Emerging role of CCN family proteins in tumorigenesis and cancer metastasis (Review)
- Authors:
- Published online on: October 23, 2015 https://doi.org/10.3892/ijmm.2015.2390
- Pages: 1451-1463
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Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
1. Introduction
The CCN family of proteins is an acronym for cysteine-rich protein 61 (CYR61), connective tissue growth factor (CTGF) and nephroblastoma overexpressed (NOV), which were first identified in mouse, human and chicken in the early 1990s (1–3). Another three family members exhibiting the same basic structure domains of the first three CCN members have since been identified. The latter three members are involved in the Wnt-1 inducible signalling pathway and consist of Wnt-1-induced secreted protein-1 (WISP-1), WISP-2, and WISP-3 (4). As each CCN family member has several names associated with its structures or functions, the official nomenclature has been recommended (Table I).
CCNs are present in vertebrates, including zebrafish, poultry such as chickens, rodents including mice and rats, as well as humans and have been conserved during evolution. CCNs, with the exception of CCN5, which lacks a cysteine knot domain (CT) module, comprise an N-terminal secretory signal peptide and four functional domains: an insulin-like growth factor-binding protein domain (IGFBP), a Von Willebrand factor domain (VWC), a thrombospondin type-1 repeat module (TSP-1), and a CT (Fig. 1A). The two N-terminal domains are separated from the two C-domains by a variable linking sequence of amino acids (5). According to the domains CCNs, except CCN5, share five common exons, the first of which codes the signal sequence, while the other CCNs sequentially code the four functional domains with corresponding numbers of amino acids ranging from 349 to 381 (6).
The four discrete functional domains have different molecular structures that determine the types of binding partners and ligands with which they interact, resulting in a variety of biological functions. The known binding partners of each domain are different: insulin-like growth factors (IGFs) bind with IGFBP; transforming growth factor β (TGF-β), bone morphogenic proteins (BMPs) and integrins bind with VWC; vascular endothelial growth factor (VEGF), LDL receptor proteins (LRPs), heparan sulphate proteoglycans (HSPGs) and integrins bind with TSP-1; and VEGF, LRPs, integrins, neurogenic locus notch homolog protein 1 (Notch1), fibulin C1, HSPGs and integrins bind with CT (7,8) (Fig. 1B).
2. Expression profiles and subcellular localization
CCNs exhibit different expression profiles and transcript levels in different tissues, organs and tumors (Tables II and III). The different expression levels of CCNs observed in embryonic tissues compared with that of adult organs indicates a potential role in development (Table IV). The changing transcript levels in tumors mean that CCNs may also be important during tumorigenesis.
The subcellular localization of each of the CCNs is also different. Immunohistochemical localization of CCN1 protein has indicated that invasive carcinoma cells show significant cytoplasmic and perinuclear protein overexpression compared to non-neoplastic ductal epithelium in invasive ductal carcinoma, whereas in ductal carcinoma in situ and lobular carcinoma in situ, CCN1 expression was weaker and heterogeneous (9). Previous findings have shown that CCN1 was detected, albeit not abundantly, in culture medium (10). CCN2 protein was detected in the nuclei of B16 (F10) cells and at the cell membrane, but was rarely detectable in the cytoplasm and the cell culture medium (10,11). CCN3 was detected in the medium, extracellular matrix (ECM) and at the cell membrane (12–14). A previous study revealed strong immunohistochemical staining of CCN4, CCN5 and CCN6 in normal colorectal epithelial cells, which was confined primarily to the cell membrane with slight staining of stromal tissue. In colorectal cancer (CRC) tissues, cell membrane and cytoplasmic staining were assessed. Membrane staining showed a reduction in CCN4, CCN5 and CCN6, whereas cytoplasmic staining showed a reduction in CCN5 but an increase in CCN4 and CCN6 (15). Furthermore, CCN5 is mainly localized to the nucleus in rat and human tissues (16).
3. CCN receptors
Similar to some ECM proteins, CCNs mediate cell functions, embryonic development, angiogenesis, wound healing, fibrosis, inflammation, tumorigenesis and development primarily through binding and interacting with well-known receptors, including integrins, HSPGs, IGFs, and lipoprotein receptor-related proteins (LRPs). Signalling pathways, such as Wnts, TGF-β, insulin receptor signalling (IRS) and Notch, are involved in the regulation of these cell functions. The interaction of CCNs with receptors and other main cytokines has been briefly summarised (Fig. 2).
Role of integrins in CCN functions
Integrins, found as heterodimers consisting of α- and β-subunits are common transmembrane receptors that mediate cell-to-cell and cell-to-ECM adhesive interactions while also transducing signals from the ECM to the cell interior and vice versa. Currently, there are 24 members in the integrin family that have been identified to have 18 α-subunits and 8 β-subunits in their structures. In previous decades, it has been shown that integrins are associated with the different functions of CCNs (8,17) (Table V).
HSPGs
HSPGs are known to serve as co-receptors with integrins under certain circumstances (18). Heparin and HSPGs play important roles in modulating cell adhesion and fibrosis through TSP or CT domains (19,20). CCNs are also capable of binding to HSPGs and mediate cell adhesion and Wnt signalling in some cell types (21–23). Furthermore, it has been previously demonstrated that CCN2 binds to fibronectin (HSPG2) through the CT domain and regulates cell functions (24,25).
IGFs
The IGF family, which includes the polypeptide ligands IGF-I and IGF-II, two types of cell membrane receptors (IGF-IR and IGF-IIR), six binding proteins (IGFBP-1 to IGFBP-6) and IGFBP proteases play an important role in various types of cancer (26). The IGFs have interactions with various molecules that are known to be involved in cancer development and progression. CCNs may bind IGFs with low affinity (27), however, the impact on several cell functions needs to be examined. In previous decades, the regulative role of CCNs in co-ordinating cell functions has been a major research focus. Overexpression of CCN2 in chondrocytes elevates the mRNA transcript levels of IGF-I and IGF-II, resulting in increased bone growth (28). Conversely, CCN6 decreases the IGF-1-induced activation of the IGF-IR, and two of its main downstream signalling molecules, insulin receptor substrate 1 (IRS1) and extracellular signal-regulated kinase (ERK)-1/2 in inflammatory breast cancer cells (29). Downregulation of CCN6 enhances the effects of IGF-I and increases the growth, motility and invasiveness of human mammary epithelial cells (30).
Other receptors
CCNs have been reported to bind receptors, such as LRPs (21). CCN2 is known to regulate the cell adhesion and modulation of Wnt signalling in certain cell types by binding to LRP-1 and LRP-6 (22,23). CCN2 binds bone morphogenetic protein-4 (BMP-4) and TGF-β1 through its VWC domain leading to the inhibition of BMP and TGF-β signalling (31). CCN2 binds VEGF through its TSP and CT domains and inhibits VEGF-induced angiogenesis (32). CCN3 binds to the epidermal growth factor (EGF)-like repeat region of Notch1 via its CT domain. The CCN3-Notch association exerts a positive effect on the Notch signalling pathway and suppresses the differentiation of certain myogenic cells (33). Other receptors include ECM protein (fibulin 1C), a calcium-binding protein (S100A4), ion channels (calcium voltage-independent and Cx43 gap junction) and a subunit of RNA polymerase II, which have also been reported to interact with CCNs (34–36).
4. Interactions with other cytokines
TNF-α
TNF-α regulates CCN1 and CCN2 in a cell-type-specific manner. TNF-α represses CCN1 and CCN2 expression in chondrocytes but induces CCN1 expression in osteoblasts and CCN2 expression in synovial cells (37–39). Kular et al identified that TNF-α stimulated CCN3, CCN4 and CCN6 expression in melanocytes, cardiac myocytes and fibroblasts and fibroblast-like synoviocytes, respectively. By contrast, TNF-α stimulated CCN3 expression but exerted an inhibitory effect on CCN4 expression in cultured astrocytes (40).
TGF-β
TGF-β has been reported to promote the expression of CCN1, CCN2, CCN4 and CCN5 but represses the expression of CCN3 in chondrosarcoma-derived HCS-2/8 and murine osteoblastic cells (37,41). By contrast, the expression levels of CCN2, CCN3 and CCN4 were inversely correlated with TGF-β in leiomyomas (42). Thus, CCN2 is closely associated with TGF-β as this interaction represses the expression of TGF-β signalling inhibitors (such as Smad7) through the VWC domain (43).
5. Other signalling pathways
CCNs have been shown to be associated with the Wnt signalling pathway (4,41–49). Knockdown of CCN1 expression reduced the Wnt3A-induced oestrogenic differentiation demonstrating that CCN1 expression may be involved in the Wnt3A-induced osteoblast differentiation of mesenchymal stem cells (44). On the other hand, overexpression of CCN1 has also been shown to induce the expression of Wnt/β-catenin transcriptional targets and the formation of secondary body axes (45). Overexpression of CCN2 has been shown to induce the expression of Wnt/β-catenin transcriptional target genes of c-myc and cyclin D1 (46), whereas the overexpression of CCN2 decreased the effects of Wnt3 (47). Notably, CCN3 has been shown to inhibit Wnt/β-catenin signalling pathway through the suppression of BMP-2 activity (48). WISPs (CCN4, CCN5 and CCN6) have been associated with Wnt-1-induced transformation (4,49).
CCN2 has been shown to induce chondrocyte differentiation, through a p38 mitogen-activated protein kinase (p38/MAPK), and proliferation, through the p44/42 MAPK/ERK (49).
6. CCNs in pathophysiological disorders
CCNs and pathophysiological cell functions
The functions of CCNs have been revealed in a wide range of cell types, regulating their cell functions through a variety of mechanisms. CCN1 increased cell adhesion and migration through the integrin α6β1-HSPG co-receptors in fibroblasts, endothelial cells and vascular smooth muscle cells (50,51). In endothelial cells, CCN1 has also been shown to promote cell adhesion, migration, survival, growth factor-induced mitogenesis and endothelial tubule formation via integrin α6β1 (52). CCN2 promoted the adhesion and migration of microvascular endothelial cells through an integrin-αvβ3-dependent mechanism (53). CCN3 increased the adhesion of normal melanocytes to collagen type IV (54). However, CCN3 expression was also decreased immediately after wounding or re-epithelialization (55), indicating the ability of CCN3 to negatively regulate fibroblast proliferation. CCN4 stimulated the migration and proliferation through integrin α5β1 in vascular smooth muscle cells (56). CCN4 has also been verified to promote the proliferation of hepatic stellate cells in vitro (57). CCN5 increased cell proliferation and survival against Streptozotocin in pancreatic cells (58). However, in vascular smooth muscle cells, CCN5 negatively regulated smooth muscle cell proliferation and motility (59). An inhibitory effect on in vitro growth of the human mammary epithelial cells function was also assigned to CCN6 (60).
CCNs in embryonic development and angiogenesis
CCN expression profiles appear to be integral to the development of several key organ systems. CCN1 expression has been closely associated with the development of skeletal, cardiovascular, and neuronal systems during mice embryogenesis, best demonstrated by a CCN1 knockout mice model which exhibited aberrations in vascular development (61,62). CCN2 knockout mice died at birth, due to respiratory failure resulting from hypoplastic lungs and poor thoracic development (63). A CCN2 knockdown zebrafish model showed bone defects and disruption in notochord development (64). CCN3 mutant mice exhibited skeletal and cardiac abnormalities, such as cardiomyopathy, muscle atrophy, and cataract formation (65). Evidence suggests that CCN4 has an an important regulatory function in skeletal growth and bone repair (66). The role of CCN5 remains unclear; however, it may serve a multifunctional purpose in developing mice and human embryos (67). CCN6 mutations in humans cause autosomal recessive skeletal disease progressive pseudorheumatoid dysplasia, a juvenile-onset joint degenerative disease (68). However, CCN6-null or CCN6-overexpression mice exhibited no observable phenotype (69). These findings from CCN knockout mice models together with their known expression profiles in the developmental stages (Table IV) suggest that CCN1 and CCN2 play an essential role, while the other four members may play a regulatory role, in human embryonic development.
Wound healing
CCN1 and CCN2 are involved in tissue repair, as the increased expression of the two CCNs has been observed during cutaneous wound healing, liver regeneration, in the heart after myocardial infarction and after bone fracture (70–74). Xu et al showed that CCN2 acted as a downstream effector of TGF-β enhancing the production of scar tissue indicating that the suppression of CCN2 may prevent a progressive fibrotic response to TGF-β stimulation (75). Of note, CCN3 transcripts were decreased during the first three days after wound formation or re-epithelialization (55).
Fibrosis
CCN2 mRNA expression has been observed in fibrotic lesions (76–80). However, this pattern has not been observed in early non-fibrotic or atrophic lesions. The serum level of CCN2 protein was significantly increased and correlated with skin sclerosis and lung fibrosis in patients. These results indicate that CCN2 co-operates with TGF-β to maintain and possibly even exacerbate fibrosis (76). Evidence has shown that either CCN2 mRNA or the application of exogenous CCN2 protein was required for the development of persistent fibrosis in a mouse fibrosis model (77,78). Lipson et al reported that the inhibition of CCN2 was capable of preventing and reversing the process of fibrosis in liver and diabetic nephropathy models (79). CCN5 overexpression inhibited profibrotic phenotypes via the PI3K/Akt signalling pathway in lung fibroblasts and in mice (80).
Inflammation
Bacteria, such as Yersinia, Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, and Staphylococcus aureus, have been shown to induce CCN1 and CCN2 expression in epithelial cells, indicating that CCN1 and CCN2 overexpression may be useful in the adaptation of epithelial cells in stressful situations (81). HeLa cells infected by Coxsackievirus B3 induced CCN1 activation via JNK to mediate cell death (82). Bacteria-derived lipid factors have also been shown to induce CCN1 and CCN2 during infections (83,84).
7. CCNs in cancers
CCNs, except CCN5, have four highly conservative functional domains, but play different roles in the same cancer type. Each CCN member may also play different roles in varying cancer types through different signalling pathways (Fig. 2 and Table VI). Some CCN members have already been associated with cancer staging and prognosis as well as contributing to tumorigenesis or metastasis formation (85–93). Other CCN members have been considered as diagnostic or prognostic markers and therapeutic target genes in certain cancer types (46,103,104,119,120).
 | Table VIRegulations of CCN members in various types of cancer: Clinical specimens and/or cancer cells in vitro. |
CCN1
CCN1 mRNA and protein levels are increased in ovarian cancer cells and may play an important role in ovarian carcinogenesis (85). CCN1 is upregulated in prostate cancer cell lines and tumor tissues and is associated with the status of the tumor-suppressor gene p53 (86). CCN1 has also been shown to enhance prostate cancer cell migration via alterations of function to integrins (87). An immunohistochemical analysis of 112 human glioma and normal brain specimens showed that the levels of tumor-associated CCN1 protein were increased with tumor grade (P<0.001), and this trend was verified with similar results identified in glioma cells (88). These results have identified a CCN1-dependent pathway that mediates cell growth, cell migration, and long-lasting signalling events in glioma cell lines and possibly astroglial malignancies. CCN1 is overexpressed in U343 glioma cells and has been linked with the integrin-linked kinase-mediated Akt and β-catenin-TCF/Lef signalling pathways (89). CCN1 is a transcriptional target of Hh-GLI signalling leading to increased vascularity and spontaneous metastasis of breast cancer cells (90). Zuo et al demonstrated that the overexpression of CCN1 in breast cancer is associated with the tumorigenesis, migration and invasion of cancer cells (6). CCN1 was expressed in ~30% of invasive breast cancer biopsies and played a role in breast cancer progression, possibly through its interactions with the avb3 receptor (91). CCN1 was found to be overexpressed in patients with endometrial carcinoma and indicative of a poor prognosis (92). CCN1 has also been shown to be overexpressed and correlate with invasion and metastasis in CRC (93).
Other studies, however, have shown different results. For instance, CCN1 expression was found to be reduced in endometrial cancer and lung cancer tissues compared to their paired normal tissues (94,95). Notably, the expression levels of CCN1 were reduced in high-grade chondrosarcomas and advanced gastric cancers (96,97).
CCN2
CCN2 mRNA and protein levels are increased in murine and human rhabdomyosarcoma cells (98). Overexpression of CCN2 increases breast cancer cell migration in Boyden chamber assays and promotes angiogenesis in chorioallantoic membrane assays compared to control cells in vitro (99). By contrast, a reduced expression of CCN2 in clinical breast cancer samples based on a qPCR study is associated with poor prognosis (P=0.021), metastasis (P=0.012), local recurrence (P=0.0024) and mortality (P=0.0072) (100). Similarly, findings in CRC are controversial. CCN2 may play an oncogenic role in the progression of well-differentiated CRC (101). However, Lin et al showed that lower CCN2 expression levels in CRC patients were associated with a higher peritoneal recurrence rate. Additionally, CCN2 overexpression decreased the incidence of peritoneal carcinomatosis and increased the rate of mice survival, but significantly decreased CRC cell adhesion ability in vitro (102). CCN2 overexpression was also found to be associated with poor prognosis in oesophageal squamous cell carcinoma, pancreatic cancer, high-grade chondro sarcomas and enchondromas (46,100,103,104).
However, evidence suggests opposing roles for CCN2 (102,105–109). In these studies, CCN2 acted as an inhibitor, tumor suppressor or a positive prognostic indicator. CCN2 overexpression plays an important inhibitory role on cell proliferation in non-small cell lung cancer cell lines (105). By contrast, in ovarian tumorigenesis, inactivation of the CCN2 gene may play a role in disease progression (106). CCN2 expression is decreased in Wilms' tumors and a high CCN2 expression exhibits improved prognostic features in intrahepatic cholangiocarcinoma and CRC patients (102,107–109).
CCN3
In human prostate cancer, Maillard et al revealed that CCN3 overexpression in cancer cell lines compared with their epithelial localizations was consistent with a role for CCN3 in prostatic tumorigenesis (110). Manara et al found the primary musculoskeletal tumors that developed lung and/or bone metachronous metastases also exhibited CCN3 overexpression (111). A similar effect was observed for CCN3 in bone malignancies and cervical cancer, suggesting it acts as a promoter of tumor growth and thus a poor prognostic indicator (112,113). The involvement of CCN3 in cervical cancer has been confirmed by a subsequent study (114). CCN3 transcripts and protein levels were increased in cervical cancer tissues when compared with the corresponding normal tissues. Overexpression of CCN3 was significantly associated with the stage of the disease (P=0.017) and with lymph node involvement (P=0.006). These results suggest that the overexpression of CCN3 is associated with a poorer prognosis in cervical cancer (114).
Other cancer types have resulted in inconsistent results compared to those mentioned above. CCN3-transfected glioma cells induced tumors to a lesser degree than their parental counterparts, which did not express detectable amounts of CCN3 (115). In vitro, CCN3 exerted an anti-proliferative effect and interfered with the S/G2 transition of the cell cycle, thereby inducing an artificial accumulation of glioblastoma cells (G59) at the S phase (116). CCN3 restored cell growth regulatory properties that were absent in chronic myeloid leukaemia and sensitized chronic myeloid leukaemia cells to imatinib-induced apoptosis (117). CCN3 protein levels were significantly modified in malignant adrenocortical tumors, but not in benign adrenocortical tumors (118). CCN3 suppressed the cell proliferation via interaction with the gap junction protein Connexin43 in glioma cells, and high levels of CCN3 reduced tumorigenicity, resulting in a lower rate of metastasis (119,120). CCN3 in vitro has been reported to decrease the transcription and activation of matrix metal-loproteinases and suppress the invasion of melanoma cells, indicating that the downregulation of CCN3 expression is a potential mechanism for melanoma progression (121).
CCN4
CCN4 is downstream of Wnt-1 signalling and CCN4 overexpression in colon cancer and may play a role in colon tumorigenesis (4). It has been revealed that CCN4 transcripts are expressed at higher levels in tumor samples compared to normal tissue, and are higher in patients with Dukes' stage B and C compared to Dukes' A. Thus, CCN4 appears to act as a factor for stimulating aggressiveness in colon cancer (15). A similar behavior pattern was observed in oral squamous cell carcinoma cells as CCN4 enhanced their expression by increasing ICAM-1 expression through the αvβ3 integrin receptor and the ASK1, JNK/p38 and AP-1 signal transduction pathways (122).
By contrast, CCN4 inhibited the growth and metastasis of melanoma cells and its expression is increased in low metastatic cells compared to high metastatic cells (123,124). CCN4 overexpression inhibits the motility and invasion of lung cancer cells through the inhibition of Rac activation in vitro (125). Similar results have been identified in clinical specimens in which CCN4 has been shown to be reduced in chondrosarcoma and breast cancer with poor prognosis, suggesting it is a putative tumor suppressor (126,127).
CCN5
CCN5 has been shown to be increased in hepatocellular carcinoma compared to paired normal tissues (128), as well as in adrenocorticotropic hormone-secreting pituitary tumors compared to normal pituitaries (129). However, previous findings focusing on the role of CCN5 in breast cancer remain controversial. Ji et al reported that CCN5 mRNA and protein levels were increased in some breast cancer cells and in breast tumors from patients with poor prognosis (130). However, CCN5 mRNA and protein levels were significantly reduced as the cancer progressed from a non-invasive to invasive type in breast cancer, and CCN5 mRNA and protein levels were almost undetectable in poorly differentiated cancers compared to the moderately or well-differentiated samples (131). In vitro studies have shown that CCN5 was a negative regulator of growth, migration and invasion of breast cancer cells (132,133).
CCN5 exhibits differing effects in other cancer types. For example, Yang et al examined CCN5 protein expression in 46 squamous cell/adenosquamous carcinoma samples and 80 adenocarcinoma samples using immunohistochemistry. The results of that study showed that the loss of CCN5 expression was associated with the metastasis, invasion and poor prognosis of gallbladder cancer (134). CCN5 mRNA and protein expression levels have been shown to be reduced in pancreatic adenocarcinoma, salivary gland tumors and CRC compared with the respective paired normal tissues (4,15,135,136).
CCN6
CCN6 was overexpressed in 63% of the colon tumors analyzed and may be downstream of Wnt-1 signalling, thus playing a role in colon tumorigenesis (4). A similar result was obtained in a microsatellite instability subtype of CRC (4,137). However, previous findings revealed that there is no significant difference in CCN6 mRNA levels expressed in the majority of CRC in comparison with paired normal tissues (15). CCN6 transcripts may also play a positive role in the development of hepatocellular carcinoma (138). Knockdown of CCN6 expression suppressed gastric cancer cell proliferation and migration via the Wnt/β-catenin signalling pathway in vitro, while a high expression of CCN6 indicated poor prognosis in a gastric cancer clinical cohort (139).
CCN6 mRNA was reduced in 80% of poor outcome cases of breast cancer, and was found to be essential to induce the process of epithelial-mesenchymal transition (EMT) in breast cancer (60). CCN6 overexpression inhibited cell growth and invasiveness in breast cancer cell lines (140) and CCN6 expression was reduced in breast cancer samples compared to paired normal tissues (141). Taken together, the evidence suggests CCN6 is a putative tumor suppressor in breast cancer.
8. Conclusion and perspectives
The perturbed expression of CCNs has been observed in a variety of malignancies. The aberrant expression of certain CCNs is associated with disease progression and poor prognosis. Different CCNs may play contrasting roles in the same cancer, while the same CCN may play different roles in various types of cancer. Further investigations may highlight their clinical relevance and application for predicting prognosis. CCNs comprise four functional domains and exhibit differential expression and functions in different cells and tissues albeit CCN5 lacks a CT module. CCNs can regulate cell functions by acting as ligands for integrins, heparin, and HSPGs, which are regulated by certain growth factors and cytokines, including IGFs, TGF-α and TGF-β, to fulfil their role in the consequent physiological and pathological events. Additionally, CCNs interact with a variety of receptors and cytokines by modulating downstream signal transduction. Insight into the detailed mechanisms involved in CCN-mediated regulation may be useful in understanding their roles and functions in tumorigenesis and cancer metastasis. This may provide new avenues for target therapy in certain malignancies.
Abbreviations:
|
ADAM |
a disintegrin and metalloprotease |
|
BSP |
bone sialic protein |
|
COMP |
cartilage oligomeric matrix protein |
|
L1 |
CD171 |
|
LAP-TGF-β |
TGF-β latency-associated peptide |
|
iC3b |
inactivated complement component 3 |
|
PECAM-1 |
platelet and endothelial cell adhesion molecule 1 |
|
uPA |
urokinase-type plasminogen activator |
|
uPAR |
urokinase-type plasminogen activator receptor |
|
VEGF |
vascular endothelial growth factor |
Acknowledgments
The authors would like to thank the Cancer Research Wales and the Cardiff China Medical Research Collaborative (CCMRC) for supporting their study.
References
|
O'Brien TP, Yang GP, Sanders L and Lau LF: Expression of cyr61, a growth factor-inducible immediate-early gene. Mol Cell Biol. 10:3569–3577. 1990. View Article : Google Scholar : PubMed/NCBI | |
|
Bradham DM, Igarashi A, Potter RL and Grotendorst GR: Connective tissue growth factor: A cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10. J Cell Biol. 114:1285–1294. 1991. View Article : Google Scholar : PubMed/NCBI | |
|
Joliot V, Martinerie C, Dambrine G, Plassiart G, Brisac M, Crochet J and Perbal B: Proviral rearrangements and overexpression of a new cellular gene (nov) in myeloblastosis-associated virus type 1-induced nephroblastomas. Mol Cell Biol. 12:10–21. 1992. View Article : Google Scholar : PubMed/NCBI | |
|
Pennica D, Swanson TA, Welsh JW, Roy MA, Lawrence DA, Lee J, Brush J, Taneyhill LA, Deuel B, Lew M, et al: WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors. Proc Natl Acad Sci USA. 95:14717–14722. 1998. View Article : Google Scholar : PubMed/NCBI | |
|
Desnoyers L: Structural basis and therapeutic implication of the interaction of CCN proteins with glycoconjugates. Curr Pharm Des. 10:3913–3928. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Zuo GW, Kohls CD, He BC, Chen L, Zhang W, Shi Q, Zhang BQ, Kang Q, Luo J, Luo X, et al: The CCN proteins: Important signaling mediators in stem cell differentiation and tumorigenesis. Histol Histopathol. 25:795–806. 2010.PubMed/NCBI | |
|
Holbourn KP, Acharya KR and Perbal B: The CCN family of proteins: Structure-function relationships. Trends Biochem Sci. 33:461–473. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Chen CC and Lau LF: Functions and mechanisms of action of CCN matricellular proteins. Int J Biochem Cell Biol. 41:771–783. 2009. View Article : Google Scholar : | |
|
Hirschfeld M, zur Hausen A, Bettendorf H, Jäger M and Stickeler E: Alternative splicing of Cyr61 is regulated by hypoxia and significantly changed in breast cancer. Cancer Res. 69:2082–2090. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Ball DK, Surveyor GA, Diehl JR, Steffen CL, Uzumcu M, Mirando MA and Brigstock DR: Characterization of 16- to 20-kilodalton (kDa) connective tissue growth factors (CTGFs) and demonstration of proteolytic activity for 38-kDa CTGF in pig uterine luminal flushings. Biol Reprod. 59:828–835. 1998. View Article : Google Scholar : PubMed/NCBI | |
|
Sha W and Leask A: CCN2 expression and localization in melanoma cells. J Cell Commun Signal. 5:219–226. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Perbal B: CCN proteins: A centralized communication network. J Cell Commun Signal. 7:169–177. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Joliot A, Triller A, Volovitch M and Prochiantz A: Are embryonic forms of NCAM homeobox receptors? C R Acad Sci III. (Suppl 9): 59–63. 1992.In French. | |
|
Kyurkchiev S, Yeger H, Bleau AM and Perbal B: Potential cellular conformations of the CCN3(NOV) protein. Cell Commun Signal. 2(9)2004. View Article : Google Scholar : PubMed/NCBI | |
|
Davies SR, Davies ML, Sanders A, Parr C, Torkington J and Jiang WG: Differential expression of the CCN family member WISP-1, WISP-2 and WISP-3 in human colorectal cancer and the prognostic implications. Int J Oncol. 36:1129–1136. 2010.PubMed/NCBI | |
|
Wiesman KC, Wei L, Baughman C, Russo J, Gray MR and Castellot JJ: CCN5, a secreted protein, localizes to the nucleus. J Cell Commun Signal. 4:91–98. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Takada Y, Ye X and Simon S: The integrins. Genome Biol. 8(215)2007. View Article : Google Scholar : PubMed/NCBI | |
|
Yang GP and Lau LF: Cyr61, product of a growth factor-inducible immediate early gene, is associated with the extracellular matrix and the cell surface. Cell Growth Differ. 2:351–357. 1991.PubMed/NCBI | |
|
Chen CC, Young JL, Monzon RI, Chen N, Todorović V and Lau LF: Cytotoxicity of TNFalpha is regulated by integrin-mediated matrix signaling. EMBO J. 26:1257–1267. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Holbourn KP, Perbal B and Ravi Acharya K: Proteins on the catwalk: Modelling the structural domains of the CCN family of proteins. J Cell Commun Signal. 3:25–41. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Segarini PR, Nesbitt JE, Li D, Hays LG, Yates JR III and Carmichael DF: The low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor is a receptor for connective tissue growth factor. J Biol Chem. 276:40659–40667. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Gao R and Brigstock DR: Low density lipoprotein receptor-related protein (LRP) is a heparin-dependent adhesion receptor for connective tissue growth factor (CTGF) in rat activated hepatic stellate cells. Hepatol Res. 27:214–220. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Mercurio S, Latinkic B, Itasaki N, Krumlauf R and Smith JC: Connective-tissue growth factor modulates WNT signalling and interacts with the WNT receptor complex. Development. 131:2137–2147. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Nishida T, Kubota S, Fukunaga T, Kondo S, Yosimichi G, Nakanishi T, Takano-Yamamoto T and Takigawa M: CTGF/Hcs24, hypertrophic chondrocyte-specific gene product, interacts with perlecan in regulating the proliferation and differentiation of chondrocytes. J Cell Physiol. 196:265–275. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Abraham S, Riggs MJ, Nelson K, Lee V and Rao RR: Characterization of human fibroblast-derived extracellular matrix components for human pluripotent stem cell propagation. Acta Biomater. 6:4622–4633. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Yu H and Rohan T: Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst. 92:1472–1489. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Hwa V, Oh Y and Rosenfeld RG: The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr Rev. 20:761–787. 1999.PubMed/NCBI | |
|
Tomita N, Hattori T, Itoh S, Aoyama E, Yao M, Yamashiro T and Takigawa M: Cartilage-specific over-expression of CCN family member 2/connective tissue growth factor (CCN2/CTGF) stimulates insulin-like growth factor expression and bone growth. PLoS One. 8:e592262013. View Article : Google Scholar : PubMed/NCBI | |
|
Kleer CG, Zhang Y, Pan Q and Merajver SD: WISP3 (CCN6) is a secreted tumor-suppressor protein that modulates IGF signaling in inflammatory breast cancer. Neoplasia. 6:179–185. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang Y, Pan Q, Zhong H, Merajver SD and Kleer CG: Inhibition of CCN6 (WISP3) expression promotes neoplastic progression and enhances the effects of insulin-like growth factor-1 on breast epithelial cells. Breast Cancer Res. 7:R1080–R1089. 2005. View Article : Google Scholar | |
|
Abreu JG, Ketpura NI, Reversade B and De Robertis EM: Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-beta. Nat Cell Biol. 4:599–604. 2002.PubMed/NCBI | |
|
Inoki I, Shiomi T, Hashimoto G, Enomoto H, Nakamura H, Makino K, Ikeda E, Takata S, Kobayashi K and Okada Y: Connective tissue growth factor binds vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis. FASEB J. 16:219–221. 2002. | |
|
Sakamoto K, Yamaguchi S, Ando R, Miyawaki A, Kabasawa Y, Takagi M, Li CL, Perbal B and Katsube K: The nephro-blastoma overexpressed gene (NOV/ccn3) protein associates with Notch1 extracellular domain and inhibits myoblast differentiation via Notch signaling pathway. J Biol Chem. 277:29399–29405. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Perbal B, Martinerie C, Sainson R, Werner M, He B and Roizman B: The C-terminal domain of the regulatory protein NOVH is sufficient to promote interaction with fibulin 1C: A clue for a role of NOVH in cell-adhesion signaling. Proc Natl Acad Sci USA. 96:869–874. 1999. View Article : Google Scholar : PubMed/NCBI | |
|
Li CL, Martinez V, He B, Lombet A and Perbal B: A role for CCN3 (NOV) in calcium signalling. Mol Pathol. 55:250–261. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Perbal B: NOV (nephroblastoma overexpressed) and the CCN family of genes: Structural and functional issues. Mol Pathol. 54:57–79. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Moritani NH, Kubota S, Sugahara T and Takigawa M: Comparable response of ccn1 with ccn2 genes upon arthritis: An in vitro evaluation with a human chondrocytic cell line stimulated by a set of cytokines. Cell Commun Signal. 3(6)2005. View Article : Google Scholar : PubMed/NCBI | |
|
Kok SH, Hou KL, Hong CY, Wang JS, Liang PC, Chang CC, Hsiao M, Yang H, Lai EH and Lin SK: Simvastatin inhibits cytokine-stimulated Cyr61 expression in osteoblastic cells: A therapeutic benefit for arthritis. Arthritis Rheum. 63:1010–1020. 2011. View Article : Google Scholar | |
|
Nozawa K, Fujishiro M, Kawasaki M, Kaneko H, Iwabuchi K, Yanagida M, Suzuki F, Miyazawa K, Takasaki Y, Ogawa H, et al: Connective tissue growth factor promotes articular damage by increased osteoclastogenesis in patients with rheumatoid arthritis. Arthritis Res Ther. 11:R1742009. View Article : Google Scholar : PubMed/NCBI | |
|
Kular L, Pakradouni J, Kitabgi P, Laurent M and Martinerie C: The CCN family: A new class of inflammation modulators? Biochimie. 93:377–388. 2011. View Article : Google Scholar | |
|
Parisi MS, Gazzerro E, Rydziel S and Canalis E: Expression and regulation of CCN genes in murine osteoblasts. Bone. 38:671–677. 2006. View Article : Google Scholar | |
|
Luo X, Ding L and Chegini N: CCNs, fibulin-1C and S100A4 expression in leiomyoma and myometrium: Inverse association with TGF-beta and regulation by TGF-beta in leiomyoma and myometrial smooth muscle cells. Mol Hum Reprod. 12:245–256. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Mason RM: Connective tissue growth factor(CCN2), a pathogenic factor in diabetic nephropathy. What does it do? How does it do it? J Cell Commun Signal. 3:95–104. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Si W, Kang Q, Luu HH, Park JK, Luo Q, Song WX, Jiang W, Luo X, Li X, Yin H, et al: CCN1/Cyr61 is regulated by the canonical Wnt signal and plays an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells. Mol Cell Biol. 26:2955–2964. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Latinkic BV, Mercurio S, Bennett B, Hirst EM, Xu Q, Lau LF, Mohun TJ and Smith JC: Xenopus Cyr61 regulates gastrulation movements and modulates Wnt signalling. Development. 130:2429–2441. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Deng YZ, Chen PP, Wang Y, Yin D, Koeffler HP, Li B, Tong XJ and Xie D: Connective tissue growth factor is overexpressed in esophageal squamous cell carcinoma and promotes tumorigenicity through beta-catenin-T-cell factor/Lef signaling. J Biol Chem. 282:36571–36581. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Smerdel-Ramoya A, Zanotti S, Deregowski V and Canalis E: Connective tissue growth factor enhances osteoblastogenesis in vitro. J Biol Chem. 283:22690–22699. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Rydziel S, Stadmeyer L, Zanotti S, Durant D, Smerdel-Ramoya A and Canalis E: Nephroblastoma overexpressed (Nov) inhibits osteoblastogenesis and causes osteopenia. J Biol Chem. 282:19762–19772. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Yosimichi G, Nakanishi T, Nishida T, Hattori T, Takano-Yamamoto T and Takigawa M: CTGF/Hcs24 induces chondrocyte differentiation through a p38 mitogen-activated protein kinase (p38MAPK), and proliferation through a p44/42 MAPK/extracellular-signal regulated kinase (ERK). Eur J Biochem. 268:6058–6065. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Chen N, Chen CC and Lau LF: Adhesion of human skin fibroblasts to Cyr61 is mediated through integrin alpha 6beta 1 and cell surface heparan sulfate proteoglycans. J Biol Chem. 275:24953–24961. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Grzeszkiewicz TM, Lindner V, Chen N, Lam SC and Lau LF: The angiogenic factor cysteine-rich 61 (CYR61, CCN1) supports vascular smooth muscle cell adhesion and stimulates chemotaxis through integrin alpha(6)beta(1) and cell surface heparan sulfate proteoglycans. Endocrinology. 143:1441–1450. 2002.PubMed/NCBI | |
|
Leu SJ, Lam SC and Lau LF: Pro-angiogenic activities of CYR61 (CCN1) mediated through integrins alphavbeta3 and alpha6beta1 in human umbilical vein endothelial cells. J Biol Chem. 277:46248–46255. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Babic AM, Chen CC and Lau LF: Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin alphavbeta3, promotes endothelial cell survival, and induces angiogenesis in vivo. Mol Cell Biol. 19:2958–2966. 1999. View Article : Google Scholar : PubMed/NCBI | |
|
Fukunaga-Kalabis M, Martinez G, Liu ZJ, Kalabis J, Mrass P, Weninger W, Firth SM, Planque N, Perbal B and Herlyn M: CCN3 controls 3D spatial localization of melanocytes in the human skin through DDR1. J Cell Biol. 175:563–569. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Lin CG, Leu SJ, Chen N, Tebeau CM, Lin SX, Yeung CY and Lau LF: CCN3 (NOV) is a novel angiogenic regulator of the CCN protein family. J Biol Chem. 278:24200–24208. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Liu H, Dong W, Lin Z, Lu J, Wan H, Zhou Z and Liu Z: CCN4 regulates vascular smooth muscle cell migration and proliferation. Mol Cells. 36:112–118. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Jian YC, Wang JJ, Dong S, Hu JW, Hu LJ, Yang GM, Zheng YX and Xiong WJ: Wnt-induced secreted protein 1/CCN4 in liver fibrosis both in vitro and in vivo. Clin Lab. 60:29–35. 2014.PubMed/NCBI | |
|
Chowdhury S, Wang X, Srikant CB, Li Q, Fu M, Gong YJ, Ning G and Liu JL: IGF-I stimulates CCN5/WISP2 gene expression in pancreatic β-cells, which promotes cell proliferation and survival against streptozotocin. Endocrinology. 155:1629–1642. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Lake AC and Castellot JJ Jr: CCN5 modulates the antiproliferative effect of heparin and regulates cell motility in vascular smooth muscle cells. Cell Commun Signal. 1(5)2003. View Article : Google Scholar : PubMed/NCBI | |
|
Kleer CG, Zhang Y and Merajver SD: CCN6 (WISP3) as a new regulator of the epithelial phenotype in breast cancer. Cells Tissues Organs. 185:95–99. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
O'Brien TP and Lau LF: Expression of the growth factor-inducible immediate early gene cyr61 correlates with chondrogenesis during mouse embryonic development. Cell Growth Differ. 3:645–654. 1992.PubMed/NCBI | |
|
Mo FE, Muntean AG, Chen CC, Stolz DB, Watkins SC and Lau LF: CYR61 (CCN1) is essential for placental development and vascular integrity. Mol Cell Biol. 22:8709–8720. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Baguma-Nibasheka M and Kablar B: Pulmonary hypoplasia in the connective tissue growth factor (Ctgf) null mouse. Dev Dyn. 237:485–493. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Chiou MJ, Chao TT, Wu JL, Kuo CM and Chen JY: The physiological role of CTGF/CCN2 in zebrafish notochond development and biological analysis of the proximal promoter region. Biochem Biophys Res Commun. 349:750–758. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Heath E, Tahri D, Andermarcher E, Schofield P, Fleming S and Boulter CA: Abnormal skeletal and cardiac development, cardiomyopathy, muscle atrophy and cataracts in mice with a targeted disruption of the Nov (Ccn3) gene. BMC Dev Biol. 8(18)2008. View Article : Google Scholar : PubMed/NCBI | |
|
French DM, Kaul RJ, D'Souza AL, Crowley CW, Bao M, Frantz GD, Filvaroff EH and Desnoyers L: WISP-1 is an osteoblastic regulator expressed during skeletal development and fracture repair. Am J Pathol. 165:855–867. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Jones JA, Gray MR, Oliveira BE, Koch M and Castellot JJ Jr: CCN5 expression in mammals: I. Embryonic and fetal tissues of mouse and human. J Cell Commun Signal. 1:127–143. 2007. View Article : Google Scholar | |
|
Hurvitz JR, Suwairi WM, Van Hul W, El-Shanti H, Superti-Furga A, Roudier J, Holderbaum D, Pauli RM, Herd JK, Van Hul EV, et al: Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nat Genet. 23:94–98. 1999. View Article : Google Scholar : PubMed/NCBI | |
|
Kutz WE, Gong Y and Warman ML: WISP3, the gene responsible for the human skeletal disease progressive pseudorheumatoid dysplasia, is not essential for skeletal function in mice. Mol Cell Biol. 25:414–421. 2005. View Article : Google Scholar : | |
|
Hilfiker-Kleiner D, Kaminski K, Kaminska A, Fuchs M, Klein G, Podewski E, Grote K, Kiian I, Wollert KC, Hilfiker A, et al: Regulation of proangiogenic factor CCN1 in cardiac muscle: Impact of ischemia, pressure overload, and neurohumoral activation. Circulation. 109:2227–2233. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Lau LF and Lam SC: The CCN family of angiogenic regulators: The integrin connection. Exp Cell Res. 248:44–57. 1999. View Article : Google Scholar : PubMed/NCBI | |
|
Grotendorst GR: Connective tissue growth factor: A mediator of TGF-beta action on fibroblasts. Cytokine Growth Factor Rev. 8:171–179. 1997. View Article : Google Scholar | |
|
Ujike K, Shinji T, Hirasaki S, Shiraha H, Nakamura M, Tsuji T and Koide N: Kinetics of expression of connective tissue growth factor gene during liver regeneration after partial hepatectomy and D-galactosamine-induced liver injury in rats. Biochem Biophys Res Commun. 277:448–454. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Hadjiargyrou M, Ahrens W and Rubin CT: Temporal expression of the chondrogenic and angiogenic growth factor CYR61 during fracture repair. J Bone Miner Res. 15:1014–1023. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Xu S-W, Leask A and Abraham D: Regulation and function of connective tissue growth factor/CCN2 in tissue repair, scarring and fibrosis. Cytokine Growth Factor Rev. 19:133–144. 2008. View Article : Google Scholar | |
|
Takehara K: Hypothesis: Pathogenesis of systemic sclerosis. J Rheumatol. 30:755–759. 2003.PubMed/NCBI | |
|
Leask A: Targeting the TGFbeta, endothelin-1 and CCN2 axis to combat fibrosis in scleroderma. Cell Signal. 20:1409–1414. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Mori T, Kawara S, Shinozaki M, Hayashi N, Kakinuma T, Igarashi A, Takigawa M, Nakanishi T and Takehara K: Role and interaction of connective tissue growth factor with transforming growth factor-beta in persistent fibrosis: A mouse fibrosis model. J Cell Physiol. 181:153–159. 1999. View Article : Google Scholar : PubMed/NCBI | |
|
Lipson KE, Wong C, Teng Y and Spong S: CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis. Fibrogenesis Tissue Repair. 5(Suppl 1): S242012. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang L, Li Y, Liang C and Yang W: CCN5 overexpression inhibits profibrotic phenotypes via the PI3K/Akt signaling pathway in lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis and in an in vivo model of lung fibrosis. Int J Mol Med. 33:478–486. 2014. | |
|
Wiedmaier N, Müller S, Köberle M, Manncke B, Krejci J, Autenrieth IB and Bohn E: Bacteria induce CTGF and CYR61 expression in epithelial cells in a lysophosphatidic acid receptor- dependent manner. Int J Med Microbiol. 298:231–243. 2008. View Article : Google Scholar | |
|
Kim SM, Park JH, Chung SK, Kim JY, Hwang HY, Chung KC, Jo I, Park SI and Nam JH: Coxsackievirus B3 infection induces cyr61 activation via JNK to mediate cell death. J Virol. 78:13479–13488. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Muehlich S, Schneider N, Hinkmann F, Garlichs CD and Goppelt-Struebe M: Induction of connective tissue growth factor (CTGF) in human endothelial cells by lysophosphatidic acid, sphingosine-1-phosphate, and platelets. Atherosclerosis. 175:261–268. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Sakamoto S, Yokoyama M, Zhang X, Prakash K, Nagao K, Hatanaka T, Getzenberg RH and Kakehi Y: Increased expression of CYR61, an extracellular matrix signaling protein, in human benign prostatic hyperplasia and its regulation by lysophosphatidic acid. Endocrinology. 145:2929–2940. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Gery S, Xie D, Yin D, Gabra H, Miller C, Wang H, Scott D, Yi WS, Popoviciu ML, Said JW, et al: Ovarian carcinomas: CCN genes are aberrantly expressed and CCN1 promotes proliferation of these cells. Clin Cancer Res. 11:7243–7254. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Lv H, Fan E, Sun S, Ma X, Zhang X, Han DM and Cong YS: Cyr61 is up-regulated in prostate cancer and associated with the p53 gene status. J Cell Biochem. 106:738–744. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Schmitz P, Gerber U, Jüngel E, Schütze N, Blaheta R and Bendas G: Cyr61/CCN1 affects the integrin-mediated migration of prostate cancer cells (PC-3) in vitro. Int J Clin Pharmacol Ther. 51:47–50. 2013. View Article : Google Scholar | |
|
Goodwin CR, Lal B, Zhou X, Ho S, Xia S, Taeger A, Murray J and Laterra J: Cyr61 mediates hepatocyte growth factor-dependent tumor cell growth, migration, and Akt activation. Cancer Res. 70:2932–2941. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Xie D, Yin D, Tong X, O'Kelly J, Mori A, Miller C, Black K, Gui D, Said JW and Koeffler HP: Cyr61 is overexpressed in gliomas and involved in integrin-linked kinase-mediated Akt and beta-catenin-TCF/Lef signaling pathways. Cancer Res. 64:1987–1996. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Harris LG, Pannell LK, Singh S, Samant RS and Shevde LA: Increased vascularity and spontaneous metastasis of breast cancer by hedgehog signaling mediated upregulation of cyr61. Oncogene. 31:3370–3380. 2012. View Article : Google Scholar : | |
|
Tsai MS, Hornby AE, Lakins J and Lupu R: Expression and function of CYR61, an angiogenic factor, in breast cancer cell lines and tumor biopsies. Cancer Res. 60:5603–5607. 2000.PubMed/NCBI | |
|
Watari H, Xiong Y, Hassan MK and Sakuragi N: Cyr61, a member of ccn (connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed) family, predicts survival of patients with endometrial cancer of endometrioid subtype. Gynecol Oncol. 112:229–234. 2009. View Article : Google Scholar | |
|
Monnier Y, Farmer P, Bieler G, Imaizumi N, Sengstag T, Alghisi GC, Stehle JC, Ciarloni L, Andrejevic-Blant S, Moeckli R, et al: CYR61 and alphaVbeta5 integrin cooperate to promote invasion and metastasis of tumors growing in preirradiated stroma. Cancer Res. 68:7323–7331. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Chen PP, Li WJ, Wang Y, Zhao S, Li DY, Feng LY, Shi XL, Koeffler HP, Tong XJ and Xie D: Expression of Cyr61, CTGF, and WISP-1 correlates with clinical features of lung cancer. PLoS One. 2:e5342007. View Article : Google Scholar : PubMed/NCBI | |
|
Chien W, Kumagai T, Miller CW, Desmond JC, Frank JM, Said JW and Koeffler HP: Cyr61 suppresses growth of human endometrial cancer cells. J Biol Chem. 279:53087–53096. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Brigstock DR: The connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed (CCN) family. Endocr Rev. 20:189–206. 1999.PubMed/NCBI | |
|
Maeta N, Osaki M, Shomori K, Inaba A, Kidani K, Ikeguchi M and Ito H: CYR61 downregulation correlates with tumor progression by promoting MMP-7 expression in human gastric carcinoma. Oncology. 73:118–126. 2007. View Article : Google Scholar | |
|
Croci S, Landuzzi L, Nicoletti G, Palladini A, Antognoli A, De Giovanni C, Nanni P and Lollini PL: Expression of connective tissue growth factor (CTGF/CCN2) in a mouse model of rhabdomyosarcomagenesis. Pathol Oncol Res. 13:336–339. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Chien W, O'Kelly J, Lu D, Leiter A, Sohn J, Yin D, Karlan B, Vadgama J, Lyons KM and Koeffler HP: Expression of connective tissue growth factor (CTGF/CCN2) in breast cancer cells is associated with increased migration and angiogenesis. Int J Oncol. 38:1741–1747. 2011.PubMed/NCBI | |
|
Jiang WG, Watkins G, Fodstad O, Douglas-Jones A, Mokbel K and Mansel RE: Differential expression of the CCN family members Cyr61, CTGF and Nov in human breast cancer. Endocr Relat Cancer. 11:781–791. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Jacobson A and Cunningham JL: Connective tissue growth factor in tumor pathogenesis. Fibrogenesis Tissue Repair. 5(Suppl 1): S82012. View Article : Google Scholar : PubMed/NCBI | |
|
Lin BR, Chang CC, Chen RJ, Jeng YM, Liang JT, Lee PH, Chang KJ and Kuo ML: Connective tissue growth factor acts as a therapeutic agent and predictor for peritoneal carcinomatosis of colorectal cancer. Clin Cancer Res. 17:3077–3088. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Bennewith KL, Huang X, Ham CM, Graves EE, Erler JT, Kambham N, Feazell J, Yang GP, Koong A and Giaccia AJ: The role of tumor cell-derived connective tissue growth factor (CTGF/CCN2) in pancreatic tumor growth. Cancer Res. 69:775–784. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Shakunaga T, Ozaki T, Ohara N, Asaumi K, Doi T, Nishida K, Kawai A, Nakanishi T, Takigawa M and Inoue H: Expression of connective tissue growth factor in cartilaginous tumors. Cancer. 89:1466–1473. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Chien W, Yin D, Gui D, Mori A, Frank JM, Said J, Kusuanco D, Marchevsky A, McKenna R and Koeffler HP: Suppression of cell proliferation and signaling transduction by connective tissue growth factor in non-small cell lung cancer cells. Mol Cancer Res. 4:591–598. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Kikuchi R, Tsuda H, Kanai Y, Kasamatsu T, Sengoku K, Hirohashi S, Inazawa J and Imoto I: Promoter hypermethylation contributes to frequent inactivation of a putative conditional tumor suppressor gene connective tissue growth factor in ovarian cancer. Cancer Res. 67:7095–7105. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Li MH, Sanchez T, Pappalardo A, Lynch KR, Hla T and Ferrer F: Induction of antiproliferative connective tissue growth factor expression in Wilms' tumor cells by sphingosine-1-phosphate receptor 2. Mol Cancer Res. 6:1649–1656. 2008.PubMed/NCBI | |
|
Gardini A, Corti B, Fiorentino M, Altimari A, Ercolani G, Grazi GL, Pinna AD, Grigioni WF and D'Errico Grigioni A: Expression of connective tissue growth factor is a prognostic marker for patients with intrahepatic cholangiocarcinoma. Dig Liver Dis. 37:269–274. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Lin BR, Chang CC, Che TF, Chen ST, Chen RJ, Yang CY, Jeng YM, Liang JT, Lee PH, Chang KJ, et al: Connective tissue growth factor inhibits metastasis and acts as an independent prognostic marker in colorectal cancer. Gastroenterology. 128:9–23. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Maillard M, Cadot B, Ball RY, Sethia K, Edwards DR, Perbal B and Tatoud R: Differential expression of the ccn3 (nov) proto-oncogene in human prostate cell lines and tissues. Mol Pathol. 54:275–280. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Manara MC, Perbal B, Benini S, Strammiello R, Cerisano V, Perdichizzi S, Serra M, Astolfi A, Bertoni F, Alami J, et al: The expression of ccn3(nov) gene in musculoskeletal tumors. Am J Pathol. 160:849–859. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Gluk hova L, Angevin E, Lavialle C, Cadot B, Terrier-Lacombe MJ, Perbal B, Bernheim A and Goguel AF: Patterns of specific genomic alterations associated with poor prognosis in high-grade renal cell carcinomas. Cancer Genet Cytogenet. 130:105–110. 2001. View Article : Google Scholar | |
|
Perbal B: CCN3: Doctor Jekyll and Mister Hyde. J Cell Commun Signal. 2:3–7. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang T, Zhao C, Luo L, Xiang J, Sun Q, Cheng J and Chen D: The clinical and prognostic significance of CCN3 expression in patients with cervical cancer. Adv Clin Exp Med. 22:839–845. 2013. | |
|
Gupta N, Wang H, McLeod TL, Naus CC, Kyurkchiev S, Advani S, Yu J, Perbal B and Weichselbaum RR: Inhibition of glioma cell growth and tumorigenic potential by CCN3 (NOV). Mol Pathol. 54:293–299. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Bleau AM, Planque N, Lazar N, Zambelli D, Ori A, Quan T, Fisher G, Scotlandi K and Perbal B: Antiproliferative activity of CCN3: Involvement of the C-terminal module and post-translational regulation. J Cell Biochem. 101:1475–1491. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
McCallum L, Lu W, Price S, Lazar N, Perbal B and Irvine AE: CCN3 suppresses mitogenic signalling and reinstates growth control mechanisms in chronic myeloid leukaemia. J Cell Commun Signal. 6:27–35. 2012. View Article : Google Scholar : | |
|
Thibout H, Martinerie C, Créminon C, Godeau F, Boudou P, Le Bouc Y and Laurent M: Characterization of human NOV in biological fluids: An enzyme immunoassay for the quantification of human NOV in sera from patients with diseases of the adrenal gland and of the nervous system. J Clin Endocrinol Metab. 88:327–336. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Xin LW, Martinerie C, Zumkeller W, Westphal M and Perbal B: Differential expression of novH and CTGF in human glioma cell lines. Clin Mol Pathol. 49:M91–M97. 1996. View Article : Google Scholar : PubMed/NCBI | |
|
Sin WC, Bechberger JF, Rushlow WJ and Naus CC: Dose-dependent differential upregulation of CCN1/Cyr61 and CCN3/NOV by the gap junction protein Connexin43 in glioma cells. J Cell Biochem. 103:1772–1782. 2008. View Article : Google Scholar | |
|
Fukunaga-Kalabis M, Martinez G, Telson SM, Liu ZJ, Balint K, Juhasz I, Elder DE, Perbal B and Herlyn M: Downregulation of CCN3 expression as a potential mechanism for melanoma progression. Oncogene. 27:2552–2560. 2008. View Article : Google Scholar | |
|
Chuang JY, Chang AC, Chiang IP, Tsai MH and Tang CH: Apoptosis signal-regulating kinase 1 is involved in WISP-1-promoted cell motility in human oral squamous cell carcinoma cells. PLoS One. 8:e780222013. View Article : Google Scholar : PubMed/NCBI | |
|
Hashimoto Y, Shindo-Okada N, Tani M, Takeuchi K, Toma H and Yokota J: Identification of genes differentially expressed in association with metastatic potential of K-1735 murine melanoma by messenger RNA differential display. Cancer Res. 56:5266–5271. 1996.PubMed/NCBI | |
|
Hashimoto Y, Shindo-Okada N, Tani M, Nagamachi Y, Takeuchi K, Shiroishi T, Toma H and Yokota J: Expression of the Elm1 gene, a novel gene of the CCN (connective tissue growth factor, Cyr61/Cef10, and neuroblastoma overexpressed gene) family, suppresses in vivo tumor growth and metastasis of K-1735 murine melanoma cells. J Exp Med. 187:289–296. 1998. View Article : Google Scholar : PubMed/NCBI | |
|
Soon LL, Yie TA, Shvarts A, Levine AJ, Su F and Tchou-Wong KM: Overexpression of WISP-1 down-regulated motility and invasion of lung cancer cells through inhibition of Rac activation. J Biol Chem. 278:11465–11470. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Yu C, Le AT, Yeger H, Perbal B and Alman BA: NOV (CCN3) regulation in the growth plate and CCN family member expression in cartilage neoplasia. J Pathol. 201:609–615. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Davies SR, Watkins G, Mansel RE and Jiang WG: Differential expression and prognostic implications of the CCN family members WISP-1, WISP-2, and WISP-3 in human breast cancer. Ann Surg Oncol. 14:1909–1918. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Tomimaru Y, Koga H, Yano H, de la Monte S, Wands JR and Kim M: Upregulation of T-cell factor-4 isoform-responsive target genes in hepatocellular carcinoma. Liver Int. 33:1100–1112. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Colli LM, Saggioro F, Serafini LN, Camargo RC, Machado HR, Moreira AC, Antonini SR and de Castro M: Components of the canonical and non-canonical Wnt pathways are not mis-expressed in pituitary tumors. PLoS One. 8:e624242013. View Article : Google Scholar : PubMed/NCBI | |
|
Ji J, Jia S, Ji K and Jiang WG: Wnt1 inducible signalling pathway protein-2 (WISP 2/CCN5): Roles and regulation in human cancers (Review). Oncol Rep. 31:533–539. 2014. | |
|
Banerjee S, Dhar G, Haque I, Kambhampati S, Mehta S, Sengupta K, Tawfik O, Phillips TA and Banerjee SK: CCN5/WISP-2 expression in breast adenocarcinoma is associated with less frequent progression of the disease and suppresses the invasive phenotypes of tumor cells. Cancer Res. 68:7606–7612. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Dhar K, Banerjee S, Dhar G, Sengupta K and Banerjee SK: Insulin-like growth factor-1 (IGF-1) induces WISP-2/CCN5 via multiple molecular cross-talks and is essential for mitogenic switch by IGF-1 axis in estrogen receptor-positive breast tumor cells. Cancer Res. 67:1520–1526. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Banerjee SK and Banerjee S: CCN5/WISP-2: A micromanager of breast cancer progression. J Cell Commun Signal. 6:63–71. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Yang Z, Yang Z, Zou Q, Yuan Y, Li J, Li D, Liang L, Zeng G and Chen S: A comparative study of clinicopathological significance, FGFBP1, and WISP-2 expression between squamous cell/adenosquamous carcinomas and adenocarcinoma of the gallbladder. Int J Clin Oncol. 19:325–335. 2014. View Article : Google Scholar | |
|
Dhar G, Mehta S, Banerjee S, Gardner A, McCarty BM, Mathur SC, Campbell DR, Kambhampati S and Banerjee SK: Loss of WISP-2/CCN5 signaling in human pancreatic cancer: A potential mechanism for epithelial-mesenchymal-transition. Cancer Lett. 254:63–70. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Kouzu Y, Uzawa K, Kato M, Higo M, Nimura Y, Harada K, Numata T, Seki N, Sato M and Tanzawa H: WISP-2 expression in human salivary gland tumors. Int J Mol Med. 17:567–573. 2006.PubMed/NCBI | |
|
Thorstensen L, Diep CB, Meling GI, Aagesen TH, Ahrens CH, Rognum TO and Lothe RA: WNT1 inducible signaling pathway protein 3, WISP-3, a novel target gene in colorectal carcinomas with microsatellite instability. Gastroenterology. 121:1275–1280. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Cervello M, Giannitrapani L, Labbozzetta M, Notarbartolo M, D'Alessandro N, Lampiasi N, Azzolina A and Montalto G: Expression of WISPs and of their novel alternative variants in human hepatocellular carcinoma cells. Ann NY Acad Sci. 1028:432–439. 2004. View Article : Google Scholar | |
|
Fang F, Zhao WY, Li RK, Yang XM, Li J, Ao JP, Jiang SH, Kong FZ, Tu L, Zhuang C, et al: Silencing of WISP3 suppresses gastric cancer cell proliferation and metastasis and inhibits Wnt/β-catenin signaling. Int J Clin Exp Pathol. 7:6447–6461. 2014. | |
|
Huang W, Zhang Y, Varambally S, Chinnaiyan AM, Banerjee M, Merajver SD and Kleer CG: Inhibition of CCN6 (Wnt-1-induced signaling protein 3) down-regulates E-cadherin in the breast epithelium through induction of snail and ZEB1. Am J Pathol. 172:893–904. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
van Golen KL, Davies S, Wu ZF, Wang Y, Bucana CD, Root H, Chandrasekharappa S, Strawderman M, Ethier SP and Merajver SD: A novel putative low-affinity insulin-like growth factor-binding protein, LIBC (lost in inflammatory breast cancer), and RhoC GTPase correlate with the inflammatory breast cancer phenotype. Clin Cancer Res. 5:2511–2519. 1999.PubMed/NCBI |
