WISP1/CCN4: A Potential Target for Inhibiting Prostate Cancer Growth and Spread to Bone

Ono, M.; Inkson, Colette A.; Sonn, Robert; Kilts, Tina M.; Castro, Luis F de; Maeda, Akiko; Fisher, Larry W.; Robey, Pamela Gehron; Berendsen, Agnes D.; Li, L i; McCartney-Francis, Nancy; Brown, Aaron C.; Crawford, Nigel P.S.; Molinolo, Alfredo A.; Jain, Anuj; Fedarko, Neal S.; Young, Marian F.

doi:10.1371/journal.pone.0071709

Cited by 61 publications

(67 citation statements)

References 45 publications

(61 reference statements)

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“…The reduction in circulating CCN proteins after weight loss could reflect downregulation of the WNT signaling pathway in various tissues, such as adipose tissue and muscle. WISP1 increase has been found in a variety of cancers (17), and the novel variant of WISP1 is associated with invasion of cholangiocarcinomas (18). Central obesity and the metabolic syndrome are independent risk factors for cancer (29).…”

Section: Discussionmentioning

confidence: 99%

“…It regulates mesenchymal proliferation and osteoblastic differentiation as well as chondrogenic differentiation (16). Moreover, WISP1 is upregulated in a variety of cancers (17) and has been associated with invasion of cholangiocarcinoma (18). Thus, WISP1 can determine the onset and progression of apoptosis and autophagy during normal physiology, acute illness, or chronic degenerative disorders (14).…”

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confidence: 99%

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WISP1 Is a Novel Adipokine Linked to Inflammation in Obesity

et al. 2014

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WISP1 (Wnt1-inducible signaling pathway protein-1, also known as CCN4) is a member of the secreted extracellular matrix–associated proteins of the CCN family and a target gene of the Wingless-type (WNT) signaling pathway. Growing evidence links the WNT signaling pathway to the regulation of adipogenesis and low-grade inflammation in obesity. We aimed to validate WISP1 as a novel adipokine. Human adipocyte differentiation was associated with increased WISP1 expression and secretion. Stimulation of human macrophages with WISP1 led to a proinflammatory response. Circulating WISP1 and WISP1 subcutaneous adipose tissue expression were regulated by weight changes in humans and mice. WISP1 expression in visceral and subcutaneous fat tissue was associated with markers of insulin resistance and inflammation in glucose-tolerant subjects. In patients with nonalcoholic fatty liver disease, we found no correlation among disease activity score, liver fat content, and WISP1 expression. Insulin regulated WISP1 expression in adipocytes in vitro but had no acute effect on WISP1 gene expression in subcutaneous fat tissue in overweight subjects who had undergone hyperinsulinemic clamp experiments. The data suggest that WISP1 may play a role in linking obesity to inflammation and insulin resistance and could be a novel therapeutic target for obesity.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

WISP1 Is a Novel Adipokine Linked to Inflammation in Obesity

et al. 2014

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“…CCN proteins modulate interactions between cells and extracellular matrix, largely via binding to integrins (13). A review of CCN4 in all cancer types emphasized its up-regulation in non-hematological neoplasms (14); an example is prostate cancer (15). In contrast, CCN4 is a potential biomarker for multiple myeloma, and is overexpressed in peripheral T-cell lymphomas (16).…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of Ccn4 and Other Genes Between Metastatic and Non-metastatic EL4 Mouse Lymphoma Cells

Chahal

Legaspi

et al. 2016

CGP

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EL4 is a murine lymphoma cell line developed in 1945 by treating C57 black mice with 9:10-dimethyl-1:2-benzanthracene (1). The cells were originally propagated in animal hosts, prior to adaptation to cell culture. EL4 cells were used for many years as a source of interleukin-2 (IL2), which they secrete when treated with phorbol 12-myristate 13-acetate (PMA).The EL4 cell line originally provided to us, by a colleague at the University of Washington, was heterogeneous with respect to PMA response. We, therefore, developed and characterized EL4 sub-lines. Wild-type (WT)-derived cell lines, which are PMA responsive, grow readily in suspension culture as did the original strain. Variant (V)-derived (PMA-resistant) sub-lines were selected for enhanced adhesion to tissue culture plastic (2). Clonal lines were developed from both cell types by limiting dilution (3). The PMA sensitivity of WT-derived cells, as reflected by PMA-induced IL2 production and mitogen-activated protein kinase (ERK1/2) activation, has been attributed to expression of Ras guanyl nucleotide releasing protein 1 (RasGRP1), which binds PMA and directly activates Ras (4); V-derived cells do not express RasGRP1.Clonal EL4 cell lines were used for experimental metastasis studies in syngeneic mice, with WT2 and V7 as prototypes (5, 6). WT2 cells do not form tumors (nonmetastatic), while V7 cells form liver tumors (metastatic) after tail vein injection. 'Metastasis' more strictly refers to tumorigenesis in this model, since circulating EL4 cells home to the liver to form tumors (5). The clonal C5 cell line was developed after stably overexpressing human hemagllutinin (HA)-tagged phospholipase D2 (PLD2) in V7 cells in order to characterize the signaling role of PLD2 using a cell line expressing little or no endogenous PLD2 (5). As compared to V7, C5 cells exhibit increased cell migration (7) and tumor growth (5), providing an early example of the positive role of PLD2 in tumorigenesis.This report presents data from microarray analyses comparing transcripts expressed by these three EL4 cell types, with the goal of further defining their phenotypes.

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“…Many genes are upregulated by the Wnt pathway, some of which are known to modulate VSMC migration, including Wnt-1-inducible signaling pathway protein-1 (WISP-1/CCN4). 16 WISP-1 is a member of the CCN family of genes, 17 which regulates fibrosis and wound healing, 18 angiogenesis, 19 osteogenesis, 20 and cancer. 21 In cultured VSMCs, WISP-1 promotes survival, 19 proliferation, 22 and migration through integrin α5β1.…”

Section: Arterioscler Thromb Vasc Biolmentioning

confidence: 99%

“…As with Wnt2, WISP-1 has been studied in cancer cells, where it has been shown to be a chemoattractant, 20 encourage metastasis, 29 increase invasiveness, and decrease chances of survival. [30][31][32] WISP-1 has also been shown in human cancer cells to be upregulated compared with healthy cells 33 and to stimulate migration via NFκB activation of MMP-2.…”

Section: Arterioscler Thromb Vasc Biolmentioning

confidence: 99%

Wnt2 and WISP-1/CCN4 Induce Intimal Thickening via Promotion of Smooth Muscle Cell Migration

Williams

Mill

Monk

et al. 2016

ATVB

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Objective-Increased vascular smooth muscle cell (VSMC) migration leads to intimal thickening which acts as a soil for atherosclersosis, as well as causing coronary artery restenosis after stenting and vein graft failure. Investigating factors involved in VSMC migration may enable us to reduce intimal thickening and improve patient outcomes. In this study, we determined whether Wnt proteins regulate VSMC migration and thereby intimal thickening. Approach and Results-Wnt2 mRNA and protein expression were specifically increased in migrating mouse aortic VSMCs.Moreover, VSMC migration was induced by recombinant Wnt2 in vitro. Addition of recombinant Wnt2 protein increased Wnt1-inducible signaling pathway protein-1 (WISP-1) mRNA by ≈1.7-fold, via β-catenin/T-cell factor signaling, whereas silencing RNA knockdown of Wnt-2 reduced WISP-1 mRNA by ≈65%. Treatment with rWISP-1 significantly increased VSMC migration by ≈1.5-fold, whereas WISP-1 silencing RNA knockdown reduced migration by ≈40%. was not translated into protein, and recombinant Wnt2 (rWnt2) protein did not increase VSMC proliferation in vitro. 5 The Wnt pathway has also been shown to have a role in cell migration, with Wnt3a involvement in both migration and adhesion of VSMCs through integrin linked kinase regulation of β1-integrin.10 However, on initiation of this study, it was unclear which Wnt proteins modulated VSMC growth factor-induced migration and whether Wntinduced VSMC migration promoted intimal thickening in vivo. Many genes are upregulated by the Wnt pathway, some of which are known to modulate VSMC migration, including Wnt-1-inducible signaling pathway protein-1 (WISP-1/CCN4 Materials and MethodsMaterials and Methods are available in the online-only Data supplement. Nonstandard Abbreviations and Acronyms Results Wnt2 Was Upregulated in Migrating VSMCs In VitroWnt mRNA levels during VSMC migration were assessed using an in vitro scratch wound assay with multiple wounds to stimulate migration of the VSMCs. mRNA was extracted from VSMCs and applied to a focussed Wnt pathway microarray to assess whether the level of expression changed during migration. A significant increase was only observed in Wnt2 mRNA ( Figure 1A), and this change was confirmed using quantitative polymerase chain reaction ( Figure 1A). No significant change was seen in the mRNA levels of any other Wnts (see Table III in the online-only Data Supplement). It was observed by Western blotting ( Figure 1B) and immunocytochemistry ( Figure I in the online-only Data Supplement) that the increase in Wnt2 mRNA was translated into augmented Wnt2 protein levels in migrating VSMCs. Migrating VSMCs on the wound edge could be seen to express higher levels of Wnt2 protein than nonmigratory VSMCs further away from the wound edge ( Figure I in the online-only Data Supplement). Wnt2 Promoted VSMC Migration In VitroAddition of rWnt2 protein significantly increased VSMC migration in vitro, whereas knockdown of Wnt2 using silencing RNA (siRNA) inhibited migration ( Figure 1C). When rWnt2 was ad...

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WISP1/CCN4: A Potential Target for Inhibiting Prostate Cancer Growth and Spread to Bone

Cited by 61 publications

References 45 publications

WISP1 Is a Novel Adipokine Linked to Inflammation in Obesity

WISP1 Is a Novel Adipokine Linked to Inflammation in Obesity

Differential Expression of Ccn4 and Other Genes Between Metastatic and Non-metastatic EL4 Mouse Lymphoma Cells

Wnt2 and WISP-1/CCN4 Induce Intimal Thickening via Promotion of Smooth Muscle Cell Migration

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