatory factors. DC-specific β-catenin knockout mice and 6-bromoindirubin-3′-oxime (BIO) administered mice were used to observe the effect of disrupting the Wnt pathway on EAU pathogenesis. Results Wnt/β-catenin signaling was inhibited in DCs during the induction phase of EAU. The inhibition was mediated by pertussis toxin (PTX), which promoted DC maturation, in turn promoting pathogenic T cell proliferation and differentiation. In vivo experiments confirmed that deleting β-catenin in DCs enhanced EAU severity, and pre-injection of PTX advanced EAU onset. Administration of a Wnt activator (BIO) limited the effects of PTX, in turn ameliorating EAU. Conclusions Our results demonstrate that PTX plays a key role as a virulence factor in initiating autoimmune inflammation via DCs by inhibiting Wnt/β-catenin signaling in EAU, and highlight the potential mechanism by which infection can trigger apparent autoimmunity.

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Leukocyte Beta-Catenin Expression Is Disturbed in Systemic Lupus Erythematosus

Cited by 10 publications

References 43 publications

A ceRNA regulatory network in systemic lupus erythematosus and its molecular interplay with cancer

A ceRNA regulatory network in systemic lupus erythematosus and its molecular interplay with cancer

Dickkopf-1 Is a Biomarker for Systemic Lupus Erythematosus and Active Lupus Nephritis

Pertussis toxin-induced inhibition of Wnt/β-catenin signaling in dendritic cells promotes an autoimmune response in experimental autoimmune uveitis

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