Affinage

Showing CCN4 — WISP1 is a alias.

CCN4

CCN family member 4 · UniProt O95388

Length
367 aa
Mass
40.3 kDa
Annotated
2026-06-09
100 papers in source corpus 54 papers cited in narrative 54 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCN4 (WISP1) is a secreted matricellular protein, transcriptionally activated downstream of Wnt/beta-catenin through a CREB-dependent promoter element, that integrates extracellular cues into cell-survival, proliferation, differentiation, migration, and fibrotic programs (PMID:10716946, PMID:22475393, PMID:19238344). It binds extracellular matrix components and growth factors directly—dermatan-sulfate proteoglycans decorin and biglycan that anchor it to the cell surface (PMID:11598131), BMP-2 and TGF-beta3 whose Smad signaling it potentiates to drive osteoblast and chondrocyte differentiation (PMID:20684029, PMID:26555637), and type I collagen, which it linearizes in a cell-force-independent manner to facilitate invasion and breast cancer metastasis (PMID:31294477). CCN4 signals predominantly through integrins—alpha5beta1, alphavbeta3, alphavbeta5, alpha6beta1, and alpha4beta1—to engage FAK, MEK/ERK, PI3K/Akt, NF-kappaB, and AP-1 cascades, thereby inducing proteases, adhesion molecules, and angiogenic factors that promote tumor cell migration, monocyte/macrophage recruitment, and neovascularization (PMID:21453685, PMID:23343403, PMID:23313051, PMID:25738362, PMID:29627497). A recurrent pro-survival module operates through PI3K/Akt: CCN4 raises the Bcl-xL/Bax ratio, blocks mitochondrial cytochrome c release, and phosphorylates and sequesters FoxO3a and PRAS40 with 14-3-3 to sustain mTOR signaling, protecting neurons, microglia, and cardiomyocytes from apoptotic and oxidant stress (PMID:11782444, PMID:22272766, PMID:23151077, PMID:22873724). In tissue homeostasis, CCN4 maintains Wnt signaling in bone by blocking SOST binding to LRP6, supporting bone mineral density (PMID:25864198), and acts as a niche factor that drives muscle stem cell expansion via Akt (PMID:30686765). Genetic loss and antibody-blockade studies establish CCN4 as a driver of fibrosis progression, signaling through integrin-dependent activation of MRTF to reprogram the myofibroblast cytoskeleton in liver fibrosis and through Hedgehog-Gli1 in ligamentum flavum fibrosis (PMID:35987202, PMID:34158608). Its expression is post-transcriptionally repressed by miR-92a and its protein is degraded through FAT10ylation-dependent proteasomal turnover (PMID:24953558, PMID:29790184).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 High

    Established CCN4 as a Wnt/beta-catenin target and a transforming gene, defining the upstream signal that drives its expression and its oncogenic potential.

    Evidence Promoter dissection with reporter assays and overexpression with nude mouse xenograft in NRK-49F cells

    PMID:10716946

    Open questions at the time
    • CREB versus TCF/LEF contribution not resolved at single-element resolution
    • Did not identify the secreted protein's receptors or extracellular partners
  2. 2001 High

    Identified the first direct extracellular binding partners, showing CCN4 docks to the cell surface via dermatan sulfate proteoglycans.

    Evidence Solid-phase and direct binding assays with purified decorin and biglycan plus glycosaminoglycan competition and mass spectrometry

    PMID:11598131

    Open questions at the time
    • Functional consequence of proteoglycan binding for downstream signaling not defined
    • Binding domain on CCN4 not mapped
  3. 2002 High

    Defined the core pro-survival mechanism, showing CCN4 acts through Akt to block intrinsic (but not Fas-mediated) apoptosis.

    Evidence Apoptosis assays, cytochrome c release, Bcl-xL Western blot and PI3K/Akt inhibition

    PMID:11782444

    Open questions at the time
    • Receptor coupling CCN4 to PI3K/Akt not identified
    • Whether survival effect is autocrine or paracrine unresolved
  4. 2004 Medium

    Connected CCN4 to BMP and skeletal biology, showing it potentiates BMP-2-driven osteoblast differentiation while restraining chondrocyte maturation.

    Evidence In situ hybridization, stable transfection of chondrocytic lines, osteoblast differentiation assays and in vivo fracture repair

    PMID:15331410

    Open questions at the time
    • Direct BMP-2 binding not yet demonstrated at this stage
    • Opposing chondrocyte versus osteoblast effects mechanistically unexplained
  5. 2011 High

    Demonstrated direct BMP-2 binding and integrin alpha5beta1 dependence, establishing CCN4 as a co-receptor-like enhancer of BMP/Smad osteogenesis in vivo.

    Evidence Immunoprecipitation, adenoviral overexpression, shRNA, integrin-blocking antibody and transgenic mouse bone density analysis

    PMID:20684029

    Open questions at the time
    • Structural basis of the BMP-2/integrin/CCN4 ternary complex unknown
  6. 2015 High

    Showed CCN4 directly binds TGF-beta3 to drive chondrogenesis and that knockout mice fail cartilage repair, extending its growth-factor-potentiating role to TGF-beta.

    Evidence IP-Western for CCN4-TGF-beta3 binding, OE/KD Smad2/3 epistasis, micromass chondrogenesis and Ccn4-KO cartilage defect model

    PMID:26555637

    Open questions at the time
    • Reconciliation with earlier report of CCN4 suppressing TGF-beta1/Smad2 signaling not addressed
  7. 2015 High

    Established CCN4 as a positive regulator of bone mass acting upstream of Wnt by blocking the SOST-LRP6 inhibitory interaction.

    Evidence Wisp1-/- mice with DXA, micro-CT, biomechanics, differentiation assays and SOST-LRP6 binding inhibition assay

    PMID:25864198

    Open questions at the time
    • Whether SOST competition is direct or matrix-mediated not fully resolved
  8. 2013 Medium

    Mapped the integrin-to-protease signaling logic in cancer cells, linking specific integrin heterodimers to MMP induction, adhesion molecules, and migration.

    Evidence Integrin-blocking antibodies, kinase inhibitors, NF-kappaB/AP-1 reporters, ChIP and migration/adhesion assays across chondrosarcoma, synovial fibroblast and OSCC systems

    PMID:21453685 PMID:23313051 PMID:23343403 PMID:24036215 PMID:24205072

    Open questions at the time
    • Cell-type basis for integrin heterodimer selectivity unexplained
    • Most readouts from single labs with overexpression/recombinant protein
  9. 2013 Medium

    Detailed the neuronal/microglial cytoprotection module, showing CCN4 sequesters FoxO3a and PRAS40 via 14-3-3 and tunes TSC2 to sustain mTOR-dependent survival.

    Evidence PI3K/Akt inhibition, co-IP with 14-3-3, subcellular fractionation, gene silencing of PRAS40/TSC2 and apoptosis assays in primary neurons and microglia

    PMID:22272766 PMID:22873724 PMID:23151077 PMID:23244622

    Open questions at the time
    • Upstream receptor coupling CCN4 to Akt in neural cells not identified
    • All from a single lab
  10. 2019 High

    Established cell-force-independent collagen linearization as a direct biophysical CCN4 function driving metastasis.

    Evidence Cell-free in vitro collagen linearization, direct binding assay and in vivo breast cancer metastasis model

    PMID:31294477

    Open questions at the time
    • Molecular mechanism by which CCN4 reorganizes collagen fibrils unresolved
  11. 2019 High

    Identified CCN4 as a FAP-derived niche signal controlling muscle stem cell expansion via Akt, linking its decline to aging-impaired regeneration.

    Evidence Transcriptomics, genetic mouse models, FAP transplantation, systemic WISP1 rescue and Akt pathway analysis

    PMID:30686765

    Open questions at the time
    • Receptor on muscle stem cells mediating the Akt effect not defined
  12. 2022 High

    Defined CCN4 as a driver of fibrosis progression acting through integrin-dependent MRTF activation, validated by genetic loss and therapeutic antibody blockade.

    Evidence Wisp1-/- mice, NASH fibrosis models, anti-WISP1 antibody, MRTF and integrin signaling analysis

    PMID:35987202

    Open questions at the time
    • Specific integrin and intracellular link to MRTF not pinpointed
    • Whether the same axis operates in non-hepatic fibrosis unclear
  13. 2018 Medium

    Identified post-transcriptional (miR-92a) and post-translational (FAT10ylation) controls limiting CCN4 abundance, explaining mRNA/protein discordance.

    Evidence miR-92a mimic/inhibitor with fibrosis model, and FAT10 OE/KD with co-IP and proteasome inhibitor experiments

    PMID:24953558 PMID:29790184

    Open questions at the time
    • FAT10ylation site on CCN4 not mapped
    • Both from single labs without independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CCN4's distinct integrin engagements, growth-factor binding, and direct matrix remodeling are coordinated into context-specific outputs, and what defines its principal signaling receptor, remains unresolved.
  • No structural model of CCN4 with any integrin or growth factor
  • Determinants of integrin heterodimer selectivity across tissues unknown
  • Reconciliation of pro- versus anti-tumor/fibrotic roles across contexts incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3 GO:0048018 receptor ligand activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005576 extracellular region 3 GO:0031012 extracellular matrix 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1474244 Extracellular matrix organization 2
Partners
BGNBMP2COL1A1DCNITGA5ITGB5PPARGTGFB3

Evidence

Reading pass · 54 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 WISP-1 (CCN4) is transcriptionally activated by Wnt-1 and beta-catenin; the CREB site in the WISP-1 promoter plays an important role in this activation, while TCF/LEF sites play only a minor role. Overexpression in NRK-49F cells induces morphological transformation, accelerated cell growth, and tumor formation in nude mice. Promoter cloning and reporter assay; overexpression in NRK-49F cells with nude mouse xenograft Genes & development High 10716946
2002 WISP-1 (CCN4) activates the Akt/PKB anti-apoptotic signaling pathway and prevents p53-dependent cell death following DNA damage by inhibiting mitochondrial cytochrome c release and up-regulating Bcl-X(L); it does not protect against Fas-ligand-activated cell death. Cell-based apoptosis assays with WISP-1 expression, cytochrome c release measurement, Western blot for Bcl-X(L), PI3K/Akt pathway inhibition Genes & development High 11782444
2001 WISP-1 (CCN4) directly binds to the dermatan sulfate proteoglycans decorin and biglycan, and this interaction mediates and modulates WISP-1 binding to the surface of fibroblasts. Competitive inhibition with dermatan sulfate and enzymatic removal of dermatan sulfate from the cell surface blocked WISP-1 binding. Solid-phase binding assay, competitive inhibition with glycosaminoglycans and lyases, mass spectrometric identification of binding factors, direct binding assay with purified decorin and biglycan The Journal of biological chemistry High 11598131
2003 Overexpression of WISP-1 in H460 lung cancer cells inhibits Rac GTPase activation downstream of integrins (alpha-v-beta-5 and alpha-1), reduces MMP-1 expression, and suppresses cell invasion and lung metastasis. Blocking antibodies to alpha(v)beta(5) and alpha(1) integrins restored Rac activation in WISP-1-expressing cells. Rac activation pull-down assay, blocking antibody experiments, constitutively active Rac rescue (RacG12V), microarray/RT-PCR, Matrigel invasion assay, in vivo lung metastasis model The Journal of biological chemistry High 12529380
2004 WISP-1 (CCN4) promotes BMP-2-induced osteoblastic differentiation during embryonic skeletogenesis and fracture repair. In vitro, WISP-1 expression in differentiating osteoblasts potentiates BMP-2 activity; it increases proliferation and saturation density in chondrocytes but represses their differentiation. In situ hybridization, cell binding analysis, stable transfection of chondrocytic cell lines, osteoblast differentiation assays, in vivo fracture repair model The American journal of pathology Medium 15331410
2008 WISP-1 (CCN4) directly regulates TGF-beta1 signaling in human bone marrow stromal cells: recombinant WISP-1 significantly reduces TGF-beta1-induced Smad-2 phosphorylation. Full-length WISP-1 and the splice variant WISP-1va (lacking the putative BMP/TGF-beta binding site) both promote proliferation; however, only full-length WISP-1 modulates osteogenic differentiation in concert with TGF-beta1. Recombinant protein treatment, BrdU incorporation assay, alkaline phosphatase activity, Western blot for Smad-2 phosphorylation, transfection of full-length vs. splice variant Journal of cellular biochemistry Medium 18404666
2009 TNF-alpha induces WISP1 expression in primary human cardiac fibroblasts through an ERK1/2-dependent CREB phosphorylation and transcriptional activation mechanism. WISP1 knockdown attenuates TNF-alpha-stimulated collagen production and cardiac fibroblast proliferation. WISP1 also protects cardiomyocytes from TNF-alpha-mediated death. ERK1/2 inhibition, CREB knockdown, siRNA knockdown of WISP1, reporter gene assays, CREB DNA-binding assay, cell proliferation and collagen production assays The Journal of biological chemistry High 19339243
2011 WISP-1/CCN4 directly binds to BMP-2 and enhances BMP-2 binding to human bone marrow stromal cells (hBMSCs) in a dose-dependent manner, stimulating Smad-1/5/8 phosphorylation and osteogenic differentiation. WISP-1 also induces alpha5-integrin expression and binds to it; anti-integrin alpha5beta1 antibody completely neutralizes WISP-1-enhanced BMP-2 binding. Transgenic WISP-1 overexpression in preosteoblasts increased bone mineral density in vivo. Immunoprecipitation, Western blot, adenoviral overexpression, lentiviral shRNA knockdown, ectopic osteogenesis assay, integrin-blocking antibody experiments, transgenic mouse analysis Journal of bone and mineral research High 20684029
2011 WISP-1 increases MMP-2 expression and cell migration in human chondrosarcoma cells through alpha5beta1 integrin receptor signaling, activating FAK, MEK/ERK, and NF-kappaB; NF-kappaB binds to the MMP-2 promoter. Blocking alpha5beta1 antibody and MEK inhibitors abolished WISP-1-induced MMP-2 upregulation and migration. Migration assay, Western blot for FAK/MEK/ERK phosphorylation, NF-kappaB luciferase reporter, chromatin immunoprecipitation (p65 binding to MMP-2 promoter), integrin-blocking antibody Biochemical pharmacology Medium 21453685
2011 Angiotensin-II induces WISP1 expression in cardiomyocytes via AT1 receptor and NOX2-generated superoxide, activating Akt/GSK3beta/beta-catenin/TCF/LEF and CREB signaling. AT1 physically associates with NOX2 in vitro and in vivo. WISP1 knockdown reduces Ang-II-induced cardiomyocyte hypertrophy. AT1 antagonist (losartan), NOX2 knockdown, siRNA knockdown of WISP1, co-immunoprecipitation of AT1-NOX2, Western blot, in vivo Ang-II infusion model Journal of molecular and cellular cardiology Medium 21376054
2012 WISP1 (CCN4) protects primary hippocampal neurons from oxidant stress-induced apoptosis by activating PI3K/Akt1 signaling, phosphorylating Bad and GSK-3beta, minimizing Bim/Bax complex while increasing Bcl-xL/Bax ratio, and preventing mitochondrial membrane permeabilization, cytochrome c release, and caspase-3 activation. Primary neuron cultures, PI3K and Akt1 pathway inhibition, Western blot for apoptotic proteins, mitochondrial membrane permeability assay, cytochrome c release assay, caspase-3 activity assay Current neurovascular research Medium 22272766
2012 WISP1 (CCN4) prevents FoxO3a-mediated caspase-1 and caspase-3 apoptotic death in neurons via PI3K/Akt1-dependent phosphorylation and cytoplasmic sequestration of FoxO3a with 14-3-3 protein, and maintains protective SIRT1 activity through SIRT1 nuclear trafficking and prevention of caspase-mediated SIRT1 degradation. PI3K/Akt1 inhibition, FoxO3a phosphorylation Western blot, subcellular fractionation, co-immunoprecipitation with 14-3-3, caspase-1/3 activity assays, SIRT1 localization Current neurovascular research Medium 23151077
2012 WISP1 (CCN4) autoregulates its own expression by promoting beta-catenin activity and nuclear trafficking, and inhibits GSK-3beta activity post-translationally to maintain beta-catenin integrity in primary neurons during oxidant stress. WISP1 expression analysis, Akt1 activation assay, GSK-3beta phosphorylation Western blot, beta-catenin subcellular fractionation/nuclear translocation assay Current neurovascular research Medium 22475393
2012 WISP1 (CCN4) activates mTOR and phosphorylates p70S6K and 4EBP1 via control of PRAS40; WISP1 sequesters PRAS40 intracellularly through post-translational phosphorylation and binding to 14-3-3 protein, limiting PRAS40 activity and thereby providing cytoprotection to microglia against beta-amyloid toxicity. mTOR pathway Western blot (p70S6K, 4EBP1 phosphorylation), PRAS40 phosphorylation assay, co-immunoprecipitation with 14-3-3, gene silencing of PRAS40, apoptosis assays Current neurovascular research Medium 22873724
2013 WISP1 (CCN4) controls TSC2 activity by increasing Akt1-mediated TSC2 (Thr1462) phosphorylation and decreasing AMPK-mediated TSC2 (Ser1387) phosphorylation, thereby increasing p70S6K activity and providing cytoprotection to microglia; gene silencing of TSC2 further enhances WISP1-mediated p70S6K phosphorylation but impairs WISP1 cytoprotection, indicating a minimal required level of TSC2 activity. Akt1/AMPK/TSC2/p70S6K phosphorylation Western blot, TSC2 gene silencing, apoptosis assays (PS exposure, DNA degradation, mitochondrial membrane depolarization, cytochrome c release) Current neurovascular research Medium 23244622
2013 CCN4/WISP1 induces IL-6 production in human osteoarthritis synovial fibroblasts through alphavbeta5 integrin (not alpha5beta1 or alphavbeta3), activating PI3K, Akt, and NF-kappaB signaling; alphavbeta5 blocking antibody and PI3K/Akt/NF-kappaB inhibitors all attenuated CCN4-induced IL-6. Neutralizing integrin antibodies, PI3K/Akt/NF-κB pathway inhibitors, NF-κB luciferase reporter, p65 immunocytochemistry (translocation), ELISA for IL-6 Arthritis research & therapy Medium 23343403
2013 CCN4/WISP1 induces VCAM-1 expression in human osteoarthritis synovial fibroblasts via alphavbeta5 or alpha6beta1 integrin, activating Syk, PKCdelta, JNK, c-Jun, and AP-1 signaling; elevated VCAM-1 promotes monocyte adhesion to fibroblasts, which is blocked by VCAM-1 siRNA. Integrin blocking antibodies, kinase inhibitors, AP-1 luciferase reporter, chromatin immunoprecipitation (c-Jun/AP-1 element), siRNA knockdown, monocyte adhesion assay Biochimica et biophysica acta Medium 23313051
2013 WISP-1 enhances migration of human osteosarcoma cells by increasing MMP-2 and MMP-9 expression through integrin receptor-mediated activation of Ras, Raf-1, MEK, ERK, and NF-kappaB signaling; siRNA knockdown of Ras or Raf-1 and specific inhibitors abolished WISP-1-induced migration and MMP expression. Ras/Raf-1 siRNA and inhibitors, MEK/ERK inhibitors, NF-κB inhibitors, migration assay, MMP Western blot/ELISA Cellular signalling Medium 24036215
2013 WISP-1 increases OSCC cell migration and ICAM-1 expression through alphavbeta3 integrin, activating ASK1, JNK/p38, and AP-1 signaling pathways. Integrin alphavbeta3 blocking antibody, ASK1/JNK/p38 inhibitors, AP-1 luciferase reporter, migration assay, ICAM-1 Western blot PloS one Medium 24205072
2014 WISP1 (CCN4) is secreted from differentiated human adipocytes (validated as an adipokine) and stimulates a proinflammatory response in human macrophages. WISP1 expression and secretion increase during human adipocyte differentiation and are regulated by weight changes in humans and mice. WISP1 ELISA from conditioned media, macrophage stimulation assay with recombinant WISP1, in vivo weight-change models Diabetes Medium 25281430
2014 miR-92a post-transcriptionally represses WISP1 expression in lung fibroblasts; TGF-beta1 increases WISP1 expression while decreasing miR-92a, and miR-92a overexpression reverses TGF-beta1-induced WISP1 mRNA expression. An inverse relationship between WISP1 and miR-92a was confirmed in vivo in a TGF-beta1-dependent fibrosis model. Supervised machine learning miRNA target prediction, miR-92a mimic/inhibitor transfection, qPCR and ELISA for WISP1, in vivo TGF-beta1 fibrosis mouse model, ex vivo primary IPF fibroblasts The international journal of biochemistry & cell biology Medium 24953558
2015 WISP1 (CCN4) deficiency in mice reduces bone mineral density, decreases trabecular bone volume and cortical thickness, impairs osteoblast progenitor differentiation, and increases osteoclast differentiation. WISP1 inhibits SOST binding to LRP6, thereby maintaining Wnt/beta-catenin signaling in bone marrow stromal cells; Wisp1-/- cells show reduced beta-catenin and its target gene expression. Wisp1-/- knockout mouse generation, DXA, micro-CT, biomechanical testing, in vitro osteoblast/osteoclast differentiation assays, SOST-LRP6 binding inhibition assay, beta-catenin Western blot, ovariectomy model The Journal of biological chemistry High 25864198
2015 CCN4/WISP1 directly binds TGF-beta3 (shown by immunoprecipitation-western blot) and enhances TGF-beta3-induced SMAD2/3 phosphorylation and chondrogenesis of human bone marrow stromal cells in micromass culture. CCN4 knockdown inhibits TGF-beta3-induced SMAD2/3 phosphorylation and cartilage matrix synthesis. Ccn4-KO mice show reduced chondrocyte marker expression and fail to repair articular cartilage defects. Adenoviral overexpression and siRNA knockdown of CCN4, SMAD2/3 phosphorylation Western blot, micromass culture chondrogenesis assay, immunoprecipitation-western blot for CCN4-TGF-beta3 binding, Ccn4-KO mouse cartilage defect model Bone High 26555637
2015 WISP-1 promotes angiogenesis in oral squamous cell carcinoma by inducing VEGF-A expression via the integrin alphavbeta3/FAK/c-Src pathway, which transactivates EGFR/ERK/HIF-1alpha signaling. This in turn recruits endothelial progenitor cells and triggers neovascularization in vitro and in vivo. Integrin alphavbeta3 blocking, FAK/c-Src/EGFR/ERK/HIF-1alpha inhibitors and siRNA, EPC tube formation/migration assay, in vivo xenograft angiogenesis model Oncotarget Medium 25738362
2016 WISP1 is required for TGF-beta1- and TNF-alpha-dependent induction of IL-6 in primary human lung fibroblasts; siRNA-mediated WISP1 knockdown or antibody-mediated neutralization reduces fibroblast proliferation, which is partially rescued by exogenous IL-6, establishing a WISP1-IL-6 pro-proliferative axis. Luciferase reporter for WISP1 promoter, siRNA knockdown, antibody neutralization, ELISA for IL-6, proliferation assay, IL-6 rescue experiment Scientific reports Medium 26867691
2016 WISP-1 promotes VEGF-C expression and lymphangiogenesis in OSCC cells via integrin alphavbeta3/ILK/Akt signaling, and this cascade inhibits miR-300 expression. Conditioned media from WISP-1-treated OSCC cells promotes tube formation and migration in lymphatic endothelial cells. Integrin alphavbeta3/ILK/Akt inhibitors, VEGF-C ELISA, lymphatic endothelial cell tube formation and migration assay, miR-300 expression analysis Oncotarget Medium 26824419
2016 Wnt2 induces WISP-1 expression in vascular smooth muscle cells (VSMCs) via beta-catenin/TCF signaling; recombinant WISP-1 promotes VSMC migration in an integrin-dependent manner. WISP-1-/- mice show significantly suppressed intimal thickening after carotid artery ligation, and adenoviral elevation of plasma WISP-1 increases intimal thickening in vivo. siRNA knockdown of Wnt2 and WISP-1, VSMC migration assay, integrin dependence test, WISP-1-/- mouse carotid ligation model, adenoviral WISP-1 overexpression in vivo Arteriosclerosis, thrombosis, and vascular biology High 27199447
2017 Macrophage-derived IL-10, secreted following intestinal mucosal injury, activates epithelial CREB, which drives WISP-1 synthesis and secretion. WISP-1 then induces epithelial cell proliferation and wound closure. Conditional deletion of IL-10 in CD11c+ macrophages impairs wound closure, establishing an IL-10/CREB/WISP-1 signaling axis. Conditional CD11c-specific IL-10 knockout mice, Rag1-/- mice, in vitro CREB activation assay, WISP-1 protein measurement, wound closure assay, cell proliferation assay The Journal of clinical investigation High 28783045
2017 WISP-1 promotes VEGF-A expression and angiogenesis in osteosarcoma through FAK/JNK/HIF-1alpha signaling and downregulation of miR-381; FAK, JNK, and HIF-1alpha inhibitors or siRNA abolished WISP-1-induced VEGF-A expression and angiogenesis both in vitro and in vivo. FAK/JNK/HIF-1alpha inhibitors and siRNA, VEGF-A ELISA, EPC migration/tube formation assay, miR-381 expression analysis, in vivo xenograft angiogenesis model Cell death & disease Medium 28406476
2017 WISP1/CCN4 inhibits adipocyte differentiation by repressing PPARgamma transcriptional activity; a direct physical association between WISP1 and PPARgamma was demonstrated, followed by proteasome-dependent degradation of PPARgamma. Silencing WISP1 enhanced adipocyte differentiation. Overexpression and siRNA knockdown in 3T3-F442A cells, PPARgamma transcriptional activity reporter, co-immunoprecipitation of WISP1 with PPARgamma, proteasome inhibitor treatment, adipogenic marker expression Scientific reports Medium 28496206
2018 CCN4/WISP1 stimulates dermal fibroblast migration and proliferation via alpha5beta1 integrin receptors, activating ERK/JNK signaling downstream. CCN4 also counterbalances TNF-alpha-mediated inhibition of COL1A1 and FN and stimulation of MMPs by inhibiting NF-kappaB/p65 signaling. Ccn4-KO mice show delayed wound closure with reduced Col1a1 and fibronectin expression. Ccn4-KO mice, Boyden chamber migration assay, siRNA knockdown, adenoviral CCN4 transduction, integrin alpha5beta1 blocking antibody, ERK/JNK Western blot, NF-kappaB signaling assay, gene expression analysis Matrix biology High 29330021
2018 Osteoblast-derived WISP-1 promotes adherence of prostate cancer cells to osteoblasts via a VCAM-1/integrin alpha4beta1 system: WISP-1 induces VCAM-1 expression in PCa cells and integrin alpha4beta1 expression in osteoblasts via the MAPK pathway; blocking VCAM-1 or integrin alpha4beta1 attenuates cancer cell adhesion. WISP-1 also induces BMP2, BMP4, and osteopontin in osteoblasts and inhibits RANKL-dependent osteoclastogenesis. VCAM-1 and integrin alpha4beta1 blocking antibodies, MAPK pathway analysis, BMP2/4/OPN expression assay, osteoclastogenesis assay Cancer letters Medium 29627497
2018 WISP1 impairs insulin action in human skeletal muscle cells and mouse hepatocytes by inhibiting phosphorylation of insulin receptor, Akt, GSK-3beta, FOXO1, and p70S6K, and by inhibiting insulin-stimulated glycogen synthesis and suppression of gluconeogenic genes. Recombinant WISP1 treatment of primary human skeletal muscle cells and AML12 hepatocytes, insulin signaling Western blot, glycogen synthesis assay, gluconeogenic gene expression Diabetologia Medium 29754289
2018 WISP1 contributes to sepsis-induced acute lung injury via a WISP1-alphavbeta3 integrin signaling pathway in macrophages: TLR4 activation induces de novo synthesis of alphavbeta3 via ERK (MyD88/NF-kappaB dependent), enabling WISP1 to stimulate TNF-alpha release. This effect was absent in beta3-/- macrophages. TLR4-/-, MyD88-/-, TRIF-/-, beta3-/- mouse macrophages, ERK inhibitor, siRNA knockdown, anti-WISP1/anti-integrin beta5 antibodies in vivo two-hit model Scientific reports Medium 27349568
2018 In mechanical ventilation plus sepsis-induced acute lung injury, WISP1 levels are increased intrapulmonarily via TLR4 signaling; WISP1 signals through integrin beta5 to amplify TLR4-mediated inflammation. Neutralizing WISP1 or integrin beta5 antibodies partially inhibited the two-hit ALI phenotype. In macrophages, TLR4 increases integrin beta5 expression in a MyD88/NF-kappaB-dependent manner, and WISP1 requires integrin beta5 for enhanced cytokine release. TLR4-/-, MyD88-/-, TRIF-/- mice; anti-WISP1 and anti-integrin beta5 antibodies in vivo; siRNA knockdown of TLR4 and integrin beta5 in macrophages; cytokine ELISA Critical care Medium 30445996
2019 WISP1 (CCN4) is a FAP-derived matricellular signal in the muscle stem cell niche that controls expansion and asymmetric commitment of muscle stem cells (MuSCs) through Akt signaling. Loss of WISP1 from aged fibro-adipogenic progenitors (FAPs) contributes to impaired MuSC function; transplantation of young FAPs or systemic WISP1 treatment rescues myogenic capacity in aged mice. Transcriptomic profiling, genetic mouse models, FAP transplantation, systemic WISP1 administration, Akt signaling Western blot, MuSC expansion and differentiation assays Cell stem cell High 30686765
2019 WISP1 (CCN4) directly binds type I collagen to promote its linearization in vitro (in the absence of cells) and in vivo in tumors, thereby facilitating cancer cell invasion and promoting spontaneous breast cancer metastasis. This collagen linearization is independent of cell-generated mechanical forces. Cell-free in vitro collagen linearization assay with recombinant WISP1, direct WISP1-collagen binding assay, in vivo tumor collagen imaging, breast cancer metastasis mouse model with WISP1 manipulation The EMBO journal High 31294477
2019 WISP1 in glioblastoma signals through Integrin alpha6beta1-Akt to maintain glioma stem cells (GSCs) by autocrine mechanism, and promotes M2 tumor-associated macrophage survival by paracrine mechanism. WISP1 is regulated by Wnt/beta-catenin in GSCs, and carnosic acid inhibits this axis to suppress GBM growth. WISP1 silencing in GSCs, integrin alpha6beta1-Akt pathway analysis, autocrine/paracrine assays, GSC maintenance and TAM survival assays, carnosic acid treatment Nature communications Medium 32541784
2019 WISP1 knockout in melanoma cells increases proliferation but represses migration, invasion, and metastasis. WISP1 promotes an EMT-like gene expression signature (E-cadherin repression, fibronectin/N-cadherin induction) by activating AKT and MEK/ERK signaling; WISP1 knockout-associated metastasis repression is reversed by reintroduction of WISP1 or SNAI1. WISP1 knockout (B16F10, YUMM1.7), transwell invasion/migration assays, gene expression profiling, recombinant WISP1 rescue, SNAI1 reintroduction, AKT/MEK/ERK kinase inhibitors, in vivo metastasis assays in C57BL/6 and NSG mice The Journal of biological chemistry High 30723155
2019 WISP-1 promotes EMT in OSCC cells via FAK/ILK/Akt and Snail signaling and downregulates miR-153-3p expression; the miR-153-3p/Snail axis mediates WISP-1-induced EMT. FAK/ILK/Akt inhibitors, Snail expression analysis, miR-153-3p expression measurement, EMT marker Western blot Cancers Medium 31795469
2020 Wisp1 promotes proliferation of adult mouse and human pancreatic beta cells in vivo; the beta cell trophic effect is dependent on Akt signaling, as shown using isolated mouse and human islets. Wisp1 is more abundant in pre-weaning than adult mice serum. In vivo Wisp1 administration, transplanted beta cell proliferation assay, isolated islet culture with Wisp1, Akt pathway inhibition, ELISA for circulating Wisp1 Nature communications Medium 33239617
2020 FAT10 (a ubiquitin-like protein) degrades WISP1 protein via FAT10ylation (direct post-translational modification), while simultaneously stabilizing beta-catenin to increase WISP1 mRNA, creating a protein/mRNA expression discordance. FAT10 overexpression-induced WISP1 protein decrease promotes hepatocellular carcinoma proliferation. FAT10 overexpression and knockdown, co-immunoprecipitation for FAT10-WISP1 interaction, proteasome inhibitor experiments, beta-catenin stabilization assay, WISP1 mRNA and protein quantification, in vitro and in vivo HCC proliferation assays Hepatology Medium 29790184
2021 WISP-1 promotes fibrosis and hypertrophy of the ligamentum flavum by activating the Hedgehog-Gli1 signaling pathway in fibroblasts; mechanical stress increases WISP-1 expression, and WISP-1 induces myofibroblast transition via Hedgehog signaling. Cyclopamine (Hedgehog inhibitor) attenuated WISP-1-induced fibrogenesis in vitro and in the in vivo mechanical stress rabbit model. Mechanical stretch, WISP-1 treatment of LF fibroblasts, Hedgehog-Gli1 pathway Western blot/reporter, cyclopamine inhibition, alpha-SMA expression, in vivo rabbit mechanical stress model Experimental & molecular medicine Medium 34158608
2022 WISP1 drives liver fibrosis progression (not onset) through integrin-dependent activation of MRTF (myocardin-related transcription factor), leading to transcriptional reprogramming of myofibroblast cytoskeleton and motility. WISP1-deficient mice are protected against fibrosis progression; a therapeutic anti-WISP1 antibody halted progression of established fibrosis in NASH models. Wisp1-/- mice, NASH fibrosis mouse models, anti-WISP1 antibody treatment, MRTF pathway analysis, integrin signaling assay, myofibroblast cytoskeleton and motility readouts Cell metabolism High 35987202
2022 Apoptotic cancer cell-derived signals activate Notch1 signaling in cancer-associated fibroblasts (CAFs) via the DLL1/BAI1-Rac1 efferocytosis pathway, inducing WISP-1 secretion which suppresses CAF activation and inhibits cancer cell migration/invasion and lung metastasis. Notch1 inhibition or siRNA blocked WISP-1 production and reversed the antimetastatic effects. Pharmacological Notch1 inhibition, siRNA Notch1 silencing, WISP-1 immunodepletion from conditioned media, migration/invasion assays, syngeneic mouse lung metastasis model, CAF marker expression assay Cellular & molecular immunology Medium 36241874
2015 WISP-1 full-length protein and C-terminal domain-containing truncations (VWC, TSP, CT domains) promote epithelial cell adhesion in an integrin-dependent manner (partially mediated by alphavbeta5, alphavbeta3, and beta1 integrins). Beta-catenin activation and CXCL3 secretion also reside within the C-terminal domains of WISP-1 but are not blocked by integrin neutralizing antibodies. Native WISP-1 from human lung tissue exists as a high-order oligomer. Baculovirus expression of truncated WISP-1 proteins, cell adhesion assay, integrin-blocking antibodies, beta-catenin reporter assay, CXCL3 ELISA, size-exclusion analysis of native protein Journal of cell communication and signaling Medium 25657057
2012 Notch1 activation in fibroblasts induces WISP-1 expression in a Wnt11-dependent (but Wnt1-independent) manner; WISP-1 suppresses fibroblast proliferation and mediates Notch1's growth-inhibitory effect, since siRNA blockade of WISP-1 relieves Notch1-induced growth inhibition. Notch1 knockout MEFs, NICD1 overexpression, DN-MAML-1, Wnt11 knockdown, WISP-1 siRNA, cell growth and motility assays PloS one Medium 22715413
2018 WISP1 (Wisp-1) is a cardiac angiokine whose transcription is regulated by HDACs; HDAC inhibition with SAHA post-MI elevates Wisp-1 expression in the border zone. Human coronary artery endothelial cells produce WISP-1 and respond to autocrine WISP-1 signaling that promotes their pro-angiogenic behavior; altering endogenous WISP-1 in HCAECs directly impacts network density in vitro. HDAC inhibitor (SAHA) treatment, post-MI mouse model, WISP-1 expression measurement, HCAEC WISP-1 knockdown/overexpression, endothelial network formation assay JCI insight Medium 29467324
2017 WISP1 in osteoarthritis promotes expression of MMP3, MMP9, ADAMTS4, and ADAMTS5 in synovial tissue (increasing cartilage catabolism). Wisp1-/- mice show significantly decreased cartilage degeneration in three independent experimental OA models (collagenase injection, DMM, ACLT), with reduced protease expression and decreased aggrecan cleavage (NITEGE neoepitope). Aging-related spontaneous cartilage degeneration was not decreased in Wisp1-/- mice. Wisp1-/- knockout mice, three independent OA induction models, qRT-PCR for proteases, NITEGE immunohistochemistry, micro-CT, recombinant WISP1 stimulation of human OA synovium Osteoarthritis and cartilage High 28735021
2009 Nitric oxide (NO) increases WISP-1 expression in colonic epithelial cells through a beta-catenin- and CREB-dependent, but Wnt-1-independent, pathway. NO-induced WISP-1 then directly induces soluble collagen secretion in colonic fibroblast cells. In iNOS-/- mice, colitis-related WISP-1 increase was significantly attenuated. NO donor (DETA-NONOate) treatment, beta-catenin and CREB pathway inhibition, WISP-1 mRNA/protein measurement, collagen secretion assay in fibroblasts, iNOS-/- mouse colitis models Journal of molecular medicine Medium 19238344
2015 Wisp1 mediates Bmp3-stimulated mesenchymal stem cell (MSC) proliferation: Bmp3 upregulates Wisp1 expression prior to MSC proliferation, recombinant Wisp1 stimulates MSC proliferation in a concentration-dependent manner, and siRNA-mediated Wisp1 knockdown attenuates Bmp3-induced proliferation. DNA microarray, recombinant Wisp1 treatment, [3H]-thymidine incorporation, siRNA knockdown of Wisp1, Bmp3 treatment Journal of molecular endocrinology Medium 26489765
2007 CCN4/WISP1 splice variants are expressed in chondrocytes: full-length WISP1, WISP1v (lacking the second module/VWC domain), and a novel WISP1vx (lacking second, third modules and part of first). WISP1v expression increases dramatically during terminal chondrocyte differentiation and overexpression of WISP1v promotes alkaline phosphatase gene expression (a marker of terminal differentiation), suggesting WISP1v plays a role in endochondral ossification. RT-PCR characterization of splice variants, primary chondrocyte differentiation culture, WISP1v overexpression, alkaline phosphatase gene expression assay The FEBS journal Medium 17381509
2018 WISP1 promotes non-alcoholic fatty liver disease and skeletal muscle insulin resistance through a TLR4-activated inflammation/JNK signaling pathway; WISP1 increases JNK phosphorylation, NF-kappaB-dependent inflammation, lipogenesis, and triglyceride accumulation in hepatocytes and suppresses insulin signaling in muscle cells. These effects were abrogated by NF-kappaB, JNK, and TLR4 knockdown. WISP1 treatment of mouse hepatocytes and C2C12 cells, NF-kappaB/JNK/TLR4 siRNA knockdown, Western blot for insulin signaling, triglyceride accumulation assay, in vivo WISP1 knockdown in HFD mice Journal of cellular physiology Medium 29319180
2016 WISP1 overexpression stimulates proliferation and migration of human VSMCs via AKT signaling; WISP1 increases GSK3alpha/beta phosphorylation, cyclin D1, and MMP9 expression. AKT inhibitor (AZD5363) and PI3K inhibitor (LY294002) abolished WISP1-induced proliferation and migration and downstream target expression. Adenoviral WISP1 overexpression, EdU incorporation assay, scratch wound healing, transwell migration, AKT/PI3K inhibition, Western blot for cyclin D1/MMP9/GSK3 European journal of pharmacology Medium 27321870

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 WISP-1 is a Wnt-1- and beta-catenin-responsive oncogene. Genes & development 274 10716946
2001 Elevated levels of connective tissue growth factor, WISP-1, and CYR61 in primary breast cancers associated with more advanced features. Cancer research 269 11751417
2019 Aging Disrupts Muscle Stem Cell Function by Impairing Matricellular WISP1 Secretion from Fibro-Adipogenic Progenitors. Cell stem cell 255 30686765
2017 Macrophage-derived IL-10 mediates mucosal repair by epithelial WISP-1 signaling. The Journal of clinical investigation 168 28783045
2020 Dual Role of WISP1 in maintaining glioma stem cells and tumor-supportive macrophages in glioblastoma. Nature communications 140 32541784
2002 WISP-1 attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase. Genes & development 134 11782444
2004 WISP-1 is an osteoblastic regulator expressed during skeletal development and fracture repair. The American journal of pathology 130 15331410
2007 Expression of Cyr61, CTGF, and WISP-1 correlates with clinical features of lung cancer. PloS one 125 17579708
2011 WISP-1/CCN4 regulates osteogenesis by enhancing BMP-2 activity. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 121 20684029
2014 WISP1 is a novel adipokine linked to inflammation in obesity. Diabetes 105 25281430
2009 WISP1, a pro-mitogenic, pro-survival factor, mediates tumor necrosis factor-alpha (TNF-alpha)-stimulated cardiac fibroblast proliferation but inhibits TNF-alpha-induced cardiomyocyte death. The Journal of biological chemistry 104 19339243
2001 WISP-1 binds to decorin and biglycan. The Journal of biological chemistry 101 11598131
2010 WNT1 inducible signaling pathway protein 1 (WISP1): a novel mediator linking development and disease. The international journal of biochemistry & cell biology 98 21109017
2003 Overexpression of WISP-1 down-regulated motility and invasion of lung cancer cells through inhibition of Rac activation. The Journal of biological chemistry 97 12529380
2014 WISP1: Clinical insights for a proliferative and restorative member of the CCN family. Current neurovascular research 82 25219658
2015 CCN4/WISP1 (WNT1 inducible signaling pathway protein 1): a focus on its role in cancer. The international journal of biochemistry & cell biology 80 25794425
2014 miR-92a regulates TGF-β1-induced WISP1 expression in pulmonary fibrosis. The international journal of biochemistry & cell biology 80 24953558
2015 WNT1-induced Secreted Protein-1 (WISP1), a Novel Regulator of Bone Turnover and Wnt Signaling. The Journal of biological chemistry 73 25864198
2018 The official unified nomenclature adopted by the HGNC calls for the use of the acronyms, CCN1-6, and discontinuation in the use of CYR61, CTGF, NOV and WISP 1-3 respectively. Journal of cell communication and signaling 69 30393824
2011 Angiotensin-II type 1 receptor and NOX2 mediate TCF/LEF and CREB dependent WISP1 induction and cardiomyocyte hypertrophy. Journal of molecular and cellular cardiology 69 21376054
2017 WISP-1 positively regulates angiogenesis by controlling VEGF-A expression in human osteosarcoma. Cell death & disease 68 28406476
2018 CCN4/WISP1 controls cutaneous wound healing by modulating proliferation, migration and ECM expression in dermal fibroblasts via α5β1 and TNFα. Matrix biology : journal of the International Society for Matrix Biology 66 29330021
2016 Picking a bone with WISP1 (CCN4): new strategies against degenerative joint disease. Journal of translational science 65 26893943
2018 Osteoblast-secreted WISP-1 promotes adherence of prostate cancer cells to bone via the VCAM-1/integrin α4β1 system. Cancer letters 64 29627497
2013 CCN4 induces IL-6 production through αvβ5 receptor, PI3K, Akt, and NF-κB singling pathway in human synovial fibroblasts. Arthritis research & therapy 64 23343403
2012 WISP1 (CCN4) autoregulates its expression and nuclear trafficking of β-catenin during oxidant stress with limited effects upon neuronal autophagy. Current neurovascular research 59 22475393
2011 WISP-1 increases MMP-2 expression and cell motility in human chondrosarcoma cells. Biochemical pharmacology 59 21453685
2013 WISP1/CCN4: a potential target for inhibiting prostate cancer growth and spread to bone. PloS one 58 23977121
2015 WISP-1 a novel angiogenic regulator of the CCN family promotes oral squamous cell carcinoma angiogenesis through VEGF-A expression. Oncotarget 57 25738362
2012 Wnt1 inducible signaling pathway protein 1 (WISP1) targets PRAS40 to govern β-amyloid apoptotic injury of microglia. Current neurovascular research 57 22873724
2016 WISP1 mediates IL-6-dependent proliferation in primary human lung fibroblasts. Scientific reports 56 26867691
2012 Wnt1 inducible signaling pathway protein 1 (WISP1) blocks neurodegeneration through phosphoinositide 3 kinase/Akt1 and apoptotic mitochondrial signaling involving Bad, Bax, Bim, and Bcl-xL. Current neurovascular research 56 22272766
2015 Targeting WISP1 to sensitize esophageal squamous cell carcinoma to irradiation. Oncotarget 52 25749038
2008 TGF-beta1 and WISP-1/CCN-4 can regulate each other's activity to cooperatively control osteoblast function. Journal of cellular biochemistry 52 18404666
2019 The tumor cell-secreted matricellular protein WISP1 drives pro-metastatic collagen linearization. The EMBO journal 50 31294477
2016 Wnt2 and WISP-1/CCN4 Induce Intimal Thickening via Promotion of Smooth Muscle Cell Migration. Arteriosclerosis, thrombosis, and vascular biology 50 27199447
2013 Tuberous sclerosis protein 2 (TSC2) modulates CCN4 cytoprotection during apoptotic amyloid toxicity in microglia. Current neurovascular research 50 23244622
2011 Clinical significance of Wnt-induced secreted protein-1 (WISP-1/CCN4) in esophageal squamous cell carcinoma. Anticancer research 49 21498727
2022 Reprogramming of cancer-associated fibroblasts by apoptotic cancer cells inhibits lung metastasis via Notch1-WISP-1 signaling. Cellular & molecular immunology 48 36241874
2018 Mechanical ventilation enhances extrapulmonary sepsis-induced lung injury: role of WISP1-αvβ5 integrin pathway in TLR4-mediated inflammation and injury. Critical care (London, England) 47 30445996
2019 WNT1-inducible signaling pathway protein 1 (WISP1/CCN4) stimulates melanoma invasion and metastasis by promoting the epithelial-mesenchymal transition. The Journal of biological chemistry 46 30723155
2018 Human Leukocyte Antigen F Locus Adjacent Transcript 10 Overexpression Disturbs WISP1 Protein and mRNA Expression to Promote Hepatocellular Carcinoma Progression. Hepatology (Baltimore, Md.) 46 29790184
2017 WISP1 Is a Marker of Systemic and Adipose Tissue Inflammation in Dysmetabolic Subjects With or Without Type 2 Diabetes. Journal of the Endocrine Society 46 29264519
2013 WISP1 neuroprotection requires FoxO3a post-translational modulation with autoregulatory control of SIRT1. Current neurovascular research 46 23151077
2016 WISP1-αvβ3 integrin signaling positively regulates TLR-triggered inflammation response in sepsis induced lung injury. Scientific reports 45 27349568
2019 WISP-1 Promotes Epithelial-Mesenchymal Transition in Oral Squamous Cell Carcinoma Cells Via the miR-153-3p/Snail Axis. Cancers 44 31795469
2005 A comparative study of the expression of Wnt-1, WISP-1, survivin and cyclin-D1 in colorectal carcinoma. International journal of colorectal disease 43 16041507
2007 Expression and physiological role of CCN4/Wnt-induced secreted protein 1 mRNA splicing variants in chondrocytes. The FEBS journal 42 17381509
2017 WISP1/CCN4 aggravates cartilage degeneration in experimental osteoarthritis. Osteoarthritis and cartilage 41 28735021
2013 Apoptosis signal-regulating kinase 1 is involved in WISP-1-promoted cell motility in human oral squamous cell carcinoma cells. PloS one 41 24205072
2022 A WISP1 antibody inhibits MRTF signaling to prevent the progression of established liver fibrosis. Cell metabolism 40 35987202
2016 WISP-1 promotes VEGF-C-dependent lymphangiogenesis by inhibiting miR-300 in human oral squamous cell carcinoma cells. Oncotarget 40 26824419
2013 CCN4 regulates vascular smooth muscle cell migration and proliferation. Molecules and cells 40 23807044
2018 The novel adipokine WISP1 associates with insulin resistance and impairs insulin action in human myotubes and mouse hepatocytes. Diabetologia 38 29754289
2017 WISP1/CCN4 inhibits adipocyte differentiation through repression of PPARγ activity. Scientific reports 38 28496206
2013 Ras activation mediates WISP-1-induced increases in cell motility and matrix metalloproteinase expression in human osteosarcoma. Cellular signalling 37 24036215
2009 Nitric oxide increases Wnt-induced secreted protein-1 (WISP-1/CCN4) expression and function in colitis. Journal of molecular medicine (Berlin, Germany) 37 19238344
2020 Wisp1 is a circulating factor that stimulates proliferation of adult mouse and human beta cells. Nature communications 35 33239617
2003 Overexpression of a set of genes, including WISP-1, common to pulmonary metastases of both mouse D122 Lewis lung carcinoma and B16-F10.9 melanoma cell lines. British journal of cancer 35 12865923
2018 WISP1 promotes non-alcoholic fatty liver disease and skeletal muscle insulin resistance via TLR4/JNK signaling. Journal of cellular physiology 34 29319180
2014 Wnt-induced secreted protein 1/CCN4 in liver fibrosis both in vitro and in vivo. Clinical laboratory 34 24600972
2020 Prospects and Perspectives for WISP1 (CCN4) in Diabetes Mellitus. Current neurovascular research 32 32216738
2019 Circ_KATNAL1 regulates prostate cancer cell growth and invasiveness through the miR-145-3p/WISP1 pathway. Biochemistry and cell biology = Biochimie et biologie cellulaire 31 31800303
2015 CCN4/WISP-1 positively regulates chondrogenesis by controlling TGF-β3 function. Bone 31 26555637
2017 Assessment of circulating Wnt1 inducible signalling pathway protein 1 (WISP-1)/CCN4 as a novel biomarker of obesity. Journal of cell communication and signaling 30 29129025
2013 CCN4 induces vascular cell adhesion molecule-1 expression in human synovial fibroblasts and promotes monocyte adhesion. Biochimica et biophysica acta 30 23313051
2001 Differential expression of WISP-1 and WISP-2 genes in normal and transformed human breast cell lines. Molecular and cellular biochemistry 30 11855747
2019 Circulating Wnt1-inducible signaling pathway protein-1 (WISP-1/CCN4) is a novel biomarker of adiposity in subjects with type 2 diabetes. Journal of cell communication and signaling 29 31782053
2015 Blockade of CCN4 attenuates CCl4-induced liver fibrosis. Archives of medical science : AMS 29 26170860
2019 WISP1 is associated to advanced disease, EMT and an inflamed tumor microenvironment in multiple solid tumors. Oncoimmunology 27 31069142
2017 Serum levels of WNT1-inducible signaling pathway protein-1 (WISP-1): a noninvasive biomarker of renal fibrosis in subjects with chronic kidney disease. American journal of translational research 27 28670380
2015 Identification and validation of WISP1 as an epigenetic regulator of metastasis in oral squamous cell carcinoma. Genes, chromosomes & cancer 27 26391330
2015 Wisp1 mediates Bmp3-stimulated mesenchymal stem cell proliferation. Journal of molecular endocrinology 27 26489765
2017 Identification of WISP1 as a novel oncogene in glioblastoma. International journal of oncology 26 28902353
2016 WISP1 overexpression promotes proliferation and migration of human vascular smooth muscle cells via AKT signaling pathway. European journal of pharmacology 26 27321870
2014 WISP1 polymorphisms contribute to platinum-based chemotherapy toxicity in lung cancer patients. International journal of molecular sciences 26 25405734
2007 Overexpression of connective tissue growth factor WISP-1 in Chinese primary rectal cancer patients. World journal of gastroenterology 26 17657846
2021 WISP-1 induced by mechanical stress contributes to fibrosis and hypertrophy of the ligamentum flavum through Hedgehog-Gli1 signaling. Experimental & molecular medicine 25 34158608
2018 Angiokine Wisp-1 is increased in myocardial infarction and regulates cardiac endothelial signaling. JCI insight 25 29467324
2013 Expression of FAP, ADAM12, WISP1, and SOX11 is heterogeneous in aggressive fibromatosis and spatially relates to the histologic features of tumor activity. Cancer medicine 25 24402778
2020 MiR-128-3p Post-Transcriptionally Inhibits WISP1 to Suppress Apoptosis and Inflammation in Human Articular Chondrocytes via the PI3K/AKT/NF-κB Signaling Pathway. Cell transplantation 24 32830547
2015 A functional analysis of Wnt inducible signalling pathway protein -1 (WISP-1/CCN4). Journal of cell communication and signaling 24 25657057
2024 An overview of CCN4 (WISP1) role in human diseases. Journal of translational medicine 21 38937782
2020 Exercise intervention lowers aberrant serum WISP-1 levels with insulin resistance in breast cancer survivors: a randomized controlled trial. Scientific reports 21 32616883
2021 LncRNA AFAP1-AS1 Promotes the Progression of Colorectal Cancer through miR-195-5p and WISP1. Journal of oncology 20 34335760
2020 MicroRNA-29b-3p enhances radiosensitivity through modulating WISP1-mediated mitochondrial apoptosis in prostate cancer cells. Journal of Cancer 20 33033519
2016 Notch1-WISP-1 axis determines the regulatory role of mesenchymal stem cell-derived stromal fibroblasts in melanoma metastasis. Oncotarget 20 27813493
2012 Inhibition of fibroblast growth by Notch1 signaling is mediated by induction of Wnt11-dependent WISP-1. PloS one 20 22715413
2022 Antihyperglycemic effect of an anthocyanin, cyanidin-3-O-glucoside, is achieved by regulating GLUT-1 via the Wnt/β-catenin-WISP1 signaling pathway. Food & function 19 35357376
2019 Increased WISP1 expression in human osteoarthritic articular cartilage is epigenetically regulated and decreases cartilage matrix production. Rheumatology (Oxford, England) 19 30649473
2018 MicroRNA-384 regulates cell proliferation and apoptosis through directly targeting WISP1 in laryngeal cancer. Journal of cellular biochemistry 19 30548664
2014 WISP 1 is an important survival factor in human mesenchymal stromal cells. Gene 19 25200494
2021 Hepatic Wnt1 Inducible Signaling Pathway Protein 1 (WISP-1/CCN4) Associates with Markers of Liver Fibrosis in Severe Obesity. Cells 18 33946738
2020 Association of WISP1/CCN4 with Risk of Overweight and Gestational Diabetes Mellitus in Chinese Pregnant Women. Disease markers 18 32377270
2020 WISP1 alleviates lipid deposition in macrophages via the PPARγ/CD36 pathway in the plaque formation of atherosclerosis. Journal of cellular and molecular medicine 18 32851768
2024 Silencing of METTL3 prevents the proliferation, migration, epithelial-mesenchymal transition, and renal fibrosis of high glucose-induced HK2 cells by mediating WISP1 in m6A-dependent manner. Aging 17 38289593
2021 Knockdown of long non-coding RNA CCAT2 suppresses growth and metastasis of esophageal squamous cell carcinoma by inhibiting the β-catenin/WISP1 signaling pathway. The Journal of international medical research 17 34057837
2020 Endogenous CCN family member WISP1 inhibits trauma-induced heterotopic ossification. JCI insight 17 32484792
2016 WISP1 mediates hepatic warm ischemia reperfusion injury via TLR4 signaling in mice. Scientific reports 17 26821752
2016 WISP1 Is Increased in Intestinal Mucosa and Contributes to Inflammatory Cascades in Inflammatory Bowel Disease. Disease markers 17 27403031

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