CYR61

Gene Summary

Gene:CYR61; cysteine-rich, angiogenic inducer, 61
Aliases: CCN1, GIG1, IGFBP10
Location:1p22.3
Summary:The secreted protein encoded by this gene is growth factor-inducible and promotes the adhesion of endothelial cells. The encoded protein interacts with several integrins and with heparan sulfate proteoglycan. This protein also plays a role in cell proliferation, differentiation, angiogenesis, apoptosis, and extracellular matrix formation. [provided by RefSeq, Sep 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:protein CYR61
HPRD
Source:NCBIAccessed: 17 August, 2015

Ontology:

What does this gene/protein do?
Show (36)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Stem Cells
  • Proto-Oncogene Proteins
  • Staurosporine
  • Immunohistochemistry
  • Cancer Gene Expression Regulation
  • Immediate-Early Proteins
  • Cancer RNA
  • Case-Control Studies
  • Tumor Markers
  • Angiogenesis
  • Cell Movement
  • Lung Cancer
  • Neoplasm Proteins
  • Species Specificity
  • Neoplasm Invasiveness
  • VHL
  • Messenger RNA
  • Gene Expression Profiling
  • Chromosome 1
  • Oligonucleotide Array Sequence Analysis
  • Gene Expression
  • Cell Proliferation
  • Intercellular Signaling Peptides and Proteins
  • Esophageal Cancer
  • RNA Interference
  • Prostate Cancer
  • Signal Transduction
  • Cysteine-Rich Protein 61
  • Western Blotting
  • Promoter Regions
  • Connective Tissue Growth Factor
  • RTPCR
  • Breast Cancer
  • Down-Regulation
  • Bone Cancer
  • Osteosarcoma
  • Apoptosis
  • NOV
  • Staging
  • CCN Intercellular Signaling Proteins
  • Translocation
Tag cloud generated 17 August, 2015 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: CYR61 (cancer-related)

Yu OM, Brown JH
G Protein-Coupled Receptor and RhoA-Stimulated Transcriptional Responses: Links to Inflammation, Differentiation, and Cell Proliferation.
Mol Pharmacol. 2015; 88(1):171-80 [PubMed] Article available free on PMC after 01/07/2016 Related Publications
The low molecular weight G protein RhoA (rat sarcoma virus homolog family member A) serves as a node for transducing signals through G protein-coupled receptors (GPCRs). Activation of RhoA occurs through coupling of G proteins, most prominently, G12/13, to Rho guanine nucleotide exchange factors. The GPCR ligands that are most efficacious for RhoA activation include thrombin, lysophosphatidic acid, sphingosine-1-phosphate, and thromboxane A2. These ligands also stimulate proliferation, differentiation, and inflammation in a variety of cell and tissues types. The molecular events underlying these responses are the activation of transcription factors, transcriptional coactivators, and downstream gene programs. This review describes the pathways leading from GPCRs and RhoA to the regulation of activator protein-1, NFκB (nuclear factor κ-light-chain-enhancer of activated B cells), myocardin-related transcription factor A, and Yes-associated protein. We also focus on the importance of two prominent downstream transcriptional gene targets, the inflammatory mediator cyclooxygenase 2, and the matricellular protein cysteine-rich angiogenic inducer 61 (CCN1). Finally, we describe the importance of GPCR-induced activation of these pathways in the pathophysiology of cancer, fibrosis, and cardiovascular disease.

Cheng G, Zhang H, Zhang L, Zhang J
Cyr61 promotes growth of glioblastoma in vitro and in vivo.
Tumour Biol. 2015; 36(4):2869-73 [PubMed] Related Publications
The molecular regulation of the growth of glioblastoma (GBM) is not completely understood. Here, we show that the Cyr61 levels were significantly higher in GBM than in the adjacent non-tumor tissues. Overexpression of Cyr61 enhanced the viability of GBM cells, while inhibition of Cyr61 decreased the viability of GBM cells, in vitro and in vivo. Further analyses revealed that Cyr61 seemed to activate PI3K/Akt/mTor signaling pathway to increase cell growth in GBM cells. Taken together, our findings suggest a potential role of Cyr61 in GBM growth and highlight Cyr61 as a novel target for GBM therapy.

Fang F, Zhao WY, Li RK, et al.
Silencing of WISP3 suppresses gastric cancer cell proliferation and metastasis and inhibits Wnt/β-catenin signaling.
Int J Clin Exp Pathol. 2014; 7(10):6447-61 [PubMed] Article available free on PMC after 01/07/2016 Related Publications
CCN6/Wnt1-inducible signaling protein-3 (CCN6/WISP3) is a cysteine-rich protein that belongs to the CCN (Cyr61, CTGF, Nov) family of matricellular proteins, which are often dysregulated in cancers. However, the functional role and clinical significance of WISP3 in gastric cancer remain unclear. In this study, we found that silencing of WISP3 suppressed gastric cancer cell proliferation, migration and invasion. Cell adhesion to collagens (collagen I and IV), but not to fibronectin, were significantly inhibited by silencing of WISP3. Furthermore, silencing of WISP3 prevented β-catenin transferring from cell cytoplasm to nuclear, and suppressed canonical Wnt/β-catenin signaling and its downstream target genes, cyclin D1 and TCF-4. By immunohistochemical analysis of 379 patients, we found that the expression of WISP3 is closely associated with gastric cancer size and tumor invasion, and indicates a poor prognosis in both test cohort (253 patients) and validation cohort (126 patients). Moreover, the expression of WISP3 was positively correlated with the expression of cyclin D1 and TCF-4 in gastric cancer tissues. Taken together, our data suggests that WISP3 might be a promising prognostic factor and WISP3-Wnt/β-catenin axis may be a new therapeutic target for the intervention of gastric cancer growth and metastasis.

Johnson SK, Stewart JP, Bam R, et al.
CYR61/CCN1 overexpression in the myeloma microenvironment is associated with superior survival and reduced bone disease.
Blood. 2014; 124(13):2051-60 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
Secreted protein CCN1, encoded by CYR61, is involved in wound healing, angiogenesis, and osteoblast differentiation. We identified CCN1 as a microenvironmental factor produced by mesenchymal cells and overexpressed in bones of a subset of patients with monoclonal gammopathy of undetermined significance (MGUS), asymptomatic myeloma (AMM), and multiple myeloma (MM). Our analysis showed that overexpression of CYR61 was independently associated with superior overall survival of MM patients enrolled in our Total Therapy 3 protocol. Moreover, elevated CCN1 was associated with a longer time for MGUS/AMM to progress to overt MM. During remission from MM, high levels of CCN1 were associated with superior progression-free and overall survival and stratified patients with molecularly defined high-risk MM. Recombinant CCN1 directly inhibited in vitro growth of MM cells, and overexpression of CYR61 in MM cells reduced tumor growth and prevented bone destruction in vivo in severe combined immunodeficiency-hu mice. Signaling through αvβ3 was required for CCN1 prevention of bone disease. CYR61 expression may signify early perturbation of the microenvironment before conversion to overt MM and may be a compensatory mechanism to control MM progression. Therapeutics that upregulate CYR61 should be investigated for treating MM bone disease.

Wu G, Zhu YZ, Zhang JC
Sox4 up-regulates Cyr61 expression in colon cancer cells.
Cell Physiol Biochem. 2014; 34(2):405-12 [PubMed] Related Publications
BACKGROUND/AIMS: Genetic changes leading to aberrant activation of oncogenes are viewed as a crucial step in colon cancer. Sox4, a member of Sox (Sry-box) family of transcription factors, plays a critical role in tumorigenesis.
METHODS: PCR-based microarrays were used to identify potential transcriptional target of Sox4. siRNA was used to knockdown the expression of Sox4. Luciferase and chromatin immunoprecipitation (ChIP) assays were used to test the transcriptional regulations.
RESULTS: PCR-based microarrays found that Cyr61, a secreted extracellular matrix-associated signaling protein, was a transcriptional target of Sox4. Overexpression of Sox4 increased, while its knockdown using small interfering RNA (siRNA) reduced Cyr61 expression. A potential Sox4 binding motif located at the proximal Cyr61 promoter was identified.
CONCLUSION: Thus, our results suggest a previously unknown Sox4-Cyr61 molecular network, which may control colon cancer cell proliferation and survival.

Shen H, Cai M, Zhao S, et al.
CYR61 overexpression associated with the development and poor prognosis of ovarian carcinoma.
Med Oncol. 2014; 31(8):117 [PubMed] Related Publications
Cysteine-rich 61 (CYR61) has been proven to be an oncogene with potential predictive and prognostic implications in a variety of human cancers. However, the expression pattern of CYR61 and its role in ovarian carcinoma remains largely unknown. In this study, the mRNA and protein levels of CYR61 in normal ovaries and ovarian carcinoma tissues were evaluated using reverse transcription-polymerase chain reaction, immunohistochemistry, and Western blotting. Compared to normal ovarian tissues, the mRNA and protein levels of CYR61 were significantly higher in ovarian carcinoma tissues. Moreover, receiver operating characteristic (ROC) curve analysis, Spearman's rank correlation, Kaplan-Meier plots, and the Cox proportional hazards regression model were used to investigate the potential association of the CYR61 protein with the development of ovarian carcinoma in an ovarian carcinoma cohort. Based on ROC curve analysis, high expression of CYR61 was defined as a tumor in which more than 70 % of cells were positively stained. Based on this cutoff value, high expression of CYR61 was detected in 51.5 % of invasive carcinomas, 35.3 % of borderline tumors, 25.9 % of cystadenomas, and 20 % in the normal ovaries. In ovarian carcinomas, CYR61 overexpression was associated with advanced FIGO stage. Univariate survival analysis on the ovarian carcinoma cohorts showed that overexpression of CYR61 was associated with poor survival of ovarian cancer patients. Multivariate analysis suggested that the protein level of CYR61 was an independent and significant prognostic factor for ovarian carcinoma. Our results suggest that the CYR61 protein is an important and independent biomarker for prognostic implications of ovarian carcinoma.

Liao XH, Wang N, Liu LY, et al.
MRTF-A and STAT3 synergistically promote breast cancer cell migration.
Cell Signal. 2014; 26(11):2370-80 [PubMed] Related Publications
Breast cancer is the leading cause of cancer death in women worldwide which is closely related to metastasis. But the exact molecular mechanism on metastasis is still not fully understood; we now report that both MRTF-A and STAT3 play important role in breast cancer migration of MDA-MB-231 cells. Moreover, MRTF-A and STAT3 synergistically increased MDA-MB-231 cell migration by promoting the expression of migration markers Myl-9 and Cyr-61. Importantly, we identified a detailed molecular mechanism of MDA-MB-231 cell migration controlled via physical interaction between MRTF-A and STAT3, which synergistically promote the transactivity of the migration marker Myl-9 and Cyr-61 by CArG box binding. Interestingly, the two signaling pathways RhoA-MRTF-A and JAK-STAT3 across talk to regulate MDA-MB-231 cell migration. Our data thus provide important and novel insights into the roles of MRTF-A and STAT3 in regulating MDA-MB-231 cell migration.

Hollern DP, Honeysett J, Cardiff RD, Andrechek ER
The E2F transcription factors regulate tumor development and metastasis in a mouse model of metastatic breast cancer.
Mol Cell Biol. 2014; 34(17):3229-43 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
While the E2F transcription factors (E2Fs) have a clearly defined role in cell cycle control, recent work has uncovered new functions. Using genomic signature methods, we predicted a role for the activator E2F transcription factors in the mouse mammary tumor virus (MMTV)-polyomavirus middle T oncoprotein (PyMT) mouse model of metastatic breast cancer. To genetically test the hypothesis that the E2Fs function to regulate tumor development and metastasis, we interbred MMTV-PyMT mice with E2F1, E2F2, or E2F3 knockout mice. With the ablation of individual E2Fs, we noted alterations of tumor latency, histology, and vasculature. Interestingly, we noted striking reductions in metastatic capacity and in the number of circulating tumor cells in both the E2F1 and E2F2 knockout backgrounds. Investigating E2F target genes that mediate metastasis, we found that E2F loss led to decreased levels of vascular endothelial growth factor (Vegfa), Bmp4, Cyr61, Nupr1, Plod 2, P4ha1, Adamts1, Lgals3, and Angpt2. These gene expression changes indicate that the E2Fs control the expression of genes critical to angiogenesis, the remodeling of the extracellular matrix, tumor cell survival, and tumor cell interactions with vascular endothelial cells that facilitate metastasis to the lungs. Taken together, these results reveal that the E2F transcription factors play key roles in mediating tumor development and metastasis in addition to their well-characterized roles in cell cycle control.

Saglam O, Dai F, Husain S, et al.
Matricellular protein CCN1 (CYR61) expression is associated with high-grade ductal carcinoma in situ.
Hum Pathol. 2014; 45(6):1269-75 [PubMed] Related Publications
Cysteine-rich protein 61, connective tissue growth factor, and nephroblastoma overexpressed gene (CCN) comprise a family of matricellular proteins that have multiple physiologic functions including development, tissue repair, cell adhesion, migration, and proliferation. The expression of CCN1, cyclin D1, β-catenin, and p53 was explored by immunohistochemistry in different grades of ductal carcinoma in situ (DCIS) cases. These cases did not contain any infiltrating carcinoma components. In addition, all cysteine-rich protein 61 gene exons (encoding the CCN1 protein) were sequenced in 30 samples. Allred and H-scores were calculated for expression in both DCIS and the surrounding benign breast tissue. All cases of DCIS showed degrees of cytoplasmic CCN1 staining with median H-scores of 170, 160, and 60 in grades 3, 2, and 1, respectively (P = .043). Twelve of 28 DCIS 3, 1 of 15 DCIS 2, and 0 of 18 DCIS 1 also showed nuclear staining for CCN1. The cytoplasmic staining difference was preserved when the cases were divided into estrogen receptor (ER)+/DCIS grade 1, ER+/DCIS 2 and 3, and ER-/DCIS 2 and 3 by the H-score (P = .037). Cyclin D1 expression was positively correlated with the CCN1 cytoplasmic H-score in all DCIS samples (P = .038). Membranous β-catenin expression correlated with the grade of intraepithelial carcinoma by both H-score (P = .047) and Allred score (P = .026). Our results suggest that CCN1 has a role in the development of intraepithelial carcinoma. CCN1 expression correlates with grade of DCIS independent of ER status. It can induce cell cycle progression through cyclin D1. It is warranted to study high expression of CCN1 in DCIS as an independent risk factor in a larger cohort.

Jeong D, Heo S, Sung Ahn T, et al.
Cyr61 expression is associated with prognosis in patients with colorectal cancer.
BMC Cancer. 2014; 14:164 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
BACKGROUND: Cysteine-rich 61 (Cyr61), a member of the CCN protein family, possesses diverse functionality in cellular processes such as adhesion, migration, proliferation, and survival. Cyr61 can also function as an oncogene or a tumour suppressor, depending on the origin of the cancer. Only a few studies have reported Cyr61 expression in colorectal cancer. In this study, we assessed the Cyr61 expression in 251 colorectal cancers with clinical follow up.
METHODS: We examined Cyr61 expression in 6 colorectal cancer cell lines (HT29, Colo205, Lovo, HCT116, SW480, SW620) and 20 sets of paired normal and colorectal cancer tissues by western blot. To validate the association of Cyr61 expression with clinicopathological parameters, we assessed Cyr61 expression using tissue microarray analysis of primary colorectal cancer by immunohistochemical analysis.
RESULTS: We verified that all of the cancer cell lines expressed Cyr61; 2 cell lines (HT29 and Colo205) demonstrated Cyr61 expression to a slight extent, while 4 cell lines (Lovo, HCT116, SW480, SW620) demonstrated greater Cyr61 expression than HT29 and Colo205 cell lines. Among the 20 cases of paired normal and tumour tissues, greater Cyr61 expression was observed in 16 (80%) tumour tissues than in normal tissues. Furthermore, 157 out of 251 cases (62.5%) of colorectal cancer examined in this study displayed strong Cyr61 expression. Cyr61 expression was found to be associated with pN (p = 0.018). Moreover, Cyr61 expression was associated with statistically significant cancer-specific mortality (p = 0.029). The duration of survival was significantly lesser in patients with Cyr61 high expression than in patients with Cyr61 low expression (p = 0.001). These results suggest that Cyr61 expression plays several important roles in carcinogenesis and may also be a good prognostic marker for colorectal cancer.
CONCLUSIONS: Our data confirmed that Cyr61 was expressed in colorectal cancers and the expression was correlated with worse prognosis of colorectal cancers.

Lin Y, Xu T, Tian G, Cui M
Cysteine-rich, angiogenic inducer, 61 expression in patients with ovarian epithelial carcinoma.
J Int Med Res. 2014; 42(2):300-6 [PubMed] Related Publications
OBJECTIVE: Cysteine-rich, angiogenic inducer, 61 (CYR61) is a key gene in the transforming growth factor-β signalling pathway, which is involved in the development of many tumour types. This study aimed to clarify the status and clinical significance of CYR61 expression in patients with ovarian epithelial carcinoma.
METHODS: Tissue from patients with ovarian epithelial carcinoma or benign ovarian tumours were investigated retrospectively for CYR61 expression at mRNA and protein levels, using reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. Correlations between immunohistochemical scores and several clinicopathological parameters were investigated.
RESULTS: In 50 patients with ovarian epithelial carcinoma and 50 patients with benign ovarian tumours, CYR61 expression on mRNA and protein levels was significantly higher in ovarian epithelial carcinoma tissue than in benign ovarian tissue. CYR61 expression was associated with regional lymph node metastases and progression of clinical disease stage. There was no difference in CYR61 expression between patients aged <50 years and ≥ 50 years.
CONCLUSIONS: CYR61 expression was significantly upregulated in ovarian carcinoma tissue compared with benign ovarian tumour tissue samples. Protein CYR61 levels were associated with lymph node metastases and Union for International Cancer Control stage. Protein CYR61 may be useful in targeted diagnosis and therapy, for patients with ovarian epithelial carcinoma.

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] Article available free on PMC after 25/09/2015 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 ZG, Li G, Feng DY, et al.
Overexpression of NDRG2 can inhibit neuroblastoma cell proliferation through negative regulation by CYR61.
Asian Pac J Cancer Prev. 2014; 15(1):239-44 [PubMed] Related Publications
Several recent studies have showed that the n-myc downstream regulated gene 2 (NDRG2) is a new tumor suppressor gene, and that it plays an important role in tumor suppression in several cancers or cancer cell lines. However, few studies focused on its function in neuroblastoma cells. In the present investigation, we demonstrated that NDRG2 overexpression inhibited their proliferation. Using a cDNA microarray, we found that overexpression of NDRG2 inhibited the expression of cysteine-rich protein 61 (CYR61), a proliferation related gene. From our research, CYR61 may partially hinder NDRG2-mediated inhibition of cell proliferation. Overexpression of NDRG2 resulted in accumulation of cells in the G1 phase, which was accompanied by upregulation of p21 and p27 and downregulation of CDK4 and cyclin D1. Taken together, these data indicate that NDRG2 inhibits the proliferation of neuroblastoma cells partially through suppression of CYR61. Our findings offer novel insights into the physiological roles of NDRG2 in neuroblastoma cell proliferation, and NDRG2 may prove to be effective candidate for the treatment of children with neuroblastoma.

Quan T, Xu Y, Qin Z, et al.
Elevated YAP and its downstream targets CCN1 and CCN2 in basal cell carcinoma: impact on keratinocyte proliferation and stromal cell activation.
Am J Pathol. 2014; 184(4):937-43 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
Yes-associated protein (YAP) is a transcriptional co-activator of hippo signaling pathway, which plays an important role in organ size control and tumorigenesis. Here we report that YAP and its downstream transcriptional targets CCN1 and CCN2 are markedly elevated in keratinocytes in human skin basal cell carcinoma tumor islands. In human keratinocytes, knockdown of YAP significantly reduced expression of CCN1 and CCN2, and repressed proliferation and survival. This inhibition of proliferation and survival was rescued by restoration of CCN1 expression, but not by CCN2 expression. In basal cell carcinoma stroma, CCN2-regulated genes type I collagen, fibronectin, and α-smooth muscle actin were highly expressed. Furthermore, atomic force microscopy revealed increased tissue stiffness in basal cell carcinoma stroma compared to normal dermis. These data provide evidence that up-regulation of YAP in basal cell carcinoma impacts both aberrant keratinocyte proliferation, via CCN1, and tumor stroma cell activation and stroma remodeling, via CCN2. Targeting YAP and/or CCN1 and CCN2 may provide clinical benefit in basal cell carcinoma.

Lim B, Park JL, Kim HJ, et al.
Integrative genomics analysis reveals the multilevel dysregulation and oncogenic characteristics of TEAD4 in gastric cancer.
Carcinogenesis. 2014; 35(5):1020-7 [PubMed] Related Publications
Tumorigenesis is a consequence of failures of multistep defense mechanisms against deleterious perturbations that occur at the genomic, epigenomic, transcriptomic and proteomic levels. To uncover previously unrecognized genes that undergo multilevel perturbations in gastric cancer (GC), we integrated epigenomic and transcriptomic approaches using two recently developed tools: MENT and GENT. This integrative analysis revealed that nine Hippo pathway-related genes, including components [FAT, JUB, LATS2, TEA domain family member 4 (TEAD4) and Yes-associated protein 1 (YAP1)] and targets (CRIM1, CYR61, CTGF and ITGB2), are concurrently hypomethylated at promoter CpG sites and overexpressed in GC tissues. In particular, TEAD4, a link between Hippo pathway components and targets, was significantly hypomethylated at CpG site cg21637033 (P = 3.8 × 10(-) (20)) and overexpressed (P = 5.2 × 10(-) (10)) in 108 Korean GC tissues compared with the normal counterparts. A reduced level of methylation at the TEAD4 promoter was significantly associated with poor outcomes, including large tumor size, high-grade tumors and low survival rates. Compared with normal tissues, the TEAD4 protein was more frequently found in the nuclei of tumor cells along with YAP1 in 53 GC patients, demonstrating the posttranslational activation of this protein. Moreover, the knockdown of TEAD4 resulted in the reduced growth of GC cells both in vitro and in vivo. Finally, chromatin immunoprecipitation-sequencing and microarray analysis revealed the oncogenic properties of TEAD4 and its novel targets (ADM, ANG, ARID5B, CALD1, EDN2, FSCN1 and OSR2), which are involved in cell proliferation and migration. In conclusion, the multilevel perturbations of TEAD4 at epigenetic, transcriptional and posttranslational levels may contribute to GC development.

Huang J, Gao K, Lin J, Wang Q
MicroRNA-100 inhibits osteosarcoma cell proliferation by targeting Cyr61.
Tumour Biol. 2014; 35(2):1095-100 [PubMed] Related Publications
Increasing evidence indicates that microRNAs (miRNAs) participate in almost every step of cellular processes and are often aberrantly expressed in human cancer. Therefore, the discovery of miRNAs may provide a new and powerful tool for understanding the mechanism and treatment of carcinogenesis. The aim of this study was to investigate the functional significance of miR-100 and to identify its possible target genes in osteosarcoma (OS) cells. Here, we found that expression level of miR-100 was significantly decreased in osteosarcoma tissues in comparison with the adjacent normal tissues. The enforced expression of miR-100 was able to inhibit cell proliferation in Saos-2 and MG63 cells, while its antisense oligonucleotides (antisense miR-100) promoted cell proliferation. Moreover, our results further revealed that expression of Cyr61, an extracellular matrix-associated growth factor, was negatively regulated by miR-100. Therefore, we consider that miR-100 acts as a tumor suppressor for osteosarcoma. It may provide novel diagnostic and therapeutic options for human osteosarcoma in the future.

Zhang C, Luo X, Liu L, et al.
Myocardin-related transcription factor A is up-regulated by 17β-estradiol and promotes migration of MCF-7 breast cancer cells via transactivation of MYL9 and CYR61.
Acta Biochim Biophys Sin (Shanghai). 2013; 45(11):921-7 [PubMed] Related Publications
Many lines of evidence have suggested that estrogen plays important roles not only in the initiation and proliferation of breast cancer, but also in cancer metastasis. However, the mechanistic basis of the latter events is poorly understood. In addition, recent studies have suggested that myocardin-related transcription factor A (MRTF-A) might be related to cancer metastasis. However, as reports are contradictory, certain of its roles still remain confusing. In the present study, we showed that excessive 17β-estradiol could promote the migration of MCF-7 breast cancer cells and up-regulate the expression of MRTF-A, myosin regulatory light chain 9 (MYL9), and cysteine-rich angiogenic inducer 61 (CYR61). Overexpression of MRTF-A significantly promoted the migration of MCF-7 cells through its transactivation effects on MYL9 and CYR61 genes, while RNA interference-mediated knockdown of MRTF-A strongly inhibited transcription and expression of the target genes and reduced the migration ability of MCF-7 cells. These results provided novel evidence supporting the metastasis-promoting functions of MRTF-A, and implied that MRTF-A might be a switch for the estrogen pathway to change its proliferation-promoting roles into migration-stimulating roles in breast cancer.

Wu CL, Tsai HC, Chen ZW, et al.
Ras activation mediates WISP-1-induced increases in cell motility and matrix metalloproteinase expression in human osteosarcoma.
Cell Signal. 2013; 25(12):2812-22 [PubMed] Related Publications
WISP-1 is a cysteine-rich protein that belongs to the CCN (Cyr61, CTGF, Nov) family of matrix cellular proteins. Osteosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. However, the effect of WISP-1 on migration activity in human osteosarcoma cells is mostly unknown. In this study, we first found that the expression of WISP-1 in osteosarcoma patients was significantly higher than that in normal bone and corrected with tumor stage. Exogenous treatment of osteosarcoma cells with WISP-1 promoted cell motility and matrix metalloproteinase (MMP)-2 and MMP-9 expression. In addition, the Ras and Raf-1 inhibitor or siRNA abolished WISP-1-induced cell migration and MMP expression. On the other hand, activation of the Ras, Raf-1, MEK, ERK, and NF-κB signaling pathway after WISP-1 treatment was demonstrated, and WISP-1-induced expression of MMPs and migration activity were inhibited by the specific inhibitor, and mutant of MEK, ERK, and NF-κB cascades. Taken together, our results indicated that WISP-1 enhances the migration of osteosarcoma cells by increasing MMP-2 and MMP-9 expression through the integrin receptor, Ras, Raf-1, MEK, ERK, and NF-κB signal transduction pathway.

Wang H, Feng Y, Bao Z, et al.
Epigenetic silencing of KAZALD1 confers a better prognosis and is associated with malignant transformation/progression in glioma.
Oncol Rep. 2013; 30(5):2089-96 [PubMed] Related Publications
In order to more thoroughly analyze aberrant DNA methylation in glioma, we applied a large cohort methylation microarray including 119 glioma samples. Six genes, ADCY1, KAZALD1, KLF4, SLMAP, TETRAN and TP53INP1, were screened out through significance analysis of microarray (SAM), survival Cox-regression and certain other pre-set conditions. We focused on the KAZALD1 oncogene. KAZALD1, also known as IGFBP-rP10, belongs to the IGFBP family. We found that KAZALD1 was hypomethylated in high-grade glioma (anaplastic gliomas and glioblastomas) compared to low-grade glioma (astrocytoma, oligodendrocytoma and oligoastrocytoma) using methylation microarrays (p<0.001). Immunohistochemistry (IHC) of 91 glioma samples showed that the KAZALD1 expression scores of high-grade glioma samples were higher compared to the scores of low-grade gliomas (p<0.001). In high-grade gliomas, overall survival (OS) was shorter for patients with KAZALD1 hypomethylation or overexpression compared to those without. Decreased KAZALD1 expression in glioma inhibited cell proliferation and invasion both in vitro and in vivo. On the basis of these observations and the results from subset analysis, it is reasonable to conclude that KAZALD1 promoter hypomethylation is an important prognostic biomarker in glioma. KAZALD1 promotes glioma malignant progression through invasion and proliferation.

Jeong GO, Shin SH, Seo EJ, et al.
TAZ mediates lysophosphatidic acid-induced migration and proliferation of epithelial ovarian cancer cells.
Cell Physiol Biochem. 2013; 32(2):253-63 [PubMed] Related Publications
BACKGROUND: Transcriptional co-activator with PDZ-binding motif (TAZ), a downstream effector of the Hippo pathway, has been reported to regulate organ size, tissue homeostasis, and tumorigenesis by acting as a transcriptional co-activator. Lysophosphatidic acid (LPA) is a bioactive lipid implicated in tumorigenesis and metastasis of ovarian cancer through activation of G protein-coupled receptors. However, the involvement of TAZ in LPA-induced tumorigenesis of ovarian cancer has not been elucidated.
METHODS: In order to demonstrate the role of TAZ in LPA-stimulated tumorigenesis, the effects of LPA on TAZ expression and cell migration were determined by Western blotting and chemotaxis analyses in R182 human epithelial ovarian cancer cells.
RESULTS AND CONCLUSION: Treatment of R182 cells with the LPA receptor inhibitor Ki16425 blocked LPA-induced cell migration. In addition, transfection of R182 cells with small interfering RNA specific for LPA receptor 1 resulted in abrogation of LPA-stimulated cell migration. LPA induced phosphorylation of ERK and p38 MAP kinase in R182 cells and pretreatment of cells with the MEK-ERK pathway inhibitor U0126, but not the p38 MAPK inhibitor SB202190, resulted in abrogation of LPA-induced cell migration. Pretreatment of R182 cells with U0126 attenuated LPA-induced mRNA levels of TAZ and its transcriptional target genes, such as CTGF and CYR61, without affecting phosphorylation level of YAP. These results suggest that MEK-ERK pathway plays a key role in LPA-induced cell migration and mRNA expression of TAZ in R182 cells, without affecting stability of TAZ protein. In addition, small interfering RNA-mediated silencing of TAZ expression attenuated LPA-stimulated migration of R182 cells. These results suggest that TAZ plays a key role in LPA-stimulated migration of epithelial ovarian cancer cells.

Ahmad SS, Glatzle J, Bajaeifer K, et al.
Phosphoglycerate kinase 1 as a promoter of metastasis in colon cancer.
Int J Oncol. 2013; 43(2):586-90 [PubMed] Related Publications
Oxidative stress due to intratumoral hypoxia in solid cancer has been shown to be associated with increased mortality. Phosphoglycerate kinase 1 (PGK1) is an enzyme of the glycolytic pathway, which is regulated by hypoxia-inducible factor-1α (HIF-1α) and has been described for its role in tumor progression and metastasis in several malignancies. We investigated whether the expression of PGK1 varies between metastatic and non-metastatic colon cancer. We compared PGK1 expression in colon cancer patients either with or without metastasis via polymerase chain reaction (PCR) and immunohistochemistry. Microarray analysis was performed to test altered gene expression after PGK1 silencing, using isolates from HCT116 cell lines. PCR results showed an increased expression of PGK1 in colon cancer tissue from metastatic patients in comparison to patients with no metastasis (fold change 2.6, p<0.001). Immunohistochemical staining of PGK1 showed stronger staining in metastatic tissue in comparison to non-metastatic cancer tissue according to a semi-quantitative evaluation. Microarray and subsequent pathway analysis provided 4 genes of interest (CYR61, FOS, JUN and EGR1) used for pathway proposal. The results indicate that increased expression of PGK1 in colon cancer tissue is associated with metastasis. Furthermore, we propose several genes induced by PGK1 that could account for cell migration, mainly EGR1 and CYR61 together with the transcription factors FOS and JUN.

Lee YJ, Lee DM, Lee SH
Production of Cyr61 protein is modulated by extracellular acidification and PI3K/Akt signaling in prostate carcinoma PC-3 cells.
Food Chem Toxicol. 2013; 58:169-76 [PubMed] Related Publications
High expression of Cyr61, an extracellular cysteine-rich heparin-binding protein, has been associated with a malignant cell phenotype and poor outcome in prostate cancers. Although Cyr61 was found by us to be overproduced in androgen-independent PC-3 cells treated with N-acetylcysteine (NAC), its significance is still unclear. We therefore aimed to determine how and why Cyr61 protein is overexpressed in NAC-treated cells. Here, we found that Cyr61 protein level markedly increased in cells treated with NAC at high cell seeding density. Silencing of Cyr61 by siRNA induced enhanced activity of caspase-3/7, upregulation of the proapototic Bok, BimL and BimS, cleavage of apoptosis hallmarkers such as Bax, PARP and caspase-3, and downregulation of antiapoptotic Bcl2, Bcl-xL and Mcl-1 proteins. NAC treatment caused a reduction of extracellular medium pH to acidic and an increase in Akt phosphorylation, after which the replacement with NAC-free medium returned them to control levels within 24h. Acid stimulation increased the levels of Cyr61 and p-Akt proteins, whereas it suppressed the induction of proapoptotic and antiapoptotic proteins. Overall, our data indicate that PC-3 cells overproduce Cyr61 protein via activation of the PI3K/Akt signaling as a part of the survival mechanisms under the conditions causing extracellular acidity and further cytotoxicity.

Pobbati AV, Hong W
Emerging roles of TEAD transcription factors and its coactivators in cancers.
Cancer Biol Ther. 2013; 14(5):390-8 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
TEAD proteins are transcription factors that are crucial for development, but also play a role in cancers. Several developmentally and pathologically important genes are upregulated by TEADs. TEADs have a TEA domain that enables them to bind specific DNA elements and a transactivation domain that enables them to interact with coactivators. TEADs on their own are unable to activate transcription and they require the help of coactivators. Several TEAD-interacting coactivators are known and they can be classified into three groups: (1) YAP and its paralog TAZ; (2) Vgll proteins; and (3) p160s. Accordingly, these coactivators also play a role in development and cancers. Recent studies have shown that TEADs and their coactivators aid in the progression of various cancers, including the difficult to treat glioblastoma, liver and ovarian cancers. They facilitate cancer progression through expression of proliferation promoting genes such as c-myc, survivin, Axl, CTGF and Cyr61. There is also a good correlation between high TEAD or its coactivator expression and poor prognosis in various cancers. Given the fact that TEADs and their coactivators need to work together for a functional outcome, disrupting the interaction between them appears to be a viable option for cancer therapy. Structures of TEAD-coactivator complexes have been elucidated and will facilitate drug design and development.

Di Tommaso S, Massari S, Malvasi A, et al.
Gene expression analysis reveals an angiogenic profile in uterine leiomyoma pseudocapsule.
Mol Hum Reprod. 2013; 19(6):380-7 [PubMed] Related Publications
The pseudocapsule (PC) of the uterine leiomyoma (UL) is an anatomic entity that surrounds the myoma separating it from the myometrium (UM). Although a number of microarray experiments have identified differences in gene expression profile in the UL when compared with the UM, there is a lack of systematic studies on the PC. In this study, quantitative RT-PCR analysis was performed on 18 matched PC, UL and UM specimens and results showed that the PC displays a specific gene expression profile. The low expression level of insulin-like growth factor (IGF-2), a fibroid specific marker, that we found in the PC and the UM when compared with the UL, clearly indicates that the PC is in structural continuity with the UM. However, the significant increase in endoglin expression level in PC with respect to the UL and UM indicates that an active neoangiogenesis is present in PC. Conversely, other angiogenic factors such as von Willebrand factor (vWF) and vascular endothelial growth factor A (VEGF-A) seem to have little influence on the PC angiogenesis. Because the endoglin is preferentially expressed in proliferating endothelial cells, whereas the vWF and VEGF-A are preferentially expressed in preexisting endothelial cells, our idea is that the angiogenic activity in the PC is linked to wound healing. The angiogenic activity is also sustained by intermediate expression level of cystein-rich angiogenesis inducer 61, connective tissue growth factor and collagen 4α2 genes all involved in the neoangiogenesis, that we detected in the PC. Taken together our data demonstrate that the specific expression pattern observed in the PC could be the response of the uterine wall's smooth cells to the tension imposed by the tumor. As a consequence, a neovascular structure is generated involving regenerative processes. For these reasons, we suggest that the laparoscopic intracapsular myomectomy (LIM), a new surgical technique that preserves the PC during the UL removal, should always be preferred, to favor a faster and proper uterine healing.

Tanaka F, Rizqiawan A, Higashikawa K, et al.
Snail promotes Cyr61 secretion to prime collective cell migration and form invasive tumor nests in squamous cell carcinoma.
Cancer Lett. 2013; 329(2):243-52 [PubMed] Related Publications
We previously identified genes associated with Snail-mediated squamous cell carcinoma (SCC) invasiveness, in which we observed significant elevation of Cyr61 expression. In this study, SCC cell lines overexpressing Cyr61 exhibited constitutive activation of Rho A and upregulated invasiveness without the disruption of homophilic cell attachment. Humoral Cyr61 enhanced further production of endogenous Cyr61 by SCC cells, which stimulated collective cell migration and the development of an invasive tumor nest. We propose a Cyr61-dependent model for the development of invasive SCC nest, whereby a subset of tumor cells that highly produce Cyr61 may direct other tumor cells to undergo collective cell migration, resulting in a formation of primary SCC mass.

Xie H, Zhao Y, Caramuta S, et al.
miR-205 expression promotes cell proliferation and migration of human cervical cancer cells.
PLoS One. 2012; 7(10):e46990 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
MicroRNAs (miRNAs) are short non-coding RNA regulators that control gene expression mainly through post-transcriptional silencing. We previously identified miR-205 in a signature for human cervical cancer using a deep sequencing approach. In this study, we confirmed that miR-205 expression was frequently higher in human cervical cancer than their matched normal tissue samples. Functionally, we demonstrate that miR-205 promotes cell proliferation and migration in human cervical cancer cells. To further understand the biological roles of miR-205, we performed in vivo crosslinking and Argonaute 2 immunoprecipitation of miRNA ribonucleoprotein complexes followed by microarray analysis (CLIP-Chip) to identify its potential mRNA targets. Applying CLIP-Chip on gain- and loss-of-function experiments, we identified a set of transcripts as potential targets of miR-205. Several targets are functionally involved in cellular proliferation and migration. Two of them, CYR61 and CTGF, were further validated by Western blot analysis and quantification of mRNA enrichment in the Ago2 immunoprecipitates using qRT-PCR. Furthermore, both CYR61 and CTGF were downregulated in cervical cancer tissues. In summary, our findings reveal novel functional roles and targets of miR-205 in human cervical cancer, which may provide new insights about its role in cervical carcinogenesis and its potential value for clinical diagnosis.

Tao L, Chen J, Zhou H, et al.
A functional polymorphism in the CYR61 (IGFBP10) gene is associated with prostate cancer risk.
Prostate Cancer Prostatic Dis. 2013; 16(1):95-100 [PubMed] Related Publications
BACKGROUND: CYR61 (cysteine-rich protein 61, also named IGFBP10) is a secreted signaling molecule that promotes angiogenesis and tumor growth. The goal of this study is to determine whether a functional polymorphism in the promoter region of the CYR61 gene (rs3753793) is associated with prostate cancer (PCa) risk and gene expression in Chinese patients.
METHODS: A total of 665 patients diagnosed with PCa and 703 cancer-free controls were genotyped in this hospital-based case-control study, and 26 PCa tissue samples were evaluated for mRNA expression of CYR61 by real-time quantitative reverse-transcription PCR.
RESULTS: Men carrying the G allele of rs3753793 (TG+GG) had significantly lower risk of PCa when compared with the TT genotype (odds ratio (OR) = 0.76, 95% confidence interval (CI) = 0.61-0.95). The association was generally more pronounced among subgroups of PCa patients with advanced stage (OR = 0.70, 95% CI = 0.53-0.94), Gleason score >7 (OR = 0.63, 95% CI = 0.46-0.86) and PSA>20 ng ml(-1) (OR = 0.68, 95% CI = 0.53-0.88). Prostate tumors derived from cases with the GT/GG genotypes had significantly lower levels of CYR61 mRNA when compared with cases with the TT genotypes (P = 0.02).
CONCLUSIONS: Our results indicate that the genetic variation of rs3753793 in the CYR61 promoter may contribute to genetic predisposition to PCa and intra-tumor expression gene expression.

Haque I, De A, Majumder M, et al.
The matricellular protein CCN1/Cyr61 is a critical regulator of Sonic Hedgehog in pancreatic carcinogenesis.
J Biol Chem. 2012; 287(46):38569-79 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
CCN1 is a matricellular protein and a member of the CCN family of growth factors. CCN1 is associated with the development of various cancers including pancreatic ductal adenocarcinoma (PDAC). Our recent studies found that CCN1 plays a critical role in pancreatic carcinogenesis through the induction of EMT and stemness. CCN1 mRNA and protein were detected in the early precursor lesions, and their expression intensified with disease progression. However, biochemical activity and the molecular targets of CCN1 in pancreatic cancer cells are unknown. Here we show that CCN1 regulates the Sonic Hedgehog (SHh) signaling pathway, which is associated with the PDAC progression and poor prognosis. SHh regulation by CCN1 in pancreatic cancer cells is mediated through the active Notch-1. Notably, active Notch-1is recruited by CCN1 in these cells via the inhibition of proteasomal degradation results in stabilization of the receptor. We find that CCN1-induced activation of SHh signaling might be necessary for CCN1-dependent in vitro pancreatic cancer cell migration and tumorigenicity of the side population of pancreatic cancer cells (cancer stem cells) in a xenograft in nude mice. Moreover, the functional role of CCN1 could be mediated through the interaction with the αvβ3 integrin receptor. These extensive studies propose that targeting CCN1 can provide a new treatment option for patients with pancreatic cancer since blocking CCN1 simultaneously blocks two critical pathways (i.e. SHh and Notch1) associated with the development of the disease as well as drug resistance.

Kaczkowski B, Rossing M, Andersen DK, et al.
Integrative analyses reveal novel strategies in HPV11,-16 and -45 early infection.
Sci Rep. 2012; 2:515 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
The interaction between human papillomavirus (HPV) and host cells is not well understood. We investigate the early stage of HPV infections by global expression profiling in a cell model, in which HaCaT cells were transfected with HPV11, HPV16 or HPV45 genomes. We report the differential expression of genes not previously implicated in HPV biology, such as the PSG family and ANKRD1, and of genes implicated in the biology of other viruses, e.g. MX1, IFI44 and DDX60. Carcinogenesis-related genes, e.g. ABL2, MGLL and CYR61, were upregulated by high-risk HPV16 and -45. The integrative analysis revealed the suppression of DNA repair by HPV11 and -16, and downregulation of cytoskeleton genes by all HPV types. Various signalling pathways were affected by the HPVs: IL-2 by HPV11; JAK-STAT by HPV16; and TGF-β, NOTCH and tyrosine kinase signalling by HPV45. This study uncovered novel strategies employed by HPV to establish infection and promote uncontrolled growth.

Wang X, Deng Y, Mao Z, et al.
CCN1 promotes tumorigenicity through Rac1/Akt/NF-κB signaling pathway in pancreatic cancer.
Tumour Biol. 2012; 33(5):1745-58 [PubMed] Related Publications
Aberrant CCN1 expression has been reported to play an important role in the tumor development. However, the pattern and the role of CCN1 in pancreatic cancer remain largely unknown. Therefore, we further deciphered the role CCN1 played in pancreatic cancer. We first evaluated the CCN1 expression in human pancreatic cancer tissues and pancreatic cancer cells. Then we forced expression and silenced CCN1 expression in pancreatic cancer cell lines MIA PaCa2 and PANC-1 respectively, using lentivirus vectors. We characterized the stable cells in vitro and in vivo using a nude mouse xenograft model. In this study, we found that CCN1 expression was significantly higher in cancer specimens which positively correlated with the expression level of phosphorylated Akt and p65. and poorer outcome. Moreover, our results demonstrated that CCN1 positively regulated pancreatic cell growth in vitro and in vivo and helped cancer cells resist to tumor necrosis factor alpha-induced apoptosis. Furthermore, we disclosed that activation of CCN1/ras-related c3 botulinum toxin substrate 1 (Rac1)/V-akt murine thymoma viral oncogene homolog (Akt)/nuclear factor-kappa B pathway inhibited apoptosis in pancreatic cancer cells. CCN1 is upregulated in pancreatic cancer and promotes the survival of pancreatic cancer cells. Taken together, these results indicate that CCN1 may be a potential target for pancreatic cancer therapy.

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