Open Access

Emerging role of CCN family proteins in tumorigenesis and cancer metastasis (Review)

  • Authors:
    • Jun Li
    • Lin Ye
    • Sioned Owen
    • Hoi Ping Weeks
    • Zhongtao Zhang
    • Wen G. Jiang
  • View Affiliations

  • Published online on: October 23, 2015     https://doi.org/10.3892/ijmm.2015.2390
  • Pages: 1451-1463
  • Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The CCN family of proteins comprises the members CCN1, CCN2, CCN3, CCN4, CCN5 and CCN6. They share four evolutionarily conserved functional domains, and usually interact with various cytokines to elicit different biological functions including cell proliferation, adhesion, invasion, migration, embryonic development, angiogenesis, wound healing, fibrosis and inflammation through a variety of signalling pathways. In the past two decades, emerging functions for the CCN proteins (CCNs) have been identified in various types of cancer. 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. Insight into the detailed mechanisms involved in CCN-mediated regulation may be useful in understanding their roles and functions in tumorigenesis and cancer metastasis. In this review, we briefly introduced the functions of CCNs, especially in cancer.

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 (13). 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).

Table I

Nomenclature of the CCN family of proteins.

Table I

Nomenclature of the CCN family of proteins.

Official nameAlternative names
CCN1CYR61, CTGF-2, IGFBP10, IGFBP-rP4, CEF10
CCN2CTGF, IGFBP8, IGFBP-rP2, HBGF-0.8, HCS24, ecogenin
CCN3NOV, NOVH, IGFBP9, IGFBP-rP3
CCN4WISP-1, Elm-1, IGFBP-rP8
CCN5WISP-2, CTGF-L, CTGF-3, HICP, Cop-1, IGFBP-rP7
CCN6WISP-3, IGFBP-rP9

[i] CYR61, cysteine-rich protein 61; IGFBP, IGFBP-related protein; HBGF, heparin-binding growth factor; Hcs, human chondrosarcoma; Elm-1, expressed in low metastatic cells; HICP, haparin-induced CCN-like protein; Cop-1, card-only protein 1; WISP-1, Wnt-1 induced secreted protein-1.

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.

Table II

Expression profiles of CCN family members: Breakdown by body sites.

Table II

Expression profiles of CCN family members: Breakdown by body sites.

Breakdown by body sitesCCN1 (TPM)CCN2 (TPM)CCN3 (TPM)CCN4 (TPM)CCN5 (TPM)CCN6 (TPM)
Adipose tissue124362107700
Adrenal gland2123015483000
Ascites75750000
Bladder33660000
Blood088000
Bone4741396694100
Bone marrow619640000
Brain10410664023
Cervix123201440020
Connective tissue46217303353200
Ear31016779316200
Embryonic tissue9824402809
Eye10027743300
Heart12222110033
Intestine12025041240
Kidney20852123494
Larynx1702130000
Liver23810724400
Lung13119185170
Lymph000000
Lymph node443300011
Mammary gland856613606
Mouth4551330000
Muscle3728182800
Nerve122345064000
Oesophagus198490000
Ovary16717719900
Pancreas16828191400
Parathyroid0000048
Pharynx24240000
Pituitary gland0060000
Placenta21577002500
Prostate73121100100
Salivary gland0000980
Skin22738933004
Spleen393711037180
Stomach282553620073
Testis43962066
Thymus751000000
Thyroid36447221000
Tonsil000000
Trachea30884919000
Umbilical cord58110890000
Uterus3484002151120
Vascular12193814309000

[i] TPM, transcripts per million.

Table III

Expression profiles of CCN family members: Breakdown by health state.

Table III

Expression profiles of CCN family members: Breakdown by health state.

Breakdown by pathophysiologyCCN1 (TPM)CCN2 (TPM)CCN3 (TPM)CCN4 (TPM)CCN5 (TPM)CCN6 (TPM)
Adrenal tumor1580948000
Bladder carcinoma1132840000
Breast (mammary gland) tumor5342010010
Cervical tumor570570028
Chondrosarcoma676142410872120
Colorectal tumor79350080
Oesophageal tumor231570000
Gastrointestinal tumor278641500059
Germ cell tumor875011118015
Glioma5512137000
Head and neck tumor141186140140
Kidney tumor1011882914290
Leukemia031100021
Liver tumor22915652000
Lung tumor5890000
Lymphoma2700000
Non-neoplasia341140701000
Normal1873194510323
Ovarian tumor183249391300
Pancreatic tumor17141992800
Primitive neuroectodermal tumor2300000
Prostate cancer48199000
Retinoblastoma000000
Skin tumor317131007
Soft tissue/muscle tissue tumor526470000
Uterine tumor3213554411220

[i] TPM, transcripts per million.

Table IV

Expression profiles of CCN family members: Breakdown by developmental stage.

Table IV

Expression profiles of CCN family members: Breakdown by developmental stage.

Breakdown by developmental stageCCN1 (TPM)CCN2 (TPM)CCN3 (TPM)CCN4 (TPM)CCN5 (TPM)CCN6 (TPM)
Embryoid body21445705700
Blastocyst324800016
Fetus531325225397
Neonate38651432000
Infant0850000
Juvenile37719717000
Adult2012892614402

[i] TPM, transcripts per million.

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 (1214). 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).

Table V

Integrins are associated with the functions of CCN proteins.

Table V

Integrins are associated with the functions of CCN proteins.

IntegrinsInvolved CCN membersCell functions affectedOther ligands
α2β1CCN1Migration, invasion, motility, lymphangiogenesisLaminin, collagen, thrombospondin, E-cadherin, tenascin
α5β1CCN2, CCN3Adhesion, growth, survival, angiogenesisFibronectin, osteopontin, fibrillin, thrombospondin, ADAM, COMP, L1
α6β1CCN1, CCN2, CCN3Adhesion, growthLaminin, thrombospondin, ADAM
αDβ2CCN1AdhesionICAM, VCAM-1, fibrinogen, fibronectin, vitronectin, plasminogen
αMβ2CCN1, CCN2AdhesionICAM, iC3b, factor X, fibrinogen, ICAM-4, heparin
αvβ3CCN1, CCN2, CCN3Angiogenesis, adhesion, migration, survival, growthFibrinogen, vitronectin, thrombospondin, fibrillin, tenascin, PECAM-1, fibronectin, osteopontin, BSP, MFG-E8, ADAM-15, COMP, ICAM-4, MMP, FGF-2, uPA, uPAR, L1, angiostatin, plasmin, cardiotoxin, LAP-TGF-β, Del-1
αvβ5CCN1, CCN2, CCN3, CCN4Growth, survival, angiogenesisOsteopontin, BSP, vitronectin, LAP-TGF-β
αIIbβ3CCN1, CCN2Hemostasis, thrombosisFibrinogen, thrombospondin, fibronectin, vitronectin, ICAM-4, L1, CD40 ligand

[i] ADAM, a disintegrin and metalloprotease; BSP, bone sialic protein; COMP, cartilage oligomeric matrix protein; L1, CD171; LAP-TGF-β, TGF-β latencyassociated 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.

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 (2123). 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 (3436).

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 (3739). 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 (4,4149). 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 (7074). 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 (7680). 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 (8593). 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 VI

Regulations of CCN members in various types of cancer: Clinical specimens and/or cancer cells in vitro.

Table VI

Regulations of CCN members in various types of cancer: Clinical specimens and/or cancer cells in vitro.

Tumor type (arranged A-Z)CCN1CCN2CCN3CCN4CCN5CCN6
Breast cancer↑/↓
Cervical cancer
Chondrosarcomas
Chronic myeloid leukaemia
CRC↑/↓
Enchondromas
Endometrial cancer↑/↓
Esophageal cancer
Gallbladder cancer
Gastric cancers
Glioma
Liver cancer
Lung cancer
Malignant adrenocortical tumors
Melanoma
Oral carcinoma
Ovarian cancer
Pancreatic cancer
Pituitary tumors
Prostate cancer
Salivary gland tumors
Rhabdomyosarcoma
Wilms' tumor

[i] ↑, positive correlation or upregulation; ↓, negative correlation or downregulation; ↑/↓, controversial regulations; CRC, colorectal cancer.

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 (102,105109). 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 (102,107109).

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.

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December 2015
Volume 36 Issue 6

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APA
Li, J., Ye, L., Owen, S., Weeks, H.P., Zhang, Z., & Jiang, W.G. (2015). Emerging role of CCN family proteins in tumorigenesis and cancer metastasis (Review). International Journal of Molecular Medicine, 36, 1451-1463. https://doi.org/10.3892/ijmm.2015.2390
MLA
Li, J., Ye, L., Owen, S., Weeks, H. P., Zhang, Z., Jiang, W. G."Emerging role of CCN family proteins in tumorigenesis and cancer metastasis (Review)". International Journal of Molecular Medicine 36.6 (2015): 1451-1463.
Chicago
Li, J., Ye, L., Owen, S., Weeks, H. P., Zhang, Z., Jiang, W. G."Emerging role of CCN family proteins in tumorigenesis and cancer metastasis (Review)". International Journal of Molecular Medicine 36, no. 6 (2015): 1451-1463. https://doi.org/10.3892/ijmm.2015.2390