Gene Summary

Gene:CCN3; cellular communication network factor 3
Aliases: NOV, NOVh, IBP-9, IGFBP9, IGFBP-9
Summary:The protein encoded by this gene is a small secreted cysteine-rich protein and a member of the CCN family of regulatory proteins. CNN family proteins associate with the extracellular matrix and play an important role in cardiovascular and skeletal development, fibrosis and cancer development. [provided by RefSeq, Feb 2009]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:CCN family member 3
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NOV (cancer-related)

Li W, Liao X, Ning P, et al.
Paracrine effects of CCN3 from non-cancerous hepatic cells increase signaling and progression of hepatocellular carcinoma.
BMC Cancer. 2019; 19(1):395 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The liver microenvironment plays a key role in the progression and metastasis of hepatocellular carcinoma (HCC). Gene expression profiling of non-cancerous hepatic tissues obtained from patients with metastatic HCC exhibit a unique immune response signature, including upregulation of CCN3. However, the role of CCN3 secreted from non-cancerous hepatic tissues in the progression of HCC remains unclear.
METHODS: Using tissue microarrays, we examined CCN3 in non-cancerous hepatic tissues of patients with HCC and correlated expression with clinical and pathological features. In addition, CCN3 localization and mechanisms of HCC progression were investigated in tissues and cell lines. Finally, correlations between CCN3 and cirrhosis were explored in patients.
RESULTS: CCN3 was primarily localized to hepatic cells of non-cancerous hepatic tissues and was associated with vascular invasion and poor prognosis in patients with HCC. CCN3 expression in non-cancerous hepatic tissues also correlated with the degree of liver fibrosis. Compared with conditioned media from wild-type LO2 cells, conditioned media from hepatic cell line LO2 activated by LX2 (aLO2-CM) induced CCN3 expression and HCC cell proliferation and metastasis. Further, aLO2-CM activated MAPK signaling and epithelial-mesenchymal transition in HCC cells. Finally, CCN3 was inversely related to cirrhosis in the prognosis of HCC and negatively regulated hepatic stellate cells (HSCs) in vitro with downregulation of α-SMA, TGF-β, and collagens.
CONCLUSIONS: CCN3 was secreted from hepatic cells activated by HSCs and increased MAPK signaling, EMT, proliferation and metastasis of HCC cells. CCN3 was also inversely related to cirrhosis, regulating HSCs through a negative feedback loop.

Vatanmakanian M, Tavallaie M, Ghadami S
Imatinib independent aberrant methylation of NOV/CCN3 in chronic myelogenous leukemia patients: a mechanism upstream of BCR-ABL1 function?
Cell Commun Signal. 2019; 17(1):38 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The NOV gene product, CCN3, has been reported in a diverse range of tumors to serve as a negative growth regulator, while acting as a tumor suppressor in Chronic Myelogenous Leukemia (CML). However, the precise mechanism of its silencing in CML is poorly understood. In the current study, we aimed to query if the gene regulation of CCN3 is mediated by the promoter methylation in the patients with CML. In addition, to clarify whether the epigenetic silencing is affected by BCR-ABL1 inhibition, we assessed the methylation status in the patients at different time intervals following the tyrosine kinase inhibition using imatinib therapy, as the first-line treatment for this type of leukemia.
METHODS: To address this issue, we applied bisulfite-sequencing technique as a high-resolution method to study the regulatory segment of the CCN3 gene. The results were analyzed in newly diagnosed CML patients as well as following imatinib therapy. We also evaluated the correlation of CCN3 promoter methylation with BCR-ABL1 levels.
RESULTS: Our findings revealed that the methylation occurs frequently in the promoter region of CML patients showing a significant increase of the methylated percentage at the CpG sites compared to normal individuals. Interestingly, this hypermethylation was indicated to be independent of BCR-ABL1 titers in both groups, which might suggest a mechanism beyond the BCR-ABL1 function.
CONCLUSION: Despite suggesting that the CCN3 hypermethylation acts as a molecular mechanism independent of BCR-ABL1 function in CML patients, this scenario requires further validation by complementary experiments. In the case of acting upstream of BCR-ABL1 signaling, the methylation marker can provide early detection and a novel platform for targeted epigenetic modifiers for efficient treatment in imatinib resistant patients.

Jia Q, Xue T, Zhang Q, et al.
CCN3 is a therapeutic target relating enhanced stemness and coagulation in hepatocellular carcinoma.
Sci Rep. 2017; 7(1):13846 [PubMed] Free Access to Full Article Related Publications
The general prognosis of patients with hepatocellular carcinoma (HCC) remains extremely dismal, due to the high frequency of metastasis. Since 2003, our research group has explored the gene expression profiles of metastasized HCC tissue samples and identified a significant upregulation of CCN3. However, the role and precise pathological function of CCN3 remains elusive. We showed that CCN3 is associated with the poor prognosis of patients with HCC, the malignant phenotype of HCC, and vascular thrombosis. We further evaluated the negative roles of CCN3 in vitro and in vivo, and identified osteopontin (OPN), and coagulation factors tissue factor (TF) and thrombin as the leading genes downstream of CCN3, that are positively associated with HCC cell stemness. We demonstrated that overexpressed CCN3 in HCC cells leads to enhanced survival and increased number of pulmonary metastases in vivo. The elevated levels of OPN and TF were associated with signal activation of nuclear factor κB (NFκB) and extracellular signal-regulated kinases (ERK). Our findings suggest CCN3 is a potential therapeutic target that would affect the upregulation of OPN and coagulation factors, which would lead to an enhanced stemness and blood coagulation microenvironment in HCC tissue.

Li J, Ye L, Sun PH, et al.
Reduced NOV expression correlates with disease progression in colorectal cancer and is associated with survival, invasion and chemoresistance of cancer cells.
Oncotarget. 2017; 8(16):26231-26244 [PubMed] Free Access to Full Article Related Publications
Aberrant expression of nephroblastoma overexpressed (NOV) has been evident in certain malignancies. In the current study, we aim to investigate the role played by NOV in colorectal cancer (CRC). NOV expression was determined in a cohort of 359 CRC tissues and 174 normal colorectal tissues. Its impact on CRC cells was investigated using in vitro NOV knockdown and overexpression models. NOV transcripts were reduced in the CRC tumours compared with the paired adjacent normal colorectal tissues (p < 0.01) and was associated with distant metastases. NOV knockdown resulted in increased cell proliferation and invasion of RKO cells, whilst an opposite effect was seen in the HT115 NOV over expressing cells. A positive association between Caspase-3/-8 and NOV was seen in NOV knockdown and overexpression cell lines which contributed to the survival of serum deprived CRC cells. Further investigation showed that NOV regulated proliferation, survival and invasion through the JNK pathway. NOV knockdown in RKO cells reduced the responsiveness to 5-Fluorouracil treatment, whilst overexpression in HT115 cells exhibited a contrasting effect. Taken together, NOV is reduced in CRC tumours and this is associated with disease progression. NOV inhibits the proliferation and invasion of CRC cells in vitro. Inhibition of proliferation is mediated by a regulation of Caspase-3/-8, via the JNK pathway, which has potential for predicting and preventing chemoresistance.

Fong KW, Zhao JC, Kim J, et al.
Polycomb-Mediated Disruption of an Androgen Receptor Feedback Loop Drives Castration-Resistant Prostate Cancer.
Cancer Res. 2017; 77(2):412-422 [PubMed] Free Access to Full Article Related Publications
The lethal phenotype of castration-resistant prostate cancer (CRPC) is generally caused by augmented signaling from the androgen receptor (AR). Here, we report that the AR-repressed gene CCN3/NOV inhibits AR signaling and acts in a negative feedback loop to block AR function. Mechanistically, a cytoplasmic form of CCN3 interacted with the AR N-terminal domain to sequester AR in the cytoplasm of prostate cancer cells, thereby reducing AR transcriptional activity and inhibiting cell growth. However, constitutive repression of CCN3 by the Polycomb group protein EZH2 disrupted this negative feedback loop in both CRPC and enzalutamide-resistant prostate cancer cells. Notably, restoring CCN3 was sufficient to effectively reduce CPRC cell proliferation in vitro and to abolish xenograft tumor growth in vivo Taken together, our findings establish CCN3 as a pivotal regulator of AR signaling and prostate cancer progression and suggest a functional intersection between Polycomb and AR signaling in CRPC. Cancer Res; 77(2); 412-22. ©2016 AACR.

Li J, Gao X, Ji K, et al.
Differential expression of CCN family members CYR611, CTGF and NOV in gastric cancer and their association with disease progression.
Oncol Rep. 2016; 36(5):2517-2525 [PubMed] Free Access to Full Article Related Publications
CCN is an acronym for cysteine-rich protein 61 (CYR61), connective tissue growth factor (CTGF) and nephroblastoma overexpressed (NOV). Aberrations of certain CCN members including CYR61, CTGF, Wnt1-inducible signalling pathway protein (WISP)-1 and -3 have been reported in gastric cancer. The present study aimed to examine the clinical relevance of NOV along with CYR61 and CTGF in gastric cancer by analysing their transcript levels. CYR61, CTGF and NOV transcript expression in 324 gastric cancer samples with paired adjacent normal gastric tissues were determined using real-time quantitative PCR and the results were statistically analysed against patient clinicopathological data using SPSS software. NOV mRNA levels in gastric cancer tissues were significantly elevated when compared with levels in their paired adjacent non-cancerous tissues. Local advanced tumours with invasive expansion (T3 and T4) expressed higher levels of NOV (p=0.013) compared with the less invasive tumours (T1 and T2). CYR61 transcript levels were also significantly increased in gastric cancers compared with levels in the adjacent non-cancerous tissues. Kaplan-Meier survival curves revealed that patients with CYR61-low transcript levels had longer overall survival (OS) (p=0.018) and disease-free survival (DFS) (p=0.015). NOV overexpression promoted the in vitro proliferation of AGS cells while the knockdown resulted in a reduced proliferation of HGC27 cells. A similar effect was observed for the invasion of these two gastric cancer cell lines. NOV expression was increased in gastric cancer which was associated with local invasion and distant metastases. Taken together, the expression of NOV and CYR61 was increased in gastric cancer. The elevated expression of CYR61 was associated with poorer survival. NOV promoted proliferation and invasion of gastric cancer cells. Further investigations may highlight their predictive and therapeutic potential in gastric cancer.

Awolaran O, Brooks SA, Lavender V
Breast cancer osteomimicry and its role in bone specific metastasis; an integrative, systematic review of preclinical evidence.
Breast. 2016; 30:156-171 [PubMed] Related Publications
Metastasis accounts for most of the deaths from breast cancer and the preference of invasive breast cancer metastasising to bone has been widely reported. However, the biological basis of breast cancer osteotropism is not fully understood. This paper provides, for the first time, an integrative, systematic review of evidence of molecular factors that have functional roles in the homing of metastatic breast cancer to the bone. Pubmed, Web of Science and EBSCOhost were searched using keywords and synonyms for molecular, metastasis, breast cancer and bone to identify articles published between January 2004 and August 2016. 4491 potentially relevant citations were retrieved. 63 articles met the inclusion criteria, which were primary studies reporting evidence of molecular factors that have functional roles in predisposing breast cancer bone metastasis in vivo. 12 of those 63 articles that additionally met quality criteria were included in the review. Extracted data were tabulated and key findings that indicated biological mechanisms involved in breast cancer metastasis to bone were synthesised. 15 proteins expressed by breast cancer cells were identified as factors that mediate breast cancer bone metastasis: ICAM-1, cadherin-11, osteoactivin, bone sialoprotein, CCN3, IL-11, CCL2, CITED2, CXCR4, CTGF, OPN, CX

Hu Z, Yang A, Su G, et al.
Huaier restrains proliferative and invasive potential of human hepatoma SKHEP-1 cells partially through decreased Lamin B1 and elevated NOV.
Sci Rep. 2016; 6:31298 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is one of the most common cause of malignancy-related mortality worldwide. It is urgently needed to develop potential drugs with good efficacy and low toxicity for HCC treatment. The anti-tumor effect of Traditional Chinese Medicine (TCM) has received increasing attention worldwide. Trametes robiniophila Murr. (Huaier) has been used in TCM for approximately 1,600 years. Clinically, Huaier has satisfactory therapeutic effects in cancer treatment, especially in HCC. However, the mechanisms underlying the anti-cancer effect of Huaier remain ill defined. Herein we have demonstrated that Huaier dramatically inhibited cell proliferation and induced apoptosis in human hepatoma cell line SKHEP-1. Importantly, Huaier restrained the metastatic capability of SKHEP-1 cells. Mechanistically, down-regulation of Lamin B1 and up-regulation of Nephroblastoma overexpressed (NOV) were at least partially responsible for the inhibitory effect of Huaier on the proliferative and invasive capacity of SKHEP-1 cells. Our finding provided new insights into mechanisms of anti-HCC effect of Huaier and suggested a new scientific basis for clinical medication.

Ueda M, Iguchi T, Komatsu H, et al.
Clinical Significance of Expression of Nephroblastoma Overexpressed (NOV) in Patients with Colorectal Cancer.
Anticancer Res. 2015; 35(12):6591-7 [PubMed] Related Publications
BACKGROUND: The nephroblastoma overexpressed (NOV) gene, which belongs to the cysteine-rich, angiogenic inducer 61/connective tissue growth factor/nephroblastoma overexpressed (CCN) family, is located in the 8q24 region and promotes migration and invasiveness in several types of malignancies. We explored the clinical significance of NOV expression in colorectal cancer (CRC).
MATERIALS AND METHODS: NOV expression in CRC specimens and CRC cell lines were evaluated. The association between the clinicopathlogical factors and NOV mRNA expression of tumor tissues was assessed in 126 patients with CRC. We assessed the relationships between NOV expression and overall survival in public databases. We performed overexpression experiments in vitro.
RESULTS: CRC specimens and CRC cell lines showed high NOV expression. High NOV mRNA expression was correlated with poorer overall survival and higher Union for International Cancer Control (UICC) T factor. In public databases, high NOV expression was associated with poorer prognoses. Overexpression of NOV promoted invasiveness of CRC cells.
CONCLUSION: NOV may be an indicator of poor prognosis and a therapeutic target in CRC.

Li J, Ye L, Owen S, et al.
Emerging role of CCN family proteins in tumorigenesis and cancer metastasis (Review).
Int J Mol Med. 2015; 36(6):1451-63 [PubMed] Free Access to Full Article Related Publications
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.

Yao J, Weng Y, Yan S, et al.
NOV inhibits proliferation while promoting apoptosis and migration in osteosarcoma cell lines through p38/MAPK and JNK/MAPK pathways.
Oncol Rep. 2015; 34(4):2011-21 [PubMed] Related Publications
The nephroblastoma overexpressed (NOV) gene, a member of the CCN gene family that encodes secreted proteins involved in a variety of processes including tumorigenesis, is often altered in a variety of tumors, including osteosarcoma. Recent studies indicated that NOV promotes osteosarcoma metastasis, but its biological functions and molecular mechanisms on osteosarcoma proliferation have yet to be fully elucidated. The aim of the present study was to examine the role of NOV in osteosarcoma biology. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis were performed to characterize the endogenous expression of NOV in osteosarcoma cell lines. Recombinant adenovirus expressing NOV/siNOV (AdNOV/AdsiNOV) was used to infect osteosarcoma cell lines with a relatively low/high endogenous NOV expression to determine the functional relevance of NOV expression to osteosarcoma cell growth and migration in vitro, respectively. As a result, osteosarcoma cell proliferation was significantly reduced by NOV upregulation, indicated by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltrazolium bromide (MTT), colony forming assay and cell cycle analysis. Cell apoptosis was markedly induced, as indicated by Hoechst 33258 staining assay and flow cytometry (FCM) detection. Despite the antiproliferative effect, NOV-transfected osteosarcoma cells exhibited increased migration ability. The possible molecular mechanisms underlying the biological role of NOV were also investigated. The results demonstrated that NOV increased the phosphorylation of p38 and c-Jun N-terminal kinase (JNK) mitogen-actived protein kinases (MAPKs) in osteosarcoma cell lines. When the phosphorylation of p38 and JNK were inhibited by SB203580 (p38 inhibitor) or SP600125 (JNK inhibitor), respectively, the NOV-induced proliferation inhibition and cell apoptosis were reversed. In conclusion, the results revealed that NOV regulates the tumor growth of osteosarcoma cells through activation of the MAPK signaling pathway and promotes osteosarcoma cell migration in vitro.

Liu S, Han L, Wang X, et al.
Nephroblastoma overexpressed gene (NOV) enhances RCC cell motility through upregulation of ICAM-1 and COX-2 expression via Akt pathway.
Int J Clin Exp Pathol. 2015; 8(2):1302-11 [PubMed] Free Access to Full Article Related Publications
Renal cell carcinoma (RCC) carries a high risk of malignancy and metastasis. The inducible isoform of prostaglandin synthase, cyclooxygenase (COX)-2, and ICAM-1 may be involved in tumor metastasis. CCN3, also called nephroblastoma overexpressed gene (NOV), has been found to regulate the proliferation and differentiation of cancer cells. The effects of NOV on RCC cell migration and expression of COX-2 and ICAM-1 have not described yet in detail. But here, NOV was found to promote the migration and expression of COX-2 and ICAM-1 in human RCC cells. Akt inhibitor was found to interfere with this NOV-induced migration and up-regulation of COX-2 and ICAM-1 in RCC cells. NOV stimulation was here found to promote the phosphorylation of Akt. RCC tissue chips were subjected to IHC staining, which showed COX-2 expression in RCC tissues to be a significantly closely correlated with NOV expression, with significance determined using Pearson correlation testing (P < 0.05). The results of the current work indicate that NOV activates COX-2 and ICAM-1 through Akt, promoting the migration of RCC cells.

Zhang H, Li W, Huang P, et al.
Expression of CCN family members correlates with the clinical features of hepatocellular carcinoma.
Oncol Rep. 2015; 33(3):1481-92 [PubMed] Related Publications
Studies have reported that the CCN family of proteins plays an important role in stimulating tumorigenesis. However, the relationship between the CCN protein family members and the features of hepatocellular carcinoma (HCC) remains unclear. The objective of this study was to determine the relationship between the expression levels of CCN protein family members and the features of HCC. Expression levels of the CCN family of proteins in 80-paired primary HCC samples and 11 normal liver samples were determined by a quantitative real-time PCR assay. Enhanced expression of nephroblastoma overexpressed protein (NOV) and decreased expression of Wnt-induced secreted protein 1 (WISP1), cysteine-rich protein 61 (CYR61) and connective tissue growth factor (CTGF) were found in HCC samples when compared to levels in matched non-cancerous tissues. No significant difference in WISP2 was found between matched-pair samples; only a few samples showed WISP3 expression. Furthermore, the expression levels of NOV, WISP1 and CYR61 were closely correlated with certain clinical features, including venous invasion, cellular differentiation, pTNM stage, disease-free survival and overall survival. Our results suggest that HCC progression may be enhanced by NOV and suppressed by WISP1 and CYR61. Our statistical analysis suggests that these proteins may be valuable in determining the prognosis of this deadly disease and directs attention to modulating the levels of these proteins as a potential mode of therapy.

Chen PC, Cheng HC, Wang J, et al.
Prostate cancer-derived CCN3 induces M2 macrophage infiltration and contributes to angiogenesis in prostate cancer microenvironment.
Oncotarget. 2014; 5(6):1595-608 [PubMed] Free Access to Full Article Related Publications
Tumor-associated macrophages (TAMs) are M2-polarized macrophages that infiltrate the tumor microenvironment and promote tumorigenesis. However, the mechanisms by which TAMs modulate prostate cancer (PCa) growth are poorly understood. Here, we found that expression of Nephroblastoma Overexpressed (NOV/CCN3) is upregulated in PCa cells and correlated with M2 macrophage infiltration. RAW264.7 macrophage migration was induced by conditioned media (CM) from various PCa cells in proportion to the cellular level of CCN3 expression and was inhibited by an anti-CCN3 neutralizing antibody. CCN3 and PCaCM treatment skewed RAW264.7 cell differentiation from an M1 phenotype to an M2 phenotype. PCa-derived CCN3 induced focal adhesion kinase (FAK)/Akt/NF-κB signaling in RAW264.7 cells, which resulted in VEGF expression and subsequently increased tube formation in endothelial progenitor cells. Finally, PCa-secreted CCN3 stimulated RAW264.7 cells and promoted angiogenesis in the chick chorioallantoic membrane assay (CAM), and increased tumor growth and tumor-associated angiogenesis in a PCa xenograft mouse model. Our results indicate that PCa-secreted CCN3 can recruit macrophages and skew their differentiation to an M2 phenotype. In turn, CCN3-stimulated macrophages contribute to VEGF-dependent angiogenesis. This study reveals a novel mechanism by which TAMs enhance PCa angiogenesis and identifies a potential therapeutic target for PCa.

Chen J, Gao Y, Xu B, et al.
NOV is upregulated and promotes migration and invasion in bladder cancer.
Tumour Biol. 2014; 35(7):6749-55 [PubMed] Related Publications
NOV is pro-tumourigenic via epithelial-mesenchymal transition (EMT) in several malignancies but is not studied in bladder cancer (BCa). Whether NOV is responsible for bladder carcinogenesis and the underlying mechanism is unclear. Using immunohistochemical staining, we quantified expressions of NOV, pS6, Vimentin and E-cadherin in 66 bladder cancer and 10 normal bladder urothelium samples. EMT was profiled by EMT index (EMTi) calculated as the ratio of Vimentin to E-cadherin. In vitro and in vivo studies were carried out to profile the role of NOV in the tumourigenesis of BCa. NOV was upregulated in bladder cancer compared to normal tissue, and its expression was correlated to pS6 and EMTi. Expression of NOV was higher in recurrent and multiple tumours and was increased with progression of tumour grade. NOV expression was also higher in BCa cell lines. Silence of NOV attenuated EMT, decreased invasion and migration of BCa cells. Silence of NOV also inhibited xenograft tumour growth and decreased tumour EMT. NOV is pro-tumourigenic in bladder cancer especially in nonmuscle-invasive entities (NMIBC). NOV may promote carcinogenesis via promotion of EMT and association with increased mTOR activity.

Cheng TY, Wu MS, Hua KT, et al.
Cyr61/CTGF/Nov family proteins in gastric carcinogenesis.
World J Gastroenterol. 2014; 20(7):1694-700 [PubMed] Free Access to Full Article Related Publications
Gastric cancer (GC) is the second leading cause of cancer-related death. The poor survival rate may reflect the relatively aggressive tumor biology of GC. Recently, the importance of the tumor microenvironment in carcinogenesis has emerged. In the tumor microenvironment, tumor cells and the surrounding stromal cells aberrantly secrete matricellular proteins capable of modulating carcinogenesis and regulating metastasis. The Cyr61/CTGF/Nov (CCN) proteins are a family of matricellular proteins with variable roles in many physiological and pathological processes. The evidence suggests that CCN family proteins contribute to GC carcinogenic processes. Here, we briefly review recent research on the effects of CCN family proteins in GC carcinogenesis and the development of new targeted agents in this field.

Zhang T, Zhao C, Luo L, et al.
The clinical and prognostic significance of CCN3 expression in patients with cervical cancer.
Adv Clin Exp Med. 2013 Nov-Dec; 22(6):839-45 [PubMed] Related Publications
BACKGROUND: CCN3 plays important roles in growth, differentiation, angiogenesis and adhesion. Recently, the role of CCN3 in human carcinogenesis has become an area of great interest. However, little is known about the function of CCN3 in human cervical cancer.
OBJECTIVES: The aim of this study was to investigate the expression profile of CCN3 in cervical cancer and to assess its clinical significance.
MATERIAL AND METHODS: In this study, qRT-PCR, immunohistochemistry and Western blotting analysis were used in the detection of CCN3 mRNA and protein expression, both in cervical cancer and in corresponding normal tissue, respectively. The data was correlated with clinicopathological features. A survival analysis was performed to assess the prognostic significance.
RESULTS: CCN3 mRNA was overexpressed in cervical cancer tissue when compared with corresponding normal tissue, as was CCN3 protein. Upregulation of CCN3 was significantly associated with the stage of the disease (P = 0.017) and with lymph node involvement (P = 0.006). Using the Kaplan-Meier analysis, a comparison of survival curves of low vs. high expressers of CCN3 revealed a highly significant difference in human cervical cancer tissue (P = 0.021), which suggests that overexpression of CCN3 is associated with a poorer prognosis.
CONCLUSIONS: The results of the current study suggest that CCN3 may play an important role in cervical carcinogenesis and therefore may have potential as a biomarker for prognosis and as a therapeutic target in cervical cancer.

Suresh S, McCallum L, Crawford LJ, et al.
The matricellular protein CCN3 regulates NOTCH1 signalling in chronic myeloid leukaemia.
J Pathol. 2013; 231(3):378-87 [PubMed] Free Access to Full Article Related Publications
Deregulated NOTCH1 has been reported in lymphoid leukaemia, although its role in chronic myeloid leukaemia (CML) is not well established. We previously reported BCR-ABL down-regulation of a novel haematopoietic regulator, CCN3, in CML; CCN3 is a non-canonical NOTCH1 ligand. This study characterizes the NOTCH1–CCN3 signalling axis in CML. In K562 cells, BCR-ABL silencing reduced full-length NOTCH1 (NOTCH1-FL) and inhibited the cleavage of NOTCH1 intracellular domain (NOTCH1-ICD), resulting in decreased expression of the NOTCH1 targets c-MYC and HES1. K562 cells stably overexpressing CCN3 (K562/CCN3) or treated with recombinant CCN3(rCCN3) showed a significant reduction in NOTCH1 signalling (> 50% reduction in NOTCH1-ICD, p < 0.05).Gamma secretase inhibitor (GSI), which blocks NOTCH1 signalling, reduced K562/CCN3 colony formation but increased that of K562/control cells. GSI combined with either rCCN3 or imatinib reduced K562 colony formation with enhanced reduction of NOTCH1 signalling observed with combination treatments. We demonstrate an oncogenic role for NOTCH1 in CML and suggest that BCR-ABL disruption of NOTCH1–CCN3 signalling contributes to the pathogenesis of CML.

Cui L, Xie R, Dang S, et al.
NOV promoted the growth and migration of pancreatic cancer cells.
Tumour Biol. 2014; 35(4):3195-201 [PubMed] Related Publications
NOV, a member of the CCN (Cyr61, CTGF and NOV) family, is involved in diverse biological processes, such as cell adhesion, proliferation and angiogenesis. However, its function in pancreatic cancer remains poorly understood. Here, we found that the expression of NOV was up-regulated in pancreatic cancer tissues. Moreover, over-expression of NOV in pancreatic cancer cells promoted cell proliferation and migration, while knock down the expression of NOV impaired the tumorigenecity of pancreatic cancer cells in vitro and in vivo. Mechanistically, NOV induced epithelial-mesenchymal transition (EMT) and regulated the expression of multiple EMT marker. Taken together, our study suggested the important role of NOV in pancreatic cancer and NOV might be an important therapeutic target.

Chen PC, Cheng HC, Tang CH
CCN3 promotes prostate cancer bone metastasis by modulating the tumor-bone microenvironment through RANKL-dependent pathway.
Carcinogenesis. 2013; 34(7):1669-79 [PubMed] Related Publications
Bone metastasis in patient with advanced-stage prostate cancer, the most commonly diagnosed malignancy in Western countries, increases the risk of intractable bone pain. The nephroblastoma overexpressed (NOV/CCN3) gene, a member of the CCN gene family, is responsible for the secretion of CCN3, a matrix-associated protein involved in many cellular functions. However, the role of CCN3 in prostate cancer metastasis to bone is poorly understood. CCN3 was found to be highly expressed in bone metastasis patients and positively correlated with malignancy in human prostate cancer cells. Prostate cancer conditioned medium-induced osteoclast differentiation was inhibited by neutralizing antibody against CCN3. Specifically, CCN3 was found to induce osteoclastogenesis through the receptor activator of NF-κB ligand (RANKL)-dependent pathway, and the focal adhesion kinase/Akt/p38/NF-κB signal pathway was found to be involved in CCN3-mediated receptor activator of NF-κB expression and RANKL-dependent osteoclastogenesis. In contrast, osteoblasts were observed to play an important role in osteoclast differentiation by paracrine manner, with treatment of osteoblasts with CCN3 found to change the RANKL (osteoclastogenesis):OPG (antiosteoclastogenesis) ratio. Compared with parental PC3 cells, highly invasive PC3-I3 cells markedly enhanced osteoclast activity and bone metastasis in vivo. These results indicate that CCN3 can be used as a novel therapeutic target in the prevention of bone metastasis of prostate cancer.

Wu L, Runkle C, Jin HJ, et al.
CCN3/NOV gene expression in human prostate cancer is directly suppressed by the androgen receptor.
Oncogene. 2014; 33(4):504-13 [PubMed] Free Access to Full Article Related Publications
Androgen receptor (AR) has essential roles during prostate cancer progression. With genome-wide AR-binding sites mapped to high resolution, studies have recently reported AR as a transcriptional repressor. How AR inhibits gene expression and how this contributes to prostate cancer, however, are incompletely understood. Through meta-analysis of microarray data, here we nominate nephroblastoma overexpressed (NOV) as a top androgen-repressed gene. We show that NOV is directly suppressed by androgen through the AR. AR occupies the NOV enhancer and communicates with the NOV promoter through DNA looping. AR activation recruits the polycomb group protein EZH2, which subsequently catalyzes histone H3 lysine 27 tri-methylation around the NOV promoter, thus leading to repressive chromatin remodeling and epigenetic silencing. Concordantly, AR and EZH2 inhibition synergistically restored NOV expression. NOV is downregulated in human prostate cancer wherein AR and EZH2 are upregulated. Functionally, NOV inhibits prostate cancer cell growth in vitro and in vivo. NOV reconstitution reverses androgen-induced cell growth and NOV knockdown drives androgen-independent cell growth. In addition, NOV expression is restored by hormone-deprivation therapies in mice and prostate cancer patients. Therefore, using NOV as a model gene we gained further understanding of the mechanisms underlying AR-mediated transcriptional repression. Our findings establish a tumor-suppressive role of NOV in prostate cancer and suggest that one important, but previously underestimated, manner by which AR contributes to prostate cancer progression is through inhibition of key tumor-suppressor genes.

Chen PC, Lin TH, Cheng HC, Tang CH
CCN3 increases cell motility and ICAM-1 expression in prostate cancer cells.
Carcinogenesis. 2012; 33(4):937-45 [PubMed] Related Publications
Nephroblastoma overexpressed (NOV or CCN3) is a secreted matrix-associated protein that belongs to the CCN gene family and is involved in many cellular functions, including growth, differentiation and adhesion. The effect of CCN3 on human prostate cancer cells, however, is unknown. Here, we have shown that CCN3 increased cell migration and intercellular adhesion molecule-1 (ICAM-1) expression in prostate cancer cells. In addition, expression of CCN3 was positively correlated with both cell migration and ICAM-1 expression in human prostate cancer cells. CCN3 activated a signal transduction pathway that included αvβ3 integrin, integrin-linked kinase (ILK), Akt and nuclear factor-kappaB (NF-κB). Reagents that inhibit specific components of this pathway each diminished the ability of CCN3 to effect cell migration and ICAM-1 expression. Moreover, CCN3 increased binding of p65 to an NF-κB-binding element in the ICAM-1 promoter. Finally, knockdown of CCN3 expression markedly inhibited cell migration, tumor growth in bone and bone metastasis. Taken together, our results indicate that CCN3 enhances the migration of prostate cancer cells by increasing ICAM-1 expression through a signal transduction pathway that involves αvβ3 integrin, ILK, Akt and NF-κB. CCN3 thus represents a promising new target for treating prostate cancer.

Brisbin AG, Asmann YW, Song H, et al.
Meta-analysis of 8q24 for seven cancers reveals a locus between NOV and ENPP2 associated with cancer development.
BMC Med Genet. 2011; 12:156 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Human chromosomal region 8q24 contains several genes which could be functionally related to cancer, including the proto-oncogene c-MYC. However, the abundance of associations around 128 Mb on chromosome 8 could mask the appearance of a weaker, but important, association elsewhere on 8q24.
METHODS: In this study, we completed a meta-analysis of results from nine genome-wide association studies for seven types of solid-tumor cancers (breast, prostate, pancreatic, lung, ovarian, colon, and glioma) to identify additional associations that were not apparent in any individual study.
RESULTS: Fifteen SNPs in the 8q24 region had meta-analysis p-values < 1E-04. In particular, the region consisting of 120,576,000-120,627,000 bp contained 7 SNPs with p-values < 1.0E-4, including rs6993464 (p = 1.25E-07). This association lies in the region between two genes, NOV and ENPP2, which have been shown to play a role in tumor development and motility. An additional region consisting of 5 markers from 128,478,000 bp - 128,524,000 (around gene POU5F1B) had p-values < 1E-04, including rs6983267, which had the smallest p-value (p = 6.34E-08). This result replicates previous reports of association between rs6983267 and prostate and colon cancer.
CONCLUSIONS: Further research in this area is warranted as these results demonstrate that the chromosomal region 8q24 may contain a locus that influences general cancer susceptibility between 120,576 and 120,630 kb.

Yang W, Wagener J, Wolf N, et al.
Impact of CCN3 (NOV) glycosylation on migration/invasion properties and cell growth of the choriocarcinoma cell line Jeg3.
Hum Reprod. 2011; 26(10):2850-60 [PubMed] Related Publications
BACKGROUND: Recently we have shown that the matricellular CCN3 protein expressed in invasive extravillous trophoblast cells (EVTs) is decreased in early-onset pre-eclampsia and is regulated by oxygen tension. Pathogenesis of pre-eclampsia relies on a shallow invasion of EVTs into the spiral arteries, which leads to hypoxia accompanied by uteroplacental insufficiency. Here we investigated the function of glycosylated and non-glycosylated CCN3 protein on cell growth as well as migration and invasion properties of the malignant trophoblast cell line Jeg3 which is a widely used model for the invasive trophoblast.
METHODS AND RESULTS: Stable transfection of Jeg3 choriocarcinoma cells with full length CCN3 resulted in high expression of secreted glycosylated and cellular non-glycosylated CCN3. These cells revealed significantly reduced growth in cell numbers combined with a significantly increased migratory and invasive capacity. Matrix metalloprotease (MMP)-2 and MMP-9 activities were enhanced dependent on CCN3 expression, which could be confirmed by CCN3 knockdown studies. Using recombinant glycosylated and non-glycosylated CCN3, we revealed that CCN3 decreased growth in Jeg3 cell numbers independent of its glycosylation status, whereas only non-glycosylated CCN3 was able to enhance migration and invasion properties.
CONCLUSIONS: The present results suggest that CCN3 protein regulates the decrease in Jeg3 cell numbers independent of its glycosylation status, whereas migratory and invasive properties are influenced only by non-glycosylated CCN3. An impaired balance in the expression of glycosylated and non-glycosylated CCN3 could contribute to the shallow invasion of EVTs observed in pre-eclampsia.

Zuo HL, Peng EL, Zhao HX, et al.
[Expression of NOV and BNIP3 gene in mouse myelomonocytic leukemia and its significance].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2011; 19(2):293-7 [PubMed] Related Publications
This study was aimed to investigate the expression level of NOV and BNIP3 mRNA in mice myelomonocytic leukemia (AML-M(4)) and its significance. The mice were inoculated intravenously with myelomonocytic leukemia cells of WEHI-3, and divided randomly into chemotherapy group and control (untreated) group. Bone marrow samples were then collected from both groups at different times. The NOV and BNIP3 mRNA expression were detected by TaqMan quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), and the relationship between these expression levels and clinical significance in leukemia incidence and progression were analyzed with β-actin as the housekeeping gene. The results showed that the mean values of NOV and BNIP3 increased gradually from 2 weeks after inoculation and achieved highest level at death in control group. Expression level of NOV increased from 1.85E-05 before inoculation to 3.57E-02 at death (p < 0.05), and BNIP3 from 3.44E-03 to 3.48E-02. While 2 gene expression in the chemotherapy group decreased quickly to 2.51E-05 and 1.58E-03 (p < 0.05) respectively after chemotherapy, which were close to the level before inoculation (p > 0.05). The 2 gene expressions again rose at relapse, and difference of expression level between 2 group at death were no statistically significant (p > 0.05). It is concluded that the expression of NOV and BNIP3 in leukemia AML-M(4) is significantly higher than that in normal controls, of which high level expression is an important factor in the development of leukemia. Close relation between the therapeutic effect and expression level of these two genes suggests the great value in prognostic evaluation and MRD detection.

Ouellet V, Tiedemann K, Mourskaia A, et al.
CCN3 impairs osteoblast and stimulates osteoclast differentiation to favor breast cancer metastasis to bone.
Am J Pathol. 2011; 178(5):2377-88 [PubMed] Free Access to Full Article Related Publications
Bone is a preferred site for breast cancer metastasis, causing pain, fractures, spinal cord compressions, and hypercalcemia, all of which can significantly diminish the patient's quality of life. We identified CCN3 as a novel factor that is highly expressed in bone metastatic breast cancer cells from a xenograft mouse model and in bone metastatic lesions from patients with breast cancer. We demonstrate that CCN3 overexpression enhances the ability of weakly bone metastatic breast cancer cells to colonize and grow in the bone without altering their growth in the mammary fat pad. We further demonstrated that human recombinant CCN3 inhibits osteoblast differentiation from primary bone marrow cultures, leading to a higher receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) ratio. In conjunction with its ability to impair osteoblast differentiation, we uncovered a novel role for CCN3 in promoting osteoclast differentiation from RANKL-primed monocyte precursors. CCN3 exerts its pro-osteoclastogenic effects by promoting calcium oscillations and nuclear factor of activated T cells c1 (NFATc1) nuclear translocation. Together, these results demonstrate that CCN3 regulates the differentiation of bone resident cells to create a resorptive environment that promotes the formation of osteolytic breast cancer metastases.

Zhang Y, Wang C
Nephroblastoma overexpressed (NOV/CCN3) gene: a paired-domain-specific PAX3-FKHR transcription target that promotes survival and motility in alveolar rhabdomyosarcoma cells.
Oncogene. 2011; 30(32):3549-62 [PubMed] Free Access to Full Article Related Publications
The CCN (Cy61, CTGF and NOV) family of proteins is a group of matricellular biomolecules involved in both physiological and pathological processes. Elevated expression of the CCN3 (also known as NOV, Nephroblastoma overexpressed) gene has been detected in clinical samples of the skeletal muscle cancer rhabdomyosarcoma, with the highest expression found in the alveolar subtype (aRMS). Over 80% of aRMSs are characterized by a chromosomal translocation-derived fusion transcription factor PAX3-FKHR. In this study, we linked elevated CCN3 levels in aRMS cells to PAX3-FKHR expression. We found reduced CCN3 levels in aRMS cells following small interfering RNA knockdown of PAX3-FKHR, and increased CCN3 levels in C2 myoblasts following ectopic expression of PAX3-FKHR. Promoter, electrophoretic mobility shift assay and chromatin immunoprecipitation analyses confirmed that the CCN3 gene was a direct target for PAX3-FKHR transcriptional activation through a paired-domain DNA sequence in the first intron of the CCN3 gene. To determine the function of CCN3, we showed that knockdown and ectopic expression of CCN3 decreased survival and increased differentiation in aRMS cells, respectively. In addition, we found that exogenously supplied CCN3 protein promoted aRMS cell adhesion, migration and Matrigel invasion. Taken together, data from this study have (1) provided a mechanistic basis for the CCN3 overexpression in aRMS cells, and (2) identified CCN3 as an autocrine/paracrine factor that contributes to the aggressive behavior of aRMS cells, perhaps through a positive feedback loop. Thus, CCN3 may be an attractive target for therapeutic intervention in aRMS.

Tzeng HE, Chen JC, Tsai CH, et al.
CCN3 increases cell motility and MMP-13 expression in human chondrosarcoma through integrin-dependent pathway.
J Cell Physiol. 2011; 226(12):3181-9 [PubMed] Related Publications
Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. CCN3, also called nephroblastoma overexpressed gene (NOV), regulates proliferation and differentiation of cancer cells. However, the effect of CCN3 on migration activity in human chondrosarcoma cells is mostly unknown. Here, we found that CCN3 increased the migration and expression of matrix metalloproteinase (MMP)-13 in human chondrosarcoma cells (JJ012 cells). αvβ3 or αvβ5 monoclonal antibody (mAb), phosphatidylinositol 3-kinase (PI3K) inhibitors (Ly294002 and wortmannin) and Akt inhibitor inhibited the CCN3-induced increase of the migration and MMP-13 upregulation of chondrosarcoma cells. CCN3 stimulation increased the phosphorylation of focal adhesion kinase (FAK), PI3K, and Akt. In addition, NF-κB inhibitors also suppressed the cell migration and MMP-13 expression enhanced by CCN3. Moreover, CCN3 increased NF-κB luciferase activity and binding of p65 to the NF-κB element on the MMP-13 promoter. Taken together, our results indicate that CCN3 enhances the migration of chondrosarcoma cells by increasing MMP-13 expression through the αvβ3/αvβ5 integrin receptor, FAK, PI3K, Akt, p65, and NF-κB signal transduction pathway.

Bohr W, Kupper M, Hoffmann K, Weiskirchen R
Recombinant expression, purification, and functional characterisation of connective tissue growth factor and nephroblastoma-overexpressed protein.
PLoS One. 2010; 5(12):e16000 [PubMed] Free Access to Full Article Related Publications
The CCN family of proteins, especially its prominent member, the Connective tissue growth factor (CTGF/CCN2) has been identified as a possible biomarker for the diagnosis of fibrotic diseases. As a downstream mediator of TGF-β1 signalling, it is involved in tissue scarring, stimulates interstitial deposition of extracellular matrix proteins, and promotes proliferation of several cell types. Another member of this family, the Nephroblastoma-Overexpressed protein (NOV/CCN3), has growth-inhibiting properties. First reports further suggest that these two CCN family members act opposite to each other in regulating extracellular matrix protein expression and reciprocally influence their own expression when over-expressed. We have established stable HEK and Flp-In-293 clones as productive sources for recombinant human CCN2/CTGF. In addition, we generated an adenoviral vector for recombinant expression of rat NOV and established protocols to purify large quantities of these CCN proteins. The identity of purified human CCN2/CTGF and rat CCN3/NOV was proven by In-gel digest followed by ESI-TOF/MS mass spectrometry. The biological activity of purified proteins was demonstrated using a Smad3-sensitive reporter gene and BrdU proliferation assay in permanent cell line EA•hy 926 cells. We further demonstrate for the first time that both recombinant CCN proteins are N-glycosylated.

Huang CY, Lee CY, Chen MY, et al.
Nephroblastoma overexpressed gene (NOV) enhances cell motility and COX-2 upregulation of human osteosarcoma involves αvβ5 integrin, ILK and AP-1-dependent pathways.
Biochem Pharmacol. 2011; 81(5):577-85 [PubMed] Related Publications
Osteosarcoma is characterized by a high malignant and metastatic potential. Cyclooxygenase (COX)-2, the inducible isoform of prostaglandin synthase, has been implicated in tumor metastasis. Nephroblastoma overexpressed gene (NOV), also called CCN3, was regulated proliferation and differentiation of cancer cells. However, the effect of NOV on migration activity and COX-2 expression in human osteosarcoma cells is mostly unknown. Here we found that NOV increased the migration and expression of COX-2 in human osteosarcoma cells. αvβ5 monoclonal antibody (mAb), integrin-linked kinase (ILK) and Akt inhibitor reduced the NOV-enhanced the migration and COX-2 up-regulation of osteosarcoma cells. NOV stimulation increased the ILK kinase activity and phosphorylation of Akt. In addition, c-Jun siRNA also antagonized the NOV-mediated migration and COX-2 expression. Moreover, NOV enhanced the AP-1 binding activity and promoter activity. Taken together, these results suggest that the NOV acts through αvβ5 integrin to activate ILK and Akt, which in turn activates c-Jun and AP-1, resulting in the activations of COX-2 and contributing the migration of human osteosarcoma cells.

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