CCN1: a novel target for pancreatic cancer

Leask, Andrew

doi:10.1007/s12079-011-0127-1

Cited by 14 publications

(10 citation statements)

References 15 publications

(21 reference statements)

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“…Prior studies indicated CCN1-activated integrin receptor applying to arthritis [41], [42]: binding of CCN1 to αvβ5 or α6β1 could promote cell apoptosis and reactive oxygen species generation [43]. Our results prove αvβ3 integrin involvement in CCN1-induced OSM expression, with pretreatment of αvβ3 antibody decreasing CCN1-induced OSM production.…”

Section: Discussionsupporting

confidence: 66%

CCN1 Induces Oncostatin M Production in Osteoblasts via Integrin-Dependent Signal Pathways

Chen

Huang

et al. 2014

PLoS ONE

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Inflammatory response and articular destruction are common symptoms of osteoarthritis. Cysteine-rich 61 (CCN1 or Cyr61), a secreted protein from the CCN family, is associated with the extracellular matrix involved in many cellular activities like growth and differentiation. Yet the mechanism of CCN1 interacting with arthritic inflammatory response is unclear. This study finds CCN1 increasing expression of oncostatin m (OSM) in human osteoblastic cells. Pretreatment of αvβ3 monoclonal antibody and inhibitors of focal adhesion kinase (FAK), c-Src, phosphatidylinositol 3-kinase (PI3K), and NF-κB inhibited CCN1-induced OSM expression in osteoblastic cells. Stimulation of cells with CCN1 increased phosphorylation of FAK, c-Src, PI3K, and NF-κB via αvβ3 receptor; CCN1 treatment of osteoblasts increased NF-κB-luciferase activity and p65 binding to NF-κB element on OSM promoter. Results indicate CCN1 heightening OSM expression via αvβ3 receptor, FAK, c-Src, PI3K, and NF-κB signal pathway in osteoblastic cells, suggesting CCN1 as a novel target in arthritis treatment.

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Section: Discussionsupporting

confidence: 66%

CCN1 Induces Oncostatin M Production in Osteoblasts via Integrin-Dependent Signal Pathways

Chen

Huang

et al. 2014

PLoS ONE

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“…All these processes begin with endothelial cell proliferation. The potent pro-angiogenic properties of CCN1 have previously been demonstrated in rat models of ischemic retinopathy ( 29 , 31 ) and in relation to different tumor cell types ( 37 , 43 , 44 ). As hyperoxia and subsequent angiogenesis play important roles in tumor development, a high CCN1 expression is associated with more aggressive tumor invasion.…”

Section: Discussionmentioning

confidence: 85%

CCN1/Cyr61-PI3K/AKT signaling promotes retinal neovascularization in oxygen-induced retinopathy

Zhang

Nie

et al. 2015

International Journal of Molecular Medicine

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Retinal neovascularization (RNV) is a characteristic pathological finding of retinopathy of prematurity (ROP). Cysteine-rich 61 [Cyr61, also known as CCN family member 1 (CCN1)] has been reported to mediate angiogenesis. The aim of the present study was to investigate the mechanisms of CCN1/Cyr61-phosphoinositide 3-kinase (PI3K)/AKT signaling in ROP. The contribution of CCN1 to human umbilical vein endothelial cell (HUVEC) proliferation and apoptosis under hypoxic conditions was determined using a cell counting kit-8 (CCK-8) and Annexin V/propidium iodide (PI) staining, respectively, as well as using siRNA targeting CCN1 (CCN1 siRNA). The cells exposed to hypoxia were also treated with the PI3K/AKT inhibitor, LY294002. In addition, mouse pups with oxygen-induced retinopathy (OIR) were administered an intravitreal injection of CCN1 siRNA. RNV was assessed by magnesium-activated adenosine diphosphatease (ADPase) staining. RT-qPCR, western blot analysis, immunofluorescence staining and immunohistochemistry were used to detect the distribution and expression of CCN1, PI3K and AKT. Exposure to hypoxia increased the neovascularization clock hour scores (from 1.23±0.49 to 5.60±0.73, P<0.05) and the number of preretinal neovascular cells, as well as the mRNA and protein expression levels of CCN1, PI3K and AKT (all P<0.05). The injection of CCN1 siRNA decreased the neovascularization clock hour scores and the number of preretinal neovascular cells (1.53±0.72 vs. 4.76±1.04; 12.0±2.8 vs. 31.4±2.6, respectively, both P<0.05), as well as the mRNA and protein expression levels of CCN1, PI3K and AKT (protein, −45.3, −22.5 and −28.4%; mRNA, −43.7, −58.7 and −42.9%, respectively, all P<0.05) compared to the administration of scrambled siRNA under hypoxic conditions. Treatment with LY294002 decreased the mRNA and protein expression levels of CCN1 in the cells exposed to hypoxia (both P<0.05). The administration of CCN1 siRNA resulted in less severe neovascularization in the eyes of the the mouse pups with OIR. Thus, out data suggest that CCN1 plays an important role in RNV in ROP, and may thus be a potential target for the prevention and treatment of ROP.

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“…Analysis of KRC PCC array data revealed that 34 of the 47 pro-angiogenic genes up-regulated in KRC cells were predicted to be TGF-β targets ( Supplementary Table 3 ). To determine if TGF-βs promote pro-angiogenic gene expression in KRC cells, we suppressed TβRI signaling with SB505124, and assayed Ctgf and Wisp1 , which were elevated in the human PDACs with a pro-angiogenic signature, and Cyr61, Pdgfa and Vegfc , which are known to promote angiogenesis and which have also been reported to be expressed at high levels in human PDAC [ 25 , 38 , 39 ]. SB505124 markedly suppressed the levels of all five mRNAs (Figure 3G ).…”

Section: Resultsmentioning

confidence: 99%

TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis

et al. 2015

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Pancreatic ductal adenocarcinomas (PDACs) overexpress pro-angiogenic factors but are not viewed as vascular. Using data from The Cancer Genome Atlas we demonstrate that a subset of PDACs exhibits a strong pro-angiogenic signature that includes 37 genes, such as HDAC9, that are overexpressed in PDAC arising in KRC mice, which express mutated Kras and lack RB. Moreover, patient-derived orthotopic xenografts can exhibit tumor angiogenesis, whereas conditioned media (CM) from KRC-derived pancreatic cancer cells (PCCs) enhance endothelial cell (EC) growth and migration, and activate canonical TGF-β signaling and STAT3. Inhibition of the type I TGF-β receptor with SB505124 does not alter endothelial activation in vitro, but decreases pro-angiogenic gene expression and suppresses angiogenesis in vivo. Conversely, STAT3 silencing or JAK1–2 inhibition with ruxolitinib blocks CM-enhanced EC proliferation. STAT3 disruption also suppresses endothelial HDAC9 and blocks CM-induced HDAC9 expression, whereas HDAC9 re-expression restores CM-enhanced endothelial proliferation. Moreover, ruxolitinib blocks mitogenic EC/PCC cross-talk, and suppresses endothelial p-STAT3 and HDAC9, and PDAC progression and angiogenesis in vivo, while markedly prolonging survival of KRC mice. Thus, targeting JAK1–2 with ruxolitinib blocks a final pathway that is common to multiple pro-angiogenic factors, suppresses EC-mediated PCC proliferation, and may be useful in PDACs with a strong pro-angiogenic signature.

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CCN1: a novel target for pancreatic cancer

Cited by 14 publications

References 15 publications

CCN1 Induces Oncostatin M Production in Osteoblasts via Integrin-Dependent Signal Pathways

CCN1 Induces Oncostatin M Production in Osteoblasts via Integrin-Dependent Signal Pathways

CCN1/Cyr61-PI3K/AKT signaling promotes retinal neovascularization in oxygen-induced retinopathy

TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis

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