CTGF

Gene Summary

Gene:CTGF; connective tissue growth factor
Aliases: CCN2, NOV2, HCS24, IGFBP8
Location:6q23.2
Summary:The protein encoded by this gene is a mitogen that is secreted by vascular endothelial cells. The encoded protein plays a role in chondrocyte proliferation and differentiation, cell adhesion in many cell types, and is related to platelet-derived growth factor. Certain polymorphisms in this gene have been linked with a higher incidence of systemic sclerosis. [provided by RefSeq, Nov 2009]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:connective tissue growth factor
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
Show (58)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 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.

  • Messenger RNA
  • Immediate-Early Proteins
  • Xenograft Models
  • Breast Cancer
  • Wilms Tumour
  • Reproducibility of Results
  • Intercellular Signaling Peptides and Proteins
  • Stem Cells
  • Vascular Endothelial Growth Factors
  • Thrombospondin 1
  • Staurosporine
  • Proto-Oncogene Proteins
  • Thyroid Cancer
  • Cancer RNA
  • Transcriptional Activation
  • Angiogenesis
  • VHL
  • Testicular Cancer
  • NOV
  • Oligonucleotide Array Sequence Analysis
  • Neoplasm Invasiveness
  • Vascular Neoplasms
  • Connective Tissue Growth Factor
  • RTPCR
  • Tissue Array Analysis
  • beta Catenin
  • Severity of Illness Index
  • Bone Cancer
  • Gene Expression Profiling
  • Biomarkers, Tumor
  • Cell Proliferation
  • Chromosome 6
  • Cancer Gene Expression Regulation
  • Transforming Growth Factor beta
  • siRNA
  • Cell Movement
  • Receptors, Immunologic
  • Gene Expression
  • Signal Transduction
  • Transcription
  • Survival Rate
Tag cloud generated 16 March, 2017 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: CTGF (cancer-related)

Chen Z, Tang J, Cai X, et al.
HBx mutations promote hepatoma cell migration through the Wnt/β-catenin signaling pathway.
Cancer Sci. 2016; 107(10):1380-1389 [PubMed] Free Access to Full Article Related Publications
HBx mutations (T1753V, A1762T, G1764A, and T1768A) are frequently observed in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Aberrant activation of the Wnt/β-catenin signaling pathway is involved in the development of HCC. However, activation of the Wnt/β-catenin signaling pathway by HBx mutants has not been studied in hepatoma cells or HBV-associated HCC samples. In this study, we examined the effects of HBx mutants on the migration and proliferation of HCC cells and evaluated the activation of Wnt/β-catenin signaling in HBx-transfected HCC cells and HBV-related HCC tissues. We found that HBx mutants (T, A, TA, and Combo) promoted the migration and proliferation of hepatoma cells. The HBx Combo mutant potentiated TOP-luc activity and increased nuclear translocation of β-catenin. Moreover, the HBx Combo mutant increased and stabilized β-catenin levels through inactivation of glycogen synthase kinase-3β, resulting in upregulation of downstream target genes such as c-Myc, CTGF, and WISP2. Enhanced activation of Wnt/β-catenin was found in HCC tissues with HBx TA and Combo mutations. Knockdown of β-catenin effectively abrogated cell migration and proliferation stimulated by the HBx TA and Combo mutants. Our results indicate that HBx mutants, especially the Combo mutant, allow constitutive activation of the Wnt signaling pathway and may play a pivotal role in HBV-associated hepatocarcinogenesis.

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.

Drzewiecka H, Gałęcki B, Jarmołowska-Jurczyszyn D, et al.
Decreased expression of connective tissue growth factor in non-small cell lung cancer is associated with clinicopathological variables and can be restored by epigenetic modifiers.
J Cancer Res Clin Oncol. 2016; 142(9):1927-46 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Recent studies indicated undisputed contribution of connective tissue growth factor (CTGF) in the development of many cancers, including non-small cell lung cancer (NSCLC). However, the functional role and regulation of CTGF expression during tumorigenesis remain elusive. Our goal was to determine CTGF transcript and protein levels in tumoral and matched control tissues from 98 NSCLC patients, to correlate the results with clinicopathological features and to investigate whether the CTGF expression can be epigenetically regulated in NSCLC.
METHODS: We used quantitative PCR, Western blotting and immunohistochemistry to evaluate CTGF expression in lung cancerous and histopathologically unchanged tissues. We tested the impact of 5-Aza-2'-deoxycytidine (5-dAzaC) and trichostatin A (TSA) on CTGF transcript and protein levels in NSCLC cells (A549, Calu-1). DNA methylation status of the CTGF regulatory region was evaluated by bisulfite sequencing. The influence of 5-dAzaC and TSA on NSCLC cells viability and proliferation was monitored by the trypan blue assay.
RESULTS: We found significantly decreased levels of CTGF mRNA and protein (both p < 0.0000001) in cancerous tissues of NSCLC patients. Down-regulation of CTGF occurred regardless of gender in all histological subtypes of NSCLC. Moreover, we showed that 5-dAzaC and TSA were able to restore CTGF mRNA and protein contents in NSCLC cells. However, no methylation within CTGF regulatory region was detected. Both compounds significantly reduced NSCLC cells proliferation.
CONCLUSIONS: Decreased expression of CTGF is a common feature in NSCLC; however, it can be restored by the chromatin-modifying agents such as 5-dAzaC or TSA and consequently restrain cancer development.

Riwaldt S, Bauer J, Wehland M, et al.
Pathways Regulating Spheroid Formation of Human Follicular Thyroid Cancer Cells under Simulated Microgravity Conditions: A Genetic Approach.
Int J Mol Sci. 2016; 17(4):528 [PubMed] Free Access to Full Article Related Publications
Microgravity induces three-dimensional (3D) growth in numerous cell types. Despite substantial efforts to clarify the underlying mechanisms for spheroid formation, the precise molecular pathways are still not known. The principal aim of this paper is to compare static 1g-control cells with spheroid forming (MCS) and spheroid non-forming (AD) thyroid cancer cells cultured in the same flask under simulated microgravity conditions. We investigated the morphology and gene expression patterns in human follicular thyroid cancer cells (UCLA RO82-W-1 cell line) after a 24 h-exposure on the Random Positioning Machine (RPM) and focused on 3D growth signaling processes. After 24 h, spheroid formation was observed in RPM-cultures together with alterations in the F-actin cytoskeleton. qPCR indicated more changes in gene expression in MCS than in AD cells. Of the 24 genes analyzed VEGFA, VEGFD, MSN, and MMP3 were upregulated in MCS compared to 1g-controls, whereas ACTB, ACTA2, KRT8, TUBB, EZR, RDX, PRKCA, CAV1, MMP9, PAI1, CTGF, MCP1 were downregulated. A pathway analysis revealed that the upregulated genes code for proteins, which promote 3D growth (angiogenesis) and prevent excessive accumulation of extracellular proteins, while genes coding for structural proteins are downregulated. Pathways regulating the strength/rigidity of cytoskeletal proteins, the amount of extracellular proteins, and 3D growth may be involved in MCS formation.

Sun D, Han S, Liu C, et al.
Microrna-199a-5p Functions as a Tumor Suppressor via Suppressing Connective Tissue Growth Factor (CTGF) in Follicular Thyroid Carcinoma.
Med Sci Monit. 2016; 22:1210-7 [PubMed] Free Access to Full Article Related Publications
BACKGROUND The objective of this study was to explore the role of miR-199a-5p in the development of thyroid cancer, including its anti-proliferation effect and downstream signaling pathway. MATERIAL AND METHODS We conducted qRT-PCR analysis to detect the expressions of several microRNAs in 42 follicular thyroid carcinoma patients and 42 controls. We identified CTGF as target of miR-491, and viability and cell cycle status were determined in FTC-133 cells transfected with CTGF siRNA, miR-199a mimics, or inhibitors. RESULTS We identified an underexpression of miR-199a-5p in follicular thyroid carcinoma tissue samples compared with controls. Then we confirmed CTGF as a target of miR-199a-5p thyroid cells by using informatics analysis and luciferase reporter assay. Additionally, we found that mRNA and protein expression levels of CTGF were both clearly higher in malignant tissues than in benign tissues. miR-199a-5p mimics and CTGF siRNA similarly downregulated the expression of CTGF, and reduced the viability of FTC-133 cells by arresting the cell cycle in G0 phase. Transfection of miR-199a-5p inhibitors increased the expression of CTGF and promoted the viability of the cells by increasing the fraction of cells in G2/M and S phases. CONCLUSIONS Our study proves that the CTGF gene is a target of miR-199a-5p, demonstrating the negatively related association between CTGF and miR-199a. These findings suggest that miR-199a-5p might be a novel therapeutic target in the treatment of follicular thyroid carcinoma.

Zhou Y, Huang T, Cheng AS, et al.
The TEAD Family and Its Oncogenic Role in Promoting Tumorigenesis.
Int J Mol Sci. 2016; 17(1) [PubMed] Free Access to Full Article Related Publications
The TEAD family of transcription factors is necessary for developmental processes. The family members contain a TEA domain for the binding with DNA elements and a transactivation domain for the interaction with transcription coactivators. TEAD proteins are required for the participation of coactivators to transmit the signal of pathways for the downstream signaling processes. TEADs also play an important role in tumor initiation and facilitate cancer progression via activating a series of progression-inducing genes, such as CTGF, Cyr61, Myc and Gli2. Recent studies have highlighted that TEADs, together with their coactivators, promote or even act as the crucial parts in the development of various malignancies, such as liver, ovarian, breast and prostate cancers. Furthermore, TEADs are proposed to be useful prognostic biomarkers due to the ideal correlation between high expression and clinicopathological parameters in gastric, breast, ovarian and prostate cancers. In this review, we summarize the functional role of TEAD proteins in tumorigenesis and discuss the key role of TEAD transcription factors in the linking of signal cascade transductions. Improved knowledge of the TEAD proteins will be helpful for deep understanding of the molecular mechanisms of tumorigenesis and identifying ideal predictive or prognostic biomarkers, even providing clinical translation for anticancer therapy in human cancers.

Huang Y, Zhao S, Zhang C, Li X
Downregulation of connective tissue growth factor reduces migration and invasiveness of osteosarcoma cells.
Mol Med Rep. 2016; 13(2):1888-94 [PubMed] Related Publications
As one of the most serious types of primary bone tumor, osteosarcoma (OSA) features metastatic lesions, and resistance to chemotherapy is common. The underlying mechanisms of these characteristics may account for the failure of treatments and the poor prognosis of patients with OSA. It has been reported that inhibition of Cyr61 suppresses OSA cell proliferation as it represents a target of statins. In addition to cystein‑rich protein 61 (Cyr61) and nephroblastoma overexpression, connective tissue growth factor (CTGF) is a member of the CCN family and may therefore exhibit effects on human OSA cells similar to those of Cyr61. In the current study, acridine orange/ethidium bromide staining were used to determine the rate of apoptosis. The present study demonstrated that small interfering RNA‑mediated silencing of CTGF promoted cell death and suppressed OSA cell migration and invasion, as indicated by wound healing and Transwell assays, while lentivirus‑mediated overexpression of CTGF reversed these effects. Furthermore, a colorimetric caspase assay demonstrated that CTGF knockdown enhanced the efficacy of chemotherapeutic drugs. The results of the present study provided a novel molecular target which may be utilized for the treatment of metastatic OSA.

Nishio M, Sugimachi K, Goto H, et al.
Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice.
Proc Natl Acad Sci U S A. 2016; 113(1):E71-80 [PubMed] Free Access to Full Article Related Publications
Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway that coactivate large tumor suppressor homolog (LATS) kinases. Mob1a/1b double deficiency in mouse liver (LMob1DKO) results in hyperplasia of oval cells and immature cholangiocytes accompanied by inflammatory cell infiltration and fibrosis. More than half of mutant mice die within 3 wk of birth. All survivors eventually develop liver cancers, particularly combined hepatocellular and cholangiocarcinomas (cHC-CCs) and intrahepatic cholangiocellular carcinomas (ICCs), and die by age 60 wk. Because this phenotype is the most severe among mutant mice lacking a Hippo signaling component, MOB1A/1B constitute the critical hub of Hippo signaling in mammalian liver. LMob1DKO liver cells show hyperproliferation, increased cell saturation density, hepatocyte dedifferentiation, enhanced epithelial-mesenchymal transition and cell migration, and elevated transforming growth factor beta(TGF-β)2/3 production. These changes are strongly dependent on Yes-Associated Protein-1 (Yap1) and partially dependent on PDZ-binding motif (Taz) and Tgfbr2, but independent of connective tissue growth factor (Ctgf). In human liver cancers, YAP1 activation is frequent in cHC-CCs and ICCs and correlates with SMAD family member 2 activation. Drug screening revealed that antiparasitic macrocyclic lactones inhibit YAP1 activation in vitro and in vivo. Targeting YAP1/TAZ with these drugs in combination with inhibition of the TGF-β pathway may be effective treatment for cHC-CCs and ICCs.

Pupo M, Maggiolini M, Musti AM
GPER Mediates Non-Genomic Effects of Estrogen.
Methods Mol Biol. 2016; 1366:471-88 [PubMed] Related Publications
Estrogens are important modulators of a broad spectrum of physiological functions in humans. However, despite their beneficial actions, a number of lines of evidence correlate the sustained exposure to exogenous estrogen with increased risk of the onset of various cancers. Mainly these steroid hormones induce their effects by binding and activating estrogen receptors (ERα and ERβ). These receptors belong to the family of ligand-regulated transcription factors, and upon activation they regulate the expression of different target genes by binding directly to specific DNA sequences. On the other hand, in recent years it has become clear that the G protein-coupled estrogen receptor 30 (GPR30/GPER) is able to mediate non-genomic action of estrogens in different cell contexts. In particular, GPER has been shown to specifically bind estrogens, and in turn to functionally cross-react with diverse cell signaling systems such as the epidermal growth factor receptor (EGFR) pathway, the Notch signaling pathway and the mitogen-activated protein kinases (MAPK) pathway. In this chapter we will present some of the different experimental techniques currently used to demonstrate the functional role of GPER in mediating non-genomic actions of estrogens, such as the dual luciferase assay, assessment of the involvement of GPER in the stimulation of cell migration in breast cancer cell lines and in cancer-associated fibroblasts, and chromatin immunoprecipitation assay. Overall, the experimental procedures described herein represent key instruments for assessing the biological role of GPER in mediating non-genomic signals of estrogen.

Moran-Jones K, Gloss BS, Murali R, et al.
Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer.
Oncotarget. 2015; 6(42):44551-62 [PubMed] Free Access to Full Article Related Publications
Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer.

Chen M, Wang M, Xu S, et al.
Upregulation of miR-181c contributes to chemoresistance in pancreatic cancer by inactivating the Hippo signaling pathway.
Oncotarget. 2015; 6(42):44466-79 [PubMed] Free Access to Full Article Related Publications
The Hippo signaling pathway plays a crucial role in regulating tissue homeostasis, organ size, tumorigenesis and cancer chemoresistance when deregulated. Physiologically, the Hippo core kinase cassette that consists of mamma-lian STE20-like protein kinase 1/2 (MST1/2), and large tumour suppressor 1/2 (LATS1/2), together with the adaptor proteins Salvador homologue 1 (SAV1) and MOB kinase activator 1 (MOB1), tightly restricts the activities of homologous oncoproteins Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) to low levels. However, how the Hippo kinase cassette core components are simultaneously inhibited, to exhibit constitutively inactivated Hippo signaling and activated YAP/TAZ in cancer remains puzzling. Herein, we reported that miR-181c directly repressed MST1, LATS2, MOB1 and SAV1 expression in human pancreatic cancer cells. Overexpression of miR-181c induced hyperactivation of the YAP/TAZ and enhanced expression of the Hippo signaling downstream genes CTGF, BIRC5 and BLC2L1, leading to pancreatic cancer cell survival and chemoresistance in vitro and in vivo. Importantly, high miR-181c levels were significantly correlated with Hippo signaling inactivation in pancreatic cancer samples, and predicted a poor patient overall survival. These findings provide a novel mechanism for Hippo signaling inactivation in cancer, indicating not only a potentially pivotal role for miR-181c in the progression of pancreatic cancer, but also may represent a new therapeutic target and prognostic marker.

Minchenko DO, Kharkova AP, Tsymbal DO, et al.
IRE1 inhibition affects the expression of insulin-like growth factor binding protein genes and modifies its sensitivity to glucose deprivation in U87 glioma cells.
Endocr Regul. 2015; 49(4):185-97 [PubMed] Related Publications
OBJECTIVE: The aim of the present study was to investigate the effect of inhibition of endoplasmic reticulum stress signaling mediated by IRE1/ERN1 (inositol-requiring enzyme 1/endoplasmic reticulum to nucleus signaling 1) on the expression of genes encoding different groups of insulin-like growth binding proteins (IGFBP6 and IGFBP7) and CCN family (IGFBP8/CTGF/CCN2, IGFBP9/NOV/CCN3, IGFBP10/CYR61/CCN1, WISP1/CCN4, and WISP2/CCN5) and its sensitivity to glucose deprivation in U87 glioma cells.
METHODS: The expression of IGFBP6, IGFBP7, IGFBP8, IGFBP9, IGFBP10, WISP1, and WISP2 genes was studied by qPCR in control U87 glioma cells (wild-type) and its subline with IRE1 signaling enzyme loss of function upon glucose deprivation.
RESULTS: The expression of IGFBP8, IGFBP9, and WISP2 genes was up-regulated in control glioma cells upon glucose deprivation with most significant changes for IGFBP9 gene. At the same time, the expression of IGFBP6, IGFBP10, and WISP1 genes was resistant to glucose deprivation in these glioma cells, but the IGFBP7 gene expression was down-regulated. The inhibition of both enzymatic activities (kinase and endoribonuclease) of IRE1 in glioma cells modified the sensitivity of most studied gene expressions to glucose deprivation condition: introduced sensitivity of IGFBP10 and WISP1 genes to glucose deprivation, enhanced the effect of this deprivation on IGFBP7 and IGFBP9 gene expressions, and reduced this effect on WISP2 gene and induced suppressive effect of glucose deprivation on the expression of IGFBP8 gene. Furthermore, the inhibition of IRE1 strongly affected the expression of all studied genes in glioma cells upon regular growing condition in gene specific manner: up-regulated the expression levels of IGFBP7, IGFBP8, IGFBP10, WISP1, and WISP2 genes and down-regulated the IGFBP6 and IGFBP9 genes.
CONCLUSIONS: The data of this investigation demonstrate that the expression of IGFBP7, IGFBP8, IGFBP9, and WISP2 genes are sensitive to glucose deprivation in U87 glioma cells and that inhibition of IRE1 signaling enzyme function may significantly affect the expression of all studied genes in the presence of glucose as well as modify the effect of glucose deprivation on the expression of most studied genes. These data also show that proteins encoded by these genes may participate in the regulation of metabolic and proliferative processes via IGF/INS receptors and possibly other signaling pathways as well, via IRE1 signaling, which is a central mediator of the unfolded protein response and an important component of the tumor growth and metabolic diseases.

Piersma B, de Rond S, Werker PM, et al.
YAP1 Is a Driver of Myofibroblast Differentiation in Normal and Diseased Fibroblasts.
Am J Pathol. 2015; 185(12):3326-37 [PubMed] Related Publications
Dupuytren disease is a fibrotic disorder characterized by contraction of myofibroblast-rich cords and nodules in the hands. The Hippo member Yes-associated protein 1 (YAP1) is activated by tissue stiffness and the profibrotic transforming growth factor-β1, but its role in cell fibrogenesis is yet unclear. We hypothesized that YAP1 regulates the differentiation of dermal fibroblasts into highly contractile myofibroblasts and that YAP1 governs the maintenance of a myofibroblast phenotype in primary Dupuytren cells. Knockdown of YAP1 in transforming growth factor-β1-stimulated dermal fibroblasts decreased the formation of contractile smooth muscle α-actin stress fibers and the deposition of collagen type I, which are hallmark features of myofibroblasts. Translating our findings to a clinically relevant model, we found that YAP1 deficiency in Dupuytren disease myofibroblasts resulted in decreased expression of ACTA2, COL1A1, and CCN2 mRNA, but this did not result in decreased protein levels. YAP1-deficient Dupuytren myofibroblasts showed decreased contraction of a collagen hydrogel. Finally, we showed that YAP1 levels and nuclear localization were elevated in affected Dupuytren disease tissue compared with matched control tissue and partly co-localized with smooth muscle α-actin-positive cells. In conclusion, our data show that YAP1 is a regulator of myofibroblast differentiation and contributes to the maintenance of a synthetic and contractile phenotype, in both transforming growth factor-β1-induced myofibroblast differentiation and primary Dupuytren myofibroblasts.

Qiu Z, Yuan W, Chen T, et al.
HMGCR positively regulated the growth and migration of glioblastoma cells.
Gene. 2016; 576(1 Pt 1):22-7 [PubMed] Related Publications
The metabolic program of cancer cells is significant different from the normal cells, which makes it possible to develop novel strategies targeting cancer cells. Mevalonate pathway and its rate-limiting enzyme HMG-CoA reductase (HMGCR) have shown important roles in the progression of several cancer types. However, their roles in glioblastoma cells remain unknown. In this study, up-regulation of HMGCR in the clinical glioblastoma samples was observed. Forced expression of HMGCR promoted the growth and migration of U251 and U373 cells, while knocking down the expression of HMGCR inhibited the growth, migration and metastasis of glioblastoma cells. Molecular mechanism studies revealed that HMGCR positively regulated the expression of TAZ, an important mediator of Hippo pathway, and the downstream target gene connective tissue growth factor (CTGF), suggesting HMGCR might activate Hippo pathway in glioblastoma cells. Taken together, our study demonstrated the oncogenic roles of HMGCR in glioblastoma cells and HMGCR might be a promising therapeutic target.

Li Y, Francia G, Zhang JY
p62/IMP2 stimulates cell migration and reduces cell adhesion in breast cancer.
Oncotarget. 2015; 6(32):32656-68 [PubMed] Free Access to Full Article Related Publications
p62/IMP2 is an oncofetal protein that is overexpressed in several types of cancer, and is a member of the family of insulin-like growth factor 2 mRNA binding proteins. We previously reported that high levels of p62/IMP2 autoantibody are present in sera from cancer patients, compared to healthy individuals. Here, we report the overexpression of p62/IMP2 in tumor tissues of 72 out of 104 cases of human breast cancer, and high levels of p62/IMP2 autoantibody in patients' sera (in 63 out of 216 cases). To explore the role of p62/IMP2 in breast cancer progression, we generated p62/IMP2 transfected variants of two human breast cancer cell lines: MDA-MB-231 and LM2-4. Using in vitro assays we found that overexpression of p62/IMP2 can increase cell migration, and reduce cell adhesion to extracellular matrix (ECM) proteins. A Human Extracellular Matrix and Adhesion Molecules qPCR array was performed with our generated variants, and it identified a group of mRNAs whose expression was altered with p62/IMP2 overexpression, including connective tissue growth factor (CTGF) mRNA - which we show to be a p62/IMP2 binding partner. Overall, our results provide new insights into the molecular mechanism by which p62/IMP2 can contribute to breast cancer progression.

Yokota M, Kojima M, Higuchi Y, et al.
Gene expression profile in the activation of subperitoneal fibroblasts reflects prognosis of patients with colon cancer.
Int J Cancer. 2016; 138(6):1422-31 [PubMed] Related Publications
Tumors can create a heterogenetic tumor microenvironment. We recently identified the pathologically unique cancer microenvironment formed by peritoneal invasion (CMPI), and revealed that subperitoneal fibroblasts (SPFs) within peritoneal tissue play a crucial role in tumor progression through their interaction with cancer cells. Therefore, the genes in SPFs altered by cancer stimulation may include some biologically important factors associated with patient prognosis. In this study, we aimed to identify new biomarkers using genes specifically upregulated in SPFs by cancer-cell-conditioned medium (CCCM) stimulation (SPFs CCCM response genes; SCR genes) in colon cancer (CC). We constructed two frameworks using SCR gene data: a publicly released microarray dataset, and validation cases with freshly frozen CC samples to identify genes related to short recurrence-free survival (RFS). In the first framework, we selected differentially expressed genes between the high and low SCR gene expression groups. In the second framework, genes significantly related to short RFS were selected by univariate analysis using all SCR genes, and multivariate analysis was performed to select robust genes associated with short RFS. We identified CTGF, CALD1, INHBA and TAGLN in the first framework, and PDLIM5, MAGI1, SPTBN1 and TAGLN in the second framework. Among these seven genes, high expression of three genes (CALD1, TAGLN and SPTBN1) showed a poor prognosis in our validation cases. In a public microarray dataset, SCR gene expression was associated with the expression of ECM component, EMT, and M2-macrophage associated genes, which was concordant with the pathological features of CMPI. Thus, we successfully identified new prognostic factors.

Tang YN, Ding WQ, Guo XJ, et al.
Epigenetic regulation of Smad2 and Smad3 by profilin-2 promotes lung cancer growth and metastasis.
Nat Commun. 2015; 6:8230 [PubMed] Related Publications
Altered transforming growth factor-β (TGF-β) signalling has been implicated in tumour development and progression. However, the molecular mechanism behind this alteration is poorly understood. Here we show that profilin-2 (Pfn2) increases Smad2 and Smad3 expression via an epigenetic mechanism, and that profilin-2 and Smad expression correlate with an unfavourable prognosis of lung cancer patients. Profilin-2 overexpression promotes, whereas profilin-2 knockdown drastically reduces, lung cancer growth and metastasis. We show that profilin-2 suppresses the recruitment of HDAC1 to Smad2 and Smad3 promoters by preventing nuclear translocation of HDAC1 through protein-protein interaction at the C terminus of both proteins, leading to the transcriptional activation of Smad2 and Smad3. Increased Smad2 and Smad3 expression enhances TGF-β1-induced EMT and production of the angiogenic factors VEGF and CTGF. These findings reveal a new regulatory mechanism of TGF-β1/Smad signalling, and suggest a potential molecular target for the development of anticancer drugs.

Zhu X, Zhong J, Zhao Z, et al.
Epithelial derived CTGF promotes breast tumor progression via inducing EMT and collagen I fibers deposition.
Oncotarget. 2015; 6(28):25320-38 [PubMed] Free Access to Full Article Related Publications
Interactions among tumor cells, stromal cells, and extracellular matrix compositions are mediated through cytokines during tumor progression. Our analysis of 132 known cytokines and growth factors in published clinical breast cohorts and our 84 patient-derived xenograft models revealed that the elevated connective tissue growth factor (CTGF) in tumor epithelial cells significantly correlated with poor clinical prognosis and outcomes. CTGF was able to induce tumor cell epithelial-mesenchymal transition (EMT), and promote stroma deposition of collagen I fibers to stimulate tumor growth and metastasis. This process was mediated through CTGF-tumor necrosis factor receptor I (TNFR1)-IκB autocrine signaling. Drug treatments targeting CTGF, TNFR1, and IκB signaling each prohibited the EMT and tumor progression.

Lim T, Lee I, Kim J, Kang WK
Synergistic Effect of Simvastatin Plus Radiation in Gastric Cancer and Colorectal Cancer: Implications of BIRC5 and Connective Tissue Growth Factor.
Int J Radiat Oncol Biol Phys. 2015; 93(2):316-25 [PubMed] Related Publications
PURPOSE: We investigated the synergistic effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor plus radiation therapy, on the proliferation and survival of gastric cancer (GC) and colorectal cancer (CRC) cells. We also studied several genes involved in the simvastatin/radiation-induced effects.
METHODS AND MATERIALS: Gastric cancer (AGS, SNU601, MKN1, and MKN28) and CRC (CoLo320, SW48, HT29, and HCT8) cell lines were treated with 0.2 μM simvastatin alone, or in combination with 0 to 4 Gy of radiation, and subjected to clonogenic survival and proliferation assays in vitro. To assess the molecular mechanism of the combination treatment, we performed microarray analysis, immunoblot assays, small interfering RNA knockdown experiments, and plasmid rescue assays. The antitumoral effects of simvastatin and radiation were evaluated in vivo using xenograft models.
RESULTS: The combination therapy of simvastatin plus radiation inhibited basal clonogenic survival and proliferation of GC and CRC cells in vitro. Simvastatin suppressed the expression of BIRC5 and CTGF genes in these cancer cells. In vivo, the combined treatment with simvastatin and radiation significantly reduced the growth of xenograft tumors compared with treatment with radiation alone.
CONCLUSION: We suggest that simvastatin has a synergistic effect with radiation on GC and CRC through the induction of apoptosis, which may be mediated by a simultaneous inhibition of BIRC5 and CTGF expression. A clinical trial of simvastatin in combination with radiation in patients with GC or CRC is warranted.

Mendes FA, Coelho Aguiar JM, Kahn SA, et al.
Connective-Tissue Growth Factor (CTGF/CCN2) Induces Astrogenesis and Fibronectin Expression of Embryonic Neural Cells In Vitro.
PLoS One. 2015; 10(8):e0133689 [PubMed] Free Access to Full Article Related Publications
Connective-tissue growth factor (CTGF) is a modular secreted protein implicated in multiple cellular events such as chondrogenesis, skeletogenesis, angiogenesis and wound healing. CTGF contains four different structural modules. This modular organization is characteristic of members of the CCN family. The acronym was derived from the first three members discovered, cysteine-rich 61 (CYR61), CTGF and nephroblastoma overexpressed (NOV). CTGF is implicated as a mediator of important cell processes such as adhesion, migration, proliferation and differentiation. Extensive data have shown that CTGF interacts particularly with the TGFβ, WNT and MAPK signaling pathways. The capacity of CTGF to interact with different growth factors lends it an important role during early and late development, especially in the anterior region of the embryo. ctgf knockout mice have several cranio-facial defects, and the skeletal system is also greatly affected due to an impairment of the vascular-system development during chondrogenesis. This study, for the first time, indicated that CTGF is a potent inductor of gliogenesis during development. Our results showed that in vitro addition of recombinant CTGF protein to an embryonic mouse neural precursor cell culture increased the number of GFAP- and GFAP/Nestin-positive cells. Surprisingly, CTGF also increased the number of Sox2-positive cells. Moreover, this induction seemed not to involve cell proliferation. In addition, exogenous CTGF activated p44/42 but not p38 or JNK MAPK signaling, and increased the expression and deposition of the fibronectin extracellular matrix protein. Finally, CTGF was also able to induce GFAP as well as Nestin expression in a human malignant glioma stem cell line, suggesting a possible role in the differentiation process of gliomas. These results implicate ctgf as a key gene for astrogenesis during development, and suggest that its mechanism may involve activation of p44/42 MAPK signaling. Additionally, CTGF-induced differentiation of glioblastoma stem cells into a less-tumorigenic state could increase the chances of successful intervention, since differentiated cells are more vulnerable to cancer treatments.

Zhu G, Wang Y, Mijiti M, et al.
Upregulation of miR-130b enhances stem cell-like phenotype in glioblastoma by inactivating the Hippo signaling pathway.
Biochem Biophys Res Commun. 2015; 465(2):194-9 [PubMed] Related Publications
The Hippo signaling pathway plays a crucial role in suppressing tumorigenesis. Physiologically, The Hippo signaling largely restricts its two downstream effectors, homologous oncoproteins Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), to a low level of activity by the MST1-SAV1 complex-induced kinase cascade. However, how the negative regulation induced by MST1-SAV1 complex is disrupted to exhibit constitutive YAP/TAZ activation in cancer remains unclear. Herein, we reported that miR-130b directly repressed MST1 and SAV1 expression in human glioblastoma cells. Overexpression of miR-130b induced hyperactivation of the YAP/TAZ and enhanced expression of the Hippo signaling downstream genes CTGF and the pluripotency associated markers, including CD133, SOX2, Nanog, MYC and BMI1, leading to promotion of glioblastoma stem cell phenotype. Conversely, inhibition of miR-130b attenuated these effects. These findings provide a novel mechanism for Hippo signaling inactivation in cancer, indicating not only a potentially pivotal role for miR-130b in the progression of glioblastoma, but also may represent a new therapeutic target.

Gahr S, Mayr C, Kiesslich T, et al.
The pan-deacetylase inhibitor panobinostat affects angiogenesis in hepatocellular carcinoma models via modulation of CTGF expression.
Int J Oncol. 2015; 47(3):963-70 [PubMed] Related Publications
Post-translational modifications of chromatin components are significantly involved in the regulation of tumor suppressor gene and oncogene expression. Connective tissue growth factor (CTGF) is an epigenetically regulated growth factor with functions in angiogenesis and cell-matrix interactions and plays a pivotal role in hepatocellular carcinoma (HCC). The pharmacologic inhibition of histone and protein deacetylases represents a new approach to interfere with pathways of apoptosis and angiogenesis. We investigated the effect of the pan-deacetylase inhibitor panobinostat (LBH589) on human HCC cell lines HepG2 (p53wt) and Hep3B (p53null) and in a subcutaneous xenograft model and explored the influence on angiogenesis. Specimens were characterized by quantitative real-time PCR. Protein was separated for western blotting against CTGF, VEGF, VEGF receptor-1 (VEGFR-1/FLT-1), VEGF receptor-2 (VEGFR-2/KDR), MAPK and phospho-MAPK. In vivo, HepG2 cells were xenografted to NMRI mice and treated with daily i.p. injections of 10 mg/kg panobinostat. After 1, 7 and 28 days, real-time PCR was performed. Immunohistochemistry and western blotting were examined after 28 days. An increased significant expression of CTGF was only seen after 24 h treatment with 0.1 µM panobinostat in HepG2 cells and Hep3B cells, whereas after 72 h treatment CTGF expression clearly decreased. In the xenografts, treatment with panobinostat showed a minimal CTGF expression after 1 day and 4 weeks, respectively. In vitro as well as in vivo, VEGF was not affected by panobinostat treatment at any time. In conclusion, panobinostat influences extracellular signaling cascades via CTGF-dependent pathways.

Hutchenreuther J, Vincent KM, Carter DE, et al.
CCN2 Expression by Tumor Stroma Is Required for Melanoma Metastasis.
J Invest Dermatol. 2015; 135(11):2805-13 [PubMed] Related Publications
Metastatic melanoma has an extremely poor prognosis with few durable remissions. The secreted matricellular protein connective tissue growth factor (CCN2) is overexpressed in cancers including melanoma and may represent a viable therapeutic target. However, the mechanism underlying the contribution of CCN2 to melanoma progression is unclear. Herein, we use the highly metastatic murine melanoma cell line B16(F10) and syngeneic mice, in which CCN2 expression is knocked out in fibroblasts, to demonstrate that loss of CCN2, either in melanoma cells or in the niche, impedes the ability of melanoma cells to invade. Specifically, loss of CCN2 in melanoma cells diminished their ability to invade through collagen in vitro, and loss of fibroblast-derived CCN2 decreased spontaneous metastases of melanoma cells from the skin to the lungs in vivo. Proliferation and tumor growth were not affected by loss of CCN2. CCN2-deficient B16(F10) cells showed reduced expression of the matricellular protein periostin; addition of recombinant periostin rescued the in vitro invasion defect of these cells. Immunohistochemical analysis of CCN2-deficient mice confirmed loss of periostin expression in the absence of CCN2. CCN2 and periostin mRNA levels are positively correlated with each other and with the stromal composition of human melanoma lesions but not BRAF mutations. Thus, CCN2 promotes invasion and metastasis via periostin and should be further evaluated as a possible therapeutic target for BRAF inhibitor-resistant melanoma.

Khan FH, Pandian V, Ramraj S, et al.
Reorganization of metastamiRs in the evolution of metastatic aggressive neuroblastoma cells.
BMC Genomics. 2015; 16:501 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: MetastamiRs have momentous clinical relevance and have been correlated with disease progression in many tumors. In this study, we identified neuroblastoma metastamiRs exploiting unique mouse models of favorable and high-risk metastatic human neuroblastoma. Further, we related their deregulation to the modulation of target proteins and established their association with clinical outcomes.
RESULTS: Whole genome miRNA microarray analysis identified 74 metastamiRs across the manifold of metastatic tumors. RT-qPCR on select miRNAs validated profile expression. Results from bio-informatics across the ingenuity pathway, miRCancer, and literature data-mining endorsed the expression of these miRNAs in multiple tumor systems and showed their role in metastasis, identifying them as metastamiRs. Immunoblotting and TMA-IHC analyses revealed alterations in the expression/phosphorylation of metastamiRs' targets, including ADAMTS-1, AKT1/2/3, ASK1, AURKβ, Birc1, Birc2, Bric5, β-CATENIN, CASP8, CD54, CDK4, CREB, CTGF, CXCR4, CYCLIN-D1, EGFR, ELK1, ESR1, CFOS, FOSB, FRA, GRB10, GSK3β, IL1α, JUND, kRAS, KRTAP1, MCP1, MEGF10, MMP2, MMP3, MMP9, MMP10, MTA2, MYB, cMYC, NF2, NOS3, P21, pP38, PTPN3, CLEAVED PARP, PKC, SDF-1β, SEMA3D, SELE, STAT3, TLR3, TNFα, TNFR1, and VEGF in aggressive cells ex vivo and in a manifold of metastatic tumors in vivo. miRNA mimic (hsa-miR-125b, hsa-miR-27b, hsa-miR-93, hsa-miR-20a) and inhibitor (hsa-miR-1224-3p, hsa-miR-1260) approach for select miRNAs revealed the direct influence of the altered metastamiRs in the regulation of identified protein targets. Clinical outcome association analysis with the validated metastamiRs' targets corresponded strongly with poor overall and relapse-free survival.
CONCLUSIONS: For the first time, these results identified a comprehensive list of neuroblastoma metastamiRs, related their deregulation to altered expression of protein targets, and established their association with poor clinical outcomes. The identified set of distinctive neuroblastoma metastamiRs could serve as potential candidates for diagnostic markers for the switch from favorable to high-risk metastatic disease.

Welch MD, Howlett M, Halse HM, et al.
Novel CT domain-encoding splice forms of CTGF/CCN2 are expressed in B-lineage acute lymphoblastic leukaemia.
Leuk Res. 2015; 39(8):913-20 [PubMed] Related Publications
INTRODUCTION: Connective tissue growth factor (CTGF/CCN2) has been shown previously to be aberrantly expressed in a high proportion of paediatric precursor B cell acute lymphoblastic leukaemia (pre-B ALL), suggesting a potential oncogenic role in this tumour type. We therefore assessed CTGF mRNA transcript diversity in B-lineage ALL using primary patient specimens and cell lines.
METHODS: CTGF mRNA expression was evaluated by quantitative real-time PCR and Northern blotting. We performed a structural analysis of CTGF mRNA by nested reverse-transcriptase PCR and examined CTGF protein diversity by immunoblotting.
RESULTS: Northern blot analysis of pre-B ALL cell lines revealed short CTGF transcripts that were expressed in association with the active phase of cellular growth. Structural analysis confirmed the synthesis of several novel CTGF mRNA isoforms in B-lineage ALL cell lines that were uniformly characterised by the retention of the coding sequence for the C-terminal (CT) domain. One of these novel spliceforms was expressed in a majority (70%) of primary pre-B ALL patient specimens positive for canonical CTGF mRNA. Evidence that these alternative transcripts have coding potential was provided by cryptic CTGF proteins of predicted size detected by immunoblotting.
CONCLUSION: This study identifies for the first time alternative splicing of the CTGF gene and shows that a short CTGF splice variant associated with cell proliferation is expressed in most cases of primary CTGF-positive pre-B ALL. This novel variant encoding only the CT domain may play a role in pre-B ALL tumorigenesis and/or progression.

Xiang L, Gilkes DM, Hu H, et al.
HIF-1α and TAZ serve as reciprocal co-activators in human breast cancer cells.
Oncotarget. 2015; 6(14):11768-78 [PubMed] Free Access to Full Article Related Publications
Hypoxia-inducible factor 1α (HIF-1α) expression is a hallmark of intratumoral hypoxia that is associated with breast cancer metastasis and patient mortality. Previously, we demonstrated that HIF-1 stimulates the expression and activity of TAZ, which is a transcriptional effector of the Hippo signaling pathway, by increasing TAZ synthesis and nuclear localization. Here, we report that direct protein-protein interaction between HIF-1α and TAZ has reciprocal effects: HIF-1α stimulates transactivation mediated by TAZ and TAZ stimulates transactivation mediated by HIF-1α. Inhibition of TAZ expression impairs the hypoxic induction of HIF-1 target genes, such as PDK1, LDHA, BNIP3 and P4HA2 in response to hypoxia, whereas inhibition of HIF-1α expression impairs TAZ-mediated transactivation of the CTGF promoter. Taken together, these results complement our previous findings and establish bidirectional crosstalk between HIF-1α and TAZ that increases their transcriptional activities in hypoxic cells.

Wang M, Liu Y, Zou J, et al.
Transcriptional co-activator TAZ sustains proliferation and tumorigenicity of neuroblastoma by targeting CTGF and PDGF-β.
Oncotarget. 2015; 6(11):9517-30 [PubMed] Free Access to Full Article Related Publications
Neuroblastoma is a common childhood malignant tumor originated from the neural crest-derived sympathetic nervous system. A crucial event in the pathogenesis of neuroblastoma is to promote proliferation of neuroblasts, which is closely related to poor survival. However, mechanisms for regulation of cell proliferation and tumorigenicity in neuroblastoma are not well understood. Here, we report that overexpression of TAZ in neuroblastoma BE(2)-C cells causes increases in cell proliferation, self renewal and colony formation, which was restored back to its original levels by knockdown of TAZ in TAZ-overexpression cells. Inhibition of endogenous TAZ attenuated cell proliferation, colony formation and tumor development in neuroblastoma SK-N-AS cell, which could be rescued by re-introduction of TAZ into TAZ-knockdown cells. In addition, we found that overexpressing TAZ-mediated induction of CTGF and PDGF-β expression, cell proliferation and colony formation were inhibited by knocking down CTGF and PDGF-β with siRNA in TAZ-overexpressing cell. Overall, our findings suggested that TAZ plays an essential role in regulating cell proliferation and tumorigenesis in neuroblastoma cells. Thus, TAZ seems to be a novel and promising target for the treatment of neuroblastoma.

Tan G, Cao X, Dai Q, et al.
A novel role for microRNA-129-5p in inhibiting ovarian cancer cell proliferation and survival via direct suppression of transcriptional co-activators YAP and TAZ.
Oncotarget. 2015; 6(11):8676-86 [PubMed] Free Access to Full Article Related Publications
Transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are key oncogenes in mammalian cells. Activities of YAP and TAZ are largely restricted by the Hippo tumor suppressor pathway through phosphorylation-ubiquitination mechanisms. The involvement of microRNA in cancer progression has recently been reported, though whether they have a role in activating YAP and TAZ in human cancer cells remains unclear. Here, we report a microRNA, miR-129-5p, directly represses YAP and TAZ expression, leading to the inactivation of TEA domain (TEAD) transcription, and the downregulation of Hippo downstream genes, connective tissue growth factor (CTGF) and Cyclin A. Furthermore, we reveal miR-129-5p inhibits ovarian cancer cell proliferation, survival and tumorigenicity, and that downregulation of miR-129-5p in ovarian cancer cells highly correlates with malignant progression and poor survival. Hence, we demonstrate a novel mechanism for YAP and TAZ activation in cancers, indicating not only a potentially pivotal role for miR-129-5p in the progression of ovarian cancer, but also offering new therapeutic strategies to circumvent the disease.

Nagpal N, Ahmad HM, Chameettachal S, et al.
HIF-inducible miR-191 promotes migration in breast cancer through complex regulation of TGFβ-signaling in hypoxic microenvironment.
Sci Rep. 2015; 5:9650 [PubMed] Free Access to Full Article Related Publications
The molecular mechanisms of hypoxia induced breast cell migration remain incompletely understood. Our results show that hypoxia through hypoxia-inducible factor (HIF) brings about a time-dependent increase in the level of an oncogenic microRNA, miR-191 in various breast cancer cell lines. miR-191 enhances breast cancer aggressiveness by promoting cell proliferation, migration and survival under hypoxia. We further established that miR-191 is a critical regulator of transforming growth factor beta (TGFβ)-signaling and promotes cell migration by inducing TGFβ2 expression under hypoxia through direct binding and indirectly by regulating levels of a RNA binding protein, human antigen R (HuR). The levels of several TGFβ pathway genes (like VEGFA, SMAD3, CTGF and BMP4) were found to be higher in miR-191 overexpressing cells. Lastly, anti-miR-191 treatment given to breast tumor spheroids led to drastic reduction in spheroid tumor volume. This stands as a first report of identification of a microRNA mediator that links hypoxia and the TGFβ signaling pathways, both of which are involved in regulation of breast cancer metastasis. Together, our results show a critical role of miR-191 in hypoxia-induced cancer progression and suggest that miR-191 inhibition may offer a novel therapy for hypoxic breast tumors.

Lamarca A, Mendiola M, Bernal E, et al.
Tumoural Expression of Connective Tissue Growth Factor (CTGF) Impacts on Survival in Patients Diagnosed with Hepatocellular Carcinoma (HCC).
Curr Cancer Drug Targets. 2015; 15(5):435-44 [PubMed] Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) tends to develop in the liver when there is a high level of background inflammation (cirrhosis). Treatment options are limited and mainly based on systemic therapies such as anti-angiogenic drugs (e.g. sorafenib). Connective tissue growth factor (CTGF) is a matricellular protein involved in inflammation, tumour growth and angiogenesis. The aim of this study is to determine the expression of CTGF and hypoxia inducible factors (HIF) in HCC and to clarify its impact on relapse and survival.
MATERIAL AND METHODS: Eligibility criteria for the study consisted of patients with a diagnosis of HCC, formalin-fixed and paraffin-embedded (FFPE) biopsy tissue, as well as relapse and available survival data. A tissue microarray was constructed from ≥ 70% tumoural sections. The expressions of CTGF, HIF1α and HIF2α were analysed by immunohistochemistry. The relationship between expression of CTGF/HIF1α and CTGF/HIF2α were analysed. Univariate and multivariate analyses were performed.
RESULTS: Fifty-three patients were screened; 39 patients were eligible for this study. Patients were treated with radical intent. At the end of follow up, 59% patients relapsed (28.2% locally, 10.3% multicentric liver relapse and 7.7% distant metastases). Estimated median disease-free survival (DFS) and overall survival (OS) were 23.4 (95%CI 7.18-39.66) and 38.6 months (95%CI 30.7-46.6), respectively. Expression of CTGF was: negative 23.1%, focal 48.7% and diffuse 23.1%. A non-statistically significant relationship between expression of CTGF and HIF was shown supporting an alternative pathway for CTGF expression in HCC. In multivariate analysis CTGF expression was an independent factor related to OS, with shorter survival in those patients with focal/diffuse CTGF expression (HR 2.46; 95%CI 1.18-5.15).
CONCLUSIONS: Our results support that expression of CTGF is an independent factor associated with shorter OS in HCC. Further analysis of CTGF expression in a larger series of HCC patients is required to confirm CTGF as a prognostic biomarker in HCC.

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