Gene Summary

Gene:CTGF; connective tissue growth factor
Aliases: CCN2, NOV2, HCS24, IGFBP8
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:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:connective tissue growth factor
Source:NCBIAccessed: 11 August, 2015


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

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 11 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.

  • Chromosome 6
  • Transcription
  • Survival Rate
  • Cell Proliferation
  • Stem Cells
  • Cancer RNA
  • Neoplasm Invasiveness
  • Promoter Regions
  • Bone Cancer
  • Tumor Markers
  • Gene Expression Profiling
  • Severity of Illness Index
  • NOV
  • Cysteine-Rich Protein 61
  • Proto-Oncogene Proteins
  • VHL
  • Testicular Cancer
  • Signal Transduction
  • Cell Movement
  • Immunohistochemistry
  • Intercellular Signaling Peptides and Proteins
  • Vascular Endothelial Growth Factors
  • Gene Expression
  • Growth Substances
  • Messenger RNA
  • Xenograft Models
  • Breast Cancer
  • Transcriptional Activation
  • Connective Tissue Growth Factor
  • Species Specificity
  • beta Catenin
  • Immediate-Early Proteins
  • Oligonucleotide Array Sequence Analysis
  • Wilms Tumour
  • Staurosporine
  • Angiogenesis
  • Vascular Neoplasms
  • Western Blotting
  • Cancer Gene Expression Regulation
Tag cloud generated 11 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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)

Meng G, Li Y, Lv Y, et al.
Preliminary screening of differentially expressed genes involved in methyl-CpG-binding protein 2 gene-mediated proliferation in human osteosarcoma cells.
Tumour Biol. 2015; 36(4):3009-15 [PubMed] Related Publications
Methyl-CpG-binding protein 2 (MeCP2) is essential in human brain development and has been linked to several cancer types and neuro-developmental disorders. This study aims to screen the MeCP2 related differentially expressed genes and discover the therapeutic targets for osteosarcoma. CCK8 assay was used to detect the proliferation and SaOS2 and U2OS cells. Apoptosis of cells was detected by flow cytometry analysis that monitored Annexin V-APC/7-DD binding and 7-ADD uptake simultaneously. Denaturing formaldehyde agarose gel electrophoresis was employed to examine the quality of total RNA 18S and 28S units. Gene chip technique was utilized to discover the differentially expressed genes correlated with MeCP2 gene. Differential gene screening criteria were used to screen the changed genes. The gene up-regulation or down-regulation more than 1.5 times was regarded as significant differential expression genes. The CCK8 results indicated that the cell proliferation of MeCP2 silencing cells (LV-MeCP2-RNAi) was significantly decreased compared to non-silenced cells (LV-MeCP2-RNAi-CN) (P < 0.05). MeCP2 silencing could also induce significant apoptosis compared to non-silenced cells (P < 0.05); 107 expression changed genes were screened from a total of 49,395 transcripts. Among the total 107 transcripts, 34 transcripts were up-regulated and 73 transcripts were down-regulated. There were five significant differentially expressed genes, including IGFBP4, HOXC8, LMO4, MDK, and CTGF, which correlated with the MeCP2 gene. The methylation frequency of CpG in IGFBP4 gene could achieve 55%. In conclusion, the differentially expressed IGFBP4, HOXC8, LMO4, MDK, and CTGF genes may be involved in MeCP2 gene-mediated proliferation and apoptosis in osteosarcoma cells.

Yuan J, Xiao G, Peng G, et al.
MiRNA-125a-5p inhibits glioblastoma cell proliferation and promotes cell differentiation by targeting TAZ.
Biochem Biophys Res Commun. 2015; 457(2):171-6 [PubMed] Related Publications
Glioblastoma (GBM) is the most lethal brain tumor due to the resistance to conventional therapies, such as radiotherapy and chemotherapy. TAZ, an important mediator of the Hippo pathway, was found to be up-regulated in diverse cancers, including in GBM, and plays important roles in tumor initiation and progression. However, little is known about the regulation of TAZ expression in tumors. In this study, we found that miR-125a-5p is an important regulator of TAZ in glioma cells by directly targeting the TAZ 3' UTR. MiR-125a-5p levels are inversely correlated with that of TAZ in normal astrocytes and a panel of glioma cell lines. MiR-125a-5p represses the expression of TAZ target genes, including CTGF and survivin, and inhibits cell proliferation and induces the differentiation of GBM cells; whereas over-expression of TAZ rescues the effects of miR-125a-5p. This study revealed a mechanism for TAZ deregulation in glioma cells, and also demonstrated a tumor suppressor role of miR-125a-5p in glioblastoma cells.

Kou Y, Qiao L, Wang Q
Identification of core miRNA based on small RNA-seq and RNA-seq for colorectal cancer by bioinformatics.
Tumour Biol. 2015; 36(4):2249-55 [PubMed] Related Publications
We aimed to identify the potential microRNA (miRNA) targets for colorectal cancer (CRC). Small RNA-seq and RNA-seq data of GSE46622 were downloaded from Gene Expression Omnibus (GEO) database, including samples of tumor tissue, metastasis tissue, and normal tissue from eight CRC patients. Data comparison of small RNA-seq and RNA-seq was performed through Bowtie and TopHat softwares, respectively. Then the expressed values of each sample were calculated by Cufflinks and Cuffdiff based on fragments per kilobase of exon per millionfragments mapped (FPKM) methods. The differentially expressed miRNAs and core miRNAs were identified by paired t-test. Besides, miRNA target genes were integrated through miRanda, MirTarget2, PicTar, PITI, TargetScan, and miRecords databases, followed by functional analysis of specific miRNA. The average comparison rate of sequence reads in miRNA, noncoding RNA, and other areas of the genome is 49.75, 2.90, and 47.35 %, respectively. A total of 49 miRNAs was differentially expressed. Compared with normal controls, 3 miRNAs were upregulated and 13 miRNAs were downregulated in tumor samples as well as 48 miRNAs were upregulated and 20 miRNAs were downregulated in the metastasis samples. Among them, 18 metastasis-specific expressed miRNAs, 2 tumor-specific expressed miRNAs, and 11 normal expressed miRNA were found. miRNA-1, miRNA-338-5p, miRNA-326, and miR-490-5p were selected as important miRNAs. Besides, miRNA-338-5p target gene RAB6B, FAP, and CTGF were identified as oncogenes. The miRNAs, such as miRNA-1, miRNA-338-5p, and miRNA-326 may be used as potential targets for CRC diagnosis and treatment.

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] Free Access to Full Article 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.

Jiang W, Yao F, He J, et al.
Downregulation of VGLL4 in the progression of esophageal squamous cell carcinoma.
Tumour Biol. 2015; 36(2):1289-97 [PubMed] Related Publications
VGLL4, a member of the Vestigial-like (VGLL) proteins, has been reported to be dysregulated in several cancer types. However, its function in esophageal squamous cell carcinoma (ESCC) remains poorly understood. Here, it was found that the expression level of VGLL4 was decreased in ESCC tissues. Moreover, forced expression of VGLL4 in ESCC cells inhibited cell growth and migration, while knockdown of VGLL4 expression promoted the tumorigenecity of ESCC cells. Mechanistically, VGLL4 regulated the growth and motility of ESCC cells through downregulating the expression of connective tissue growth factor (CTGF), a known oncogene in the progression of ESCC. Taken together, our study suggested that downregulation of VGLL4 was very important in the progression of ESCC, and restoring the function of VGLL4 might be a promising therapeutic strategy for ESCC.

Uriarte I, Latasa MU, Carotti S, et al.
Ileal FGF15 contributes to fibrosis-associated hepatocellular carcinoma development.
Int J Cancer. 2015; 136(10):2469-75 [PubMed] Related Publications
Fibroblast growth factor 15 (FGF15), FGF19 in humans, is a gut-derived hormone and a key regulator of bile acids and carbohydrate metabolism. FGF15 also participates in liver regeneration after partial hepatectomy inducing hepatocellular proliferation. FGF19 is overexpressed in a significant proportion of human hepatocellular carcinomas (HCC), and activation of its receptor FGFR4 promotes HCC cell growth. Here we addressed for the first time the role of endogenous Fgf15 in hepatocarcinogenesis. Fgf15(+/+) and Fgf15(-/-) mice were subjected to a clinically relevant model of liver inflammation and fibrosis-associated carcinogenesis. Fgf15(-/-) mice showed less and smaller tumors, and histological neoplastic lesions were also smaller than in Fgf15(+/+) animals. Importantly, ileal Fgf15 mRNA expression was enhanced in mice undergoing carcinogenesis, but at variance with human HCC it was not detected in liver or HCC tissues, while circulating FGF15 protein was clearly upregulated. Hepatocellular proliferation was also reduced in Fgf15(-/-) mice, which also expressed lower levels of the HCC marker alpha-fetoprotein (AFP). Interestingly, lack of FGF15 resulted in attenuated fibrogenesis. However, in vitro experiments showed that liver fibrogenic stellate cells were not direct targets for FGF15/FGF19. Conversely we demonstrate that FGF15/FGF19 induces the expression of the pro-fibrogenic and pro-tumorigenic connective tissue growth factor (CTGF) in hepatocytes. These findings suggest the existence of an FGF15-triggered CTGF-mediated paracrine action on stellate cells, and an amplification mechanism for the hepatocarcinogenic effects of FGF15 via CTGF production. In summary, our observations indicate that ileal FGF15 may contribute to HCC development in a context of chronic liver injury and fibrosis.

Weng M, Song F, Chen J, et al.
The high-mobility group nucleosome-binding domain 5 is highly expressed in breast cancer and promotes the proliferation and invasion of breast cancer cells.
Tumour Biol. 2015; 36(2):959-66 [PubMed] Related Publications
The high-mobility group nucleosome-binding domain 5 (HMGN5) is a member of the high-mobility group proteins family. Previous study found that HMGN5 is required for tumorigenesis in vitro, and aberrations in the expression of HMGN5 were found in human osteosarcoma, prostate cancer, and squamous cell carcinoma. Nevertheless, the role of HMGN5 in breast cancer remains unclear. This study aimed to investigate the expression and clinical significance of HMGN5 in human breast cancer, confirm the oncogenic role of HMGN5, and explore the mechanism by which HMGN5 contributes to invasion and metastasis. HMGN5 expression was detected in breast cancer tissues and corresponding adjacent non-cancerous tissues from 43 patients by immunohistochemistry, and the clinicopathologic characteristics of all patients were also analyzed. Next, knockdown of HMGN5 protein in MDA-MB-231 cells was performed through a small interfering RNA (siRNA) technique, and cell viability, apoptosis, and invasion were detected by cell vitality test, flow cytometry, and transwell assay, respectively. Immunohistostaining showed that HMGN5 were highly expressed in the nucleus in all breast cancer tissues as compared with the adjacent non-cancerous tissues (ANCT;(73.5 ± 11 vs. 31.0 ± 5 %, P < 0.01). HMGN5 expression level was associated with the poorly differentiated tumor cells, lymph node involvement tumor, and T4 staging tumor. Knockdown of HMGN5 inhibited cell growth, suppressed invasion, and increased cell apoptosis in human breast cancer MDA-MB-231 cells. Western blot analysis demonstrated that the expressions of PCNA, connective tissue growth factor (CTGF), and MMP-9 were decreased in human breast MDA-MB-231 cells depleted of HMGN5. In addition, the apoptotic markers (cleaved PARP and cleaved caspase-3) were significantly increased by HMGN5 knockdown, but microtubule-associated protein 1 light chain 3-II/I (LC3-II/I) did not alter. HMGN5 plays an oncogenic role in human breast cancer by inhibiting cell proliferation and invasion, and activating apoptosis, which could be exploited as a target for therapy in human breast cancer.

Kubota S, Takigawa M
Cellular and molecular actions of CCN2/CTGF and its role under physiological and pathological conditions.
Clin Sci (Lond). 2015; 128(3):181-96 [PubMed] Related Publications
CCN family protein 2 (CCN2), also widely known as connective tissue growth factor (CTGF), is one of the founding members of the CCN family of matricellular proteins. Extensive investigation on CCN2 over decades has revealed the novel molecular action and functional properties of this unique signalling modulator. By its interaction with multiple molecular counterparts, CCN2 yields highly diverse and context-dependent biological outcomes in a variety of microenvironments. Nowadays, CCN2 is recognized to conduct the harmonized development of relevant tissues, such as cartilage and bone, in the skeletal system, by manipulating extracellular signalling molecules involved therein by acting as a hub through a web. However, on the other hand, CCN2 occasionally plays profound roles in major human biological disorders, including fibrosis and malignancies in major organs and tissues, by modulating the actions of key molecules involved in these clinical entities. In this review, the physiological and pathological roles of this unique protein are comprehensively summarized from a molecular network-based viewpoint of CCN2 functionalities.

Ammirante M, Shalapour S, Kang Y, et al.
Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts.
Proc Natl Acad Sci U S A. 2014; 111(41):14776-81 [PubMed] Free Access to Full Article Related Publications
Prostate cancer (PC) is a slowly progressing malignancy that often responds to androgen ablation or chemotherapy by becoming more aggressive, acquiring a neuroendocrine phenotype, and undergoing metastatic spread. We found that B lymphocytes recruited into regressing androgen-deprived tumors by C-X-C motif chemokine 13 (CXCL13), a chemokine whose expression correlates with clinical severity, play an important role in malignant progression and metastatic dissemination of PC. We now describe how androgen ablation induces CXCL13 expression. In both allografted and spontaneous mouse PC, CXCL13 is expressed by tumor-associated myofibroblasts that are activated on androgen ablation through a hypoxia-dependent mechanism. The same cells produce CXCL13 after chemotherapy. Myofibroblast activation and CXCL13 expression also occur in the normal prostate after androgen deprivation, and CXCL13 is expressed by myofibroblasts in human PC. Hypoxia activates hypoxia-inducible factor 1 (HIF-1) and induces autocrine TGF-β signaling that promotes myofibroblast activation and CXCL13 induction. In addition to TGF-β receptor kinase inhibitors, myofibroblast activation and CXCL13 induction are blocked by phosphodiesterase 5 (PDE5) inhibitors. Both inhibitor types and myofibroblast immunodepletion block the emergence of castration-resistant PC in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of spontaneous metastatic PC with neuroendocrine differentiation.

Pi L, Robinson PM, Jorgensen M, et al.
Connective tissue growth factor and integrin αvβ6: a new pair of regulators critical for ductular reaction and biliary fibrosis in mice.
Hepatology. 2015; 61(2):678-91 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
UNLABELLED: Connective tissue growth factor (CTGF) is a matricellular protein that mediates cell-matrix interaction through various subtypes of integrin receptors. This study investigated the role of CTGF and integrin αvβ6 in hepatic progenitor/oval cell activation, which often occurs in the form of ductular reactions (DRs) when hepatocyte proliferation is inhibited during severe liver injury. CTGF and integrin αvβ6 proteins were highly expressed in DRs of human cirrhotic livers and cholangiocarcinoma. Confocal microscopy analysis of livers from Ctgf promoter-driven green fluorescent protein reporter mice suggested that oval cells and cholangiocytes were the main sources of CTGF and integrin αvβ6 during liver injury induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Deletion of exon 4 of the Ctgf gene using tamoxifen-inducible Cre-loxP system down-regulated integrin αvβ6 in DDC-damaged livers of knockout mice. Ctgf deficiency or inhibition of integrin αvβ6, by administrating the neutralizing antibody, 6.3G9 (10 mg/kg body weight), caused low levels of epithelial cell adhesion molecule and cytokeratin 19 gene messenger RNAs. Also, there were smaller oval cell areas, fewer proliferating ductular epithelial cells, and lower cholestasis serum markers within 2 weeks after DDC treatment. Associated fibrosis was attenuated, as indicated by reduced expression of fibrosis-related genes, smaller areas of alpha-smooth muscle actin staining, and low collagen production based on hydroxyproline content and Sirius Red staining. Finally, integrin αvβ6 could bind to CTGF mediating oval cell adhesion to CTGF and fibronection substrata and promoting transforming growth factor (TGF)-β1 activation in vitro.
CONCLUSIONS: CTGF and integrin αvβ6 regulate oval cell activation and fibrosis, probably through interacting with their common matrix and signal partners, fibronectin and TGF-β1. CTGF and integrin αvβ6 are potential therapeutic targets to control DRs and fibrosis in related liver disease.

De Marco P, Romeo E, Vivacqua A, et al.
GPER1 is regulated by insulin in cancer cells and cancer-associated fibroblasts.
Endocr Relat Cancer. 2014; 21(5):739-53 [PubMed] Related Publications
Elevated insulin levels have been associated with an increased cancer risk as well as with aggressive and metastatic cancer phenotypes characterized by a poor prognosis. Insulin stimulates the proliferation, migration, and invasiveness of cancer cells through diverse transduction pathways, including estrogen signaling. As G protein estrogen receptor 1 (GPER1) mediates rapid cell responses to estrogens, we evaluated the potential of insulin to regulate GPER1 expression and function in leiomyosarcoma cancer cells (SKUT-1) and breast cancer-associated fibroblasts (CAFs), which were used as a model system. We found that insulin transactivates the GPER1 promoter sequence and increases the mRNA and protein expression of GPER1 through the activation of the PRKCD/MAPK1/c-Fos/AP1 transduction pathway, as ascertained by means of specific pharmacological inhibitors and gene-silencing experiments. Moreover, cell migration triggered by insulin occurred through GPER1 and its main target gene CTGF, whereas the insulin-induced expression of GPER1 boosted cell-cycle progression and the glucose uptake stimulated by estrogens. Notably, a positive correlation between insulin serum levels and GPER1 expression was found in cancer fibroblasts obtained from breast cancer patients. Altogether, our data indicate that GPER1 may be included among the complex network of transduction signaling triggered by insulin that drives cells toward cancer progression.

Warnke E, Pietsch J, Wehland M, et al.
Spheroid formation of human thyroid cancer cells under simulated microgravity: a possible role of CTGF and CAV1.
Cell Commun Signal. 2014; 12:32 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: Multicellular tumor spheroids (MCTS) formed scaffold-free under microgravity are of high interest for research and medicine. Their formation mechanism can be studied in space in real microgravity or on Earth using ground-based facilities (GBF), which simulate microgravity. On Earth, these experiments are more cost-efficient and easily performable. However, each GBF might exert device-specific and altered superimposingly gravity-dependent effects on the cells.
RESULTS: FTC-133 human thyroid cancer cells were cultivated on a 2D clinostat (CN) and a random positioning machine (RPM) and compared with corresponding 1 g control cells. Harvested cell samples were investigated by microscopy, quantitative realtime-PCR and Multi-Analyte Profiling. Spheroid formation and growth occurred during 72 h of cultivation on both devices. Cytokine secretion and gene activation patterns frequently altered in different ways, when the cells were cultured either on the RPM or the CN. A decreased expression of CAV1 and CTGF in MCTS compared to adherent cells was observed after cultivation on both machines.
CONCLUSION: The development of MCTS proceeds similarly on the RPM and the CN resembling the situation observed under real microgravity conditions, while no MCTS formation was observed at 1 g under identical experimental conditions. Simultaneously, changes in the regulation of CTGF and CAV1 appeared in a comparable manner on both machines. A relationship between these molecules and MCTS formation is discussed.

Wells JE, Howlett M, Cole CH, Kees UR
Deregulated expression of connective tissue growth factor (CTGF/CCN2) is linked to poor outcome in human cancer.
Int J Cancer. 2015; 137(3):504-11 [PubMed] Related Publications
Connective tissue growth factor (CTGF/CCN2) has long been associated with human cancers. The role it plays in these neoplasms is diverse and tumour specific. Recurring patterns in clinical outcome, histological desmoplasia and mechanisms of action have been found. When CTGF is overexpressed compared to low-expressing normal tissue or is underexpressed compared to high-expressing normal tissue, the functional outcome favours tumour survival and disease progression. CTGF acts by altering proliferation, drug resistance, angiogenesis, adhesion and migration contributing to metastasis. The pattern of CTGF expression and tumour response helps to clarify the role of this matricellular protein across a multitude of human cancers.

Kikuchi R, Kikuchi Y, Tsuda H, et al.
Expression and clinical significance of connective tissue growth factor in advanced head and neck squamous cell cancer.
Hum Cell. 2014; 27(3):121-8 [PubMed] Related Publications
Connective tissue growth factor (CTGF) has been reported to play critical roles in the tumorigenesis of several human malignancies. This study was performed to evaluate CTGF protein expression in head and neck squamous cell carcinoma (HNSCC). Surgical specimens from 76 primary HNSCC were obtained with written informed consents and the expression level of CTGF was immunohistochemically evaluated. The cytoplasmic immunoreactivity of CTGF in cancer cells was semiquantitatively classified into low and high expression. Among all 76 cases with or without neoadjuvant therapy, low CTGF showed significantly longer (P = 0.0282) overall survival (OS), but not disease-free survival (DFS) than high CTGF. Although low CTGF in patients with stage I, II and III did not result in any significant difference of the OS and DFS, stage IV HNSCC patients with low CTGF showed significantly longer OS (P = 0.032) and DFS (P = 0.0107) than those with high CTGF. These differences in stage IV cases were also confirmed using multivariate analyses. These results suggest that low CTGF in stage IV HNSCC is an independent prognostic factor, despite with or without neoadjuvant therapy.

Chen SK, Chung CA, Cheng YC, et al.
Toll-like receptor 6 and connective tissue growth factor are significantly upregulated in mitomycin-C-treated urothelial carcinoma cells under hydrostatic pressure stimulation.
Genet Test Mol Biomarkers. 2014; 18(6):410-6 [PubMed] Related Publications
BACKGROUND: Urothelial carcinoma (UC) is the most common histologic subtype of bladder cancer. The administration of mitomycin C (MMC) into the bladder after transurethral resection of the bladder tumor (TURBT) is a common treatment strategy for preventing recurrence after surgery. We previously applied hydrostatic pressure combined with MMC in UC cells and found that hydrostatic pressure synergistically enhanced MMC-induced UC cell apoptosis through the Fas/FasL pathways. To understand the alteration of gene expressions in UC cells caused by hydrostatic pressure and MMC, oligonucleotide microarray was used to explore all the differentially expressed genes.
RESULTS: After bioinformatics analysis and gene annotation, Toll-like receptor 6 (TLR6) and connective tissue growth factor (CTGF) showed significant upregulation among altered genes, and their gene and protein expressions with each treatment of UC cells were validated by quantitative real-time PCR and immunoblotting.
CONCLUSION: Under treatment with MMC and hydrostatic pressure, UC cells showed increasing apoptosis using extrinsic pathways through upregulation of TLR6 and CTGF.

Tsai HC, Huang CY, Su HL, Tang CH
CCN2 enhances resistance to cisplatin-mediating cell apoptosis in human osteosarcoma.
PLoS One. 2014; 9(3):e90159 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Osteosarcoma (OS) is the most common form of malignant bone tumor and is an aggressive malignant neoplasm exhibiting osteoblastic differentiation. Cisplatin is one of the most efficacious antitumor drugs for osteosarcoma patients. However, treatment failures are common due to the development of chemoresistance. CCN2 (also known as CTGF), is a secreted protein that binds to integrins, modulates the invasive behavior of certain human cancer cells. However, the effect of CCN2 in cisplatin-mediated chemotherapy is still unknown. Here, we found that CCN2 was upregulated in human osteosarcoma cells after treatment with cisplatin. Moreover, overexpression of CCN2 increased the resistance to cisplatin-mediated cell apoptosis. In contrast, reduction of CCN2 by CCN2 shRNA promoted the chemotherapeutic effect of cisplatin. We also found that CCN2 provided resistance to cisplatin-induced apoptosis through upregulation of Bcl-xL and survivin. Knockdown of Bcl-xL or survivin removed the CCN2-mediated resistance to apoptosis induced by cisplatin. On the other hand, CCN2 also promoted FAK, MEK, and ERK survival signaling pathways to enhance tumor survival during cisplatin treatment. In a mouse xenograft model, overexpression of CCN2 promoted resistance to cisplatin. However, knockdown of CCN2 increased the therapeutic effect of cisplatin. Therefore, our data suggest that CCN2 might be a critical oncogene of human osteosarcoma for cisplatin-resistance and supported osteosarcoma cell growth in vivo and in vitro.

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 01/02/2016 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.

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 01/02/2016 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.

Ren W, Sun X, Wang K, et al.
BMP9 inhibits the bone metastasis of breast cancer cells by downregulating CCN2 (connective tissue growth factor, CTGF) expression.
Mol Biol Rep. 2014; 41(3):1373-83 [PubMed] Related Publications
Bone morphogenetic proteins (BMPs), which belong to the transforming growth factor-β superfamily, regulate a wide range of cellular responses including cell proliferation, differentiation, adhesion, migration, and apoptosis. BMP9, the latest BMP to be discovered, is reportedly expressed in a variety of human carcinoma cell lines, but the role of BMP9 in breast cancer has not been fully clarified. In a previous study, BMP9 was found to inhibit the growth, migration, and invasiveness of MDA-MB-231 breast cancer cells. In the current study, the effect of BMP9 on the bone metastasis of breast cancer cells was investigated. After absent or low expression of BMP9 was detected in the MDA-MB-231 breast cancer cells and breast non-tumor adjacent tissues using Western blot and immunohistochemistry, In our previous study, BMP9 could inhibit the proliferation and invasiveness of breast cancer cells MDA-MB-231 in vitro and in vivo. This paper shows that BMP9 inhibit the bone metastasis of breast cancer cells by activating the BMP/Smad signaling pathway and downregulating connective tissue growth factor (CTGF); however, when CTGF expression was maintained, the inhibitory effect of BMP9 on the MDA-MB-231 cells was abolished. Together, these observations indicate that BMP9 is an important mediator of breast cancer bone metastasis and a potential therapeutic target for treating this deadly disease.

Shimomura T, Miyamura N, Hata S, et al.
The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity.
Biochem Biophys Res Commun. 2014; 443(3):917-23 [PubMed] Related Publications
YAP is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes, including proliferation. Hippo pathway-dependent phosphorylation of YAP negatively regulates its function. Conversely, attenuation of Hippo-mediated phosphorylation of YAP increases its ability to stimulate proliferation and eventually induces oncogenic transformation. The C-terminus of YAP contains a highly conserved PDZ-binding motif that regulates YAP's functions in multiple ways. However, to date, the importance of the PDZ-binding motif to the oncogenic cell transforming activity of YAP has not been determined. In this study, we disrupted the PDZ-binding motif in the YAP (5SA) protein, in which the sites normally targeted by Hippo pathway-dependent phosphorylation are mutated. We found that loss of the PDZ-binding motif significantly inhibited the oncogenic transformation of cultured cells induced by YAP (5SA). In addition, the increased nuclear localization of YAP (5SA) and its enhanced activation of TEAD-dependent transcription of the cell proliferation gene CTGF were strongly reduced when the PDZ-binding motif was deleted. Similarly, in mouse liver, deletion of the PDZ-binding motif suppressed nuclear localization of YAP (5SA) and YAP (5SA)-induced CTGF expression. Taken together, our results indicate that the PDZ-binding motif of YAP is critical for YAP-mediated oncogenesis, and that this effect is mediated by YAP's co-activation of TEAD-mediated CTGF transcription.

Ji J, Jia S, Ji K, Jiang WG
Wnt1 inducible signalling pathway protein-2 (WISP‑2/CCN5): roles and regulation in human cancers (review).
Oncol Rep. 2014; 31(2):533-9 [PubMed] Related Publications
Wnt1 inducible signalling pathway protein-2 (WISP‑2), also known as CCN5, CT58, CTGF-L, CTGF-3, HICP and Cop1, is one of the 3 WNT1 inducible proteins that belongs to the CCN family. This family of members has been shown to play multiple roles in a number of pathophysiological processes, including cell proliferation, adhesion, wound healing, extracellular matrix regulation, epithelial-mesenchymal transition, angiogenesis, fibrosis, skeletal development and embryo implantation. Recent results suggest that WISP-2 is relevant to tumorigenesis and malignant transformation, particularly in breast cancer, colorectal cancer and hepatocarcinoma. Notably, its roles in cancer appear to vary depending on cell/tumour type and the microenvironment. The striking difference in the structure of WISP-2 in comparison with the other 2 family members may contribute to its difference in functions, which leads to the hypothesis that WISP-2 may act as a dominant-negative regulator of other CCN family members. In the present review, we summarise the roles, regulation and underlying mechanism of WISP-2 in human cancers.

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.

Lu H, Kojima K, Battula VL, et al.
Targeting connective tissue growth factor (CTGF) in acute lymphoblastic leukemia preclinical models: anti-CTGF monoclonal antibody attenuates leukemia growth.
Ann Hematol. 2014; 93(3):485-92 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Connective tissue growth factor (CTGF/CCN2) is involved in extracellular matrix production, tumor cell proliferation, adhesion, migration, and metastasis. Recent studies have shown that CTGF expression is elevated in precursor B-acute lymphoblastic leukemia (ALL) and that increased expression of CTGF is associated with inferior outcome in B-ALL. In this study, we characterized the functional role and downstream signaling pathways of CTGF in ALL cells. First, we utilized lentiviral shRNA to knockdown CTGF in RS4;11 and REH ALL cells expressing high levels of CTGF mRNA. Silencing of CTGF resulted in significant suppression of leukemia cell growth compared to control vector, which was associated with AKT/mTOR inactivation and increased levels of cyclin-dependent kinase inhibitor p27. CTGF knockdown sensitized ALL cells to vincristine and methotrexate. Treatment with an anti-CTGF monoclonal antibody, FG-3019, significantly prolonged survival of mice injected with primary xenograft B-ALL cells when co-treated with conventional chemotherapy (vincristine, L-asparaginase and dexamethasone). Data suggest that CTGF represents a targetable molecular aberration in B-ALL, and blocking CTGF signaling in conjunction with administration of chemotherapy may represent a novel therapeutic approach for ALL patients.

van Rooyen BA, Schäfer G, Leaner VD, Parker MI
Tumour cells down-regulate CCN2 gene expression in co-cultured fibroblasts in a Smad7- and ERK-dependent manner.
Cell Commun Signal. 2013; 11:75 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: Recent studies have revealed that interactions between tumour cells and the surrounding stroma play an important role in facilitating tumour growth and invasion. Stromal fibroblasts produce most of the extracellular matrix components found in the stroma. The aim of this study was to investigate mechanisms involved in tumour cell-mediated regulation of extracellular matrix and adhesion molecules in co-cultured fibroblasts. To this end, microarray analysis was performed on CCD-1068SK human fibroblast cells after direct co-culture with MDA-MB-231 human breast tumour cells.
RESULTS: We found that the expression of both connective tissue growth factor (CTGF/CCN2) and type I collagen was negatively regulated in CCD-1068SK fibroblast cells under direct co-culture conditions. Further analysis revealed that Smad7, a known negative regulator of the Smad signalling pathway involved in CCN2 promoter regulation, was increased in directly co-cultured fibroblasts. Inhibition of Smad7 expression in CCD-1068SK fibroblasts resulted in increased CCN2 expression, while Smad7 overexpression had the opposite effect. Silencing CCN2 gene expression in fibroblasts led, in turn, to a decrease in type I collagen mRNA and protein levels. ERK signalling was also shown to be impaired in CCD-1068SK fibroblasts after direct co-culture with MDA-MB-231 tumour cells, with Smad7 overexpression in fibroblasts leading to a similar decrease in ERK activity. These effects were not, however, seen in fibroblasts that were indirectly co-cultured with tumour cells.
CONCLUSION: We therefore conclude that breast cancer cells require close contact with fibroblasts in order to upregulate Smad7 which, in turn, leads to decreased ERK signalling resulting in diminished expression of the stromal proteins CCN2 and type I collagen.

Chauhan VP, Martin JD, Liu H, et al.
Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels.
Nat Commun. 2013; 4:2516 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Cancer and stromal cells actively exert physical forces (solid stress) to compress tumour blood vessels, thus reducing vascular perfusion. Tumour interstitial matrix also contributes to solid stress, with hyaluronan implicated as the primary matrix molecule responsible for vessel compression because of its swelling behaviour. Here we show, unexpectedly, that hyaluronan compresses vessels only in collagen-rich tumours, suggesting that collagen and hyaluronan together are critical targets for decompressing tumour vessels. We demonstrate that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production, associated with decreased expression of profibrotic signals TGF-β1, CCN2 and ET-1, downstream of angiotensin-II-receptor-1 inhibition. Consequently, losartan reduces solid stress in tumours resulting in increased vascular perfusion. Through this physical mechanism, losartan improves drug and oxygen delivery to tumours, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Thus, angiotensin inhibitors -inexpensive drugs with decades of safe use - could be rapidly repurposed as cancer therapeutics.

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 L, Chen Z, Wang Y, et al.
TR1 promotes cell proliferation and inhibits apoptosis through cyclin A and CTGF regulation in non-small cell lung cancer.
Tumour Biol. 2014; 35(1):463-8 [PubMed] Related Publications
The Hippo pathway plays a major role in development and organ size control, and its dysregulation contributes to tumorigenesis. WWTR1 is a transcription coactivator acting downstream of the Hippo pathway. Recently, WWTR1 has been reported to be overexpressed in several human cancers including lung cancer. However, the molecular mechanism of WWTR1 regulating lung cancer aggressiveness remains ambiguous. In the present study, we analyzed the expression of WWTR1 in NSCLC cell lines and found that WWTR1 was overexpressed at both the mRNA and protein levels. Knockdown of WWTR1 by siRNA interference in A549 cells significantly inhibited cell proliferation and increased paclitaxel-induced apoptosis. On the other side, WWTR1 overexpression in HBE cell line promoted cell proliferation and inhibited apoptosis. In addition, we found that the decreased proliferation after siRNA treatment was due to cell cycle arrest. Further analysis showed that WWTR1 could induce cyclin A, connective tissue growth factor (CTGF) expression, and inhibit caspase3 cleavage. In conclusion, WWTR1 promotes malignant cell growth and inhibits apoptosis by cyclin A and CTGF regulation.

De Francesco EM, Lappano R, Santolla MF, et al.
HIF-1α/GPER signaling mediates the expression of VEGF induced by hypoxia in breast cancer associated fibroblasts (CAFs).
Breast Cancer Res. 2013; 15(4):R64 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
INTRODUCTION: Carcinoma-associated fibroblasts (CAFs) play a pivotal role in cancer progression by contributing to invasion, metastasis and angiogenesis. Solid tumors possess a unique microenvironment characterized by local hypoxia, which induces gene expression changes and biological features leading to poor outcomes. Hypoxia Inducible Factor 1 (HIF-1) is the main transcription factor that mediates the cell response to hypoxia through different mechanisms that include the regulation of genes strongly associated with cancer aggressiveness. Among the HIF-1 target genes, the G-protein estrogen receptor (GPER) exerts a stimulatory role in diverse types of cancer cells and in CAFs.
METHODS: We evaluated the regulation and function of the key angiogenic mediator vascular endothelial growth factor (VEGF) in CAFs exposed to hypoxia. Gene expression studies, Western blotting analysis and immunofluorescence experiments were performed in CAFs and breast cancer cells in the presence of cobalt chloride (CoCl₂) or cultured under low oxygen tension (2% O₂), in order to analyze the involvement of the HIF-1α/GPER signaling in the biological responses to hypoxia. We also explored the role of the HIF-1α/GPER transduction pathway in functional assays like tube formation in human umbilical vein endothelial cells (HUVECs) and cell migration in CAFs.
RESULTS: We first determined that hypoxia induces the expression of HIF-1α and GPER in CAFs, then we ascertained that the HIF-1α/GPER signaling is involved in the regulation of VEGF expression in breast cancer cells and in CAFs exposed to hypoxia. We also assessed by ChIP assay that HIF-1α and GPER are both recruited to the VEGF promoter sequence and required for VEGF promoter stimulation upon hypoxic condition. As a biological counterpart of these findings, conditioned medium from hypoxic CAFs promoted tube formation in HUVECs in a HIF-1α/GPER dependent manner. The functional cooperation between HIF-1α and GPER in CAFs was also evidenced in the hypoxia-induced cell migration, which involved a further target of the HIF-1α/GPER signaling like connective tissue growth factor (CTGF).
CONCLUSIONS: The present results provide novel insight into the role elicited by the HIF-1α/GPER transduction pathway in CAFs towards the hypoxia-dependent tumor angiogenesis. Our findings further extend the molecular mechanisms through which the tumor microenvironment may contribute to cancer progression.

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.

Xu CM, Liu WW, Liu CJ, et al.
Mst1 overexpression inhibited the growth of human non-small cell lung cancer in vitro and in vivo.
Cancer Gene Ther. 2013; 20(8):453-60 [PubMed] Related Publications
Mammalian STE20-like kinase 1 (Mst1) ubiquitously encodes serine threonine kinase, which is a 59-kDa class II GC kinase that shares 76% identity in amino-acid sequence with MST2, and is the closest mammalian homolog of Drosophila Hippo protein kinase, a major inhibitor of cell proliferation in Drosophila. Recent studies have shown that Mst1 and Mst2 perform tumor-suppressor function in a redundant manner and were originally identified as pro-apoptotic cytoplasmic kinases important for controlling cell growth, proliferation, apoptosis and organ size. We used recombinant eukaryotic expression vector containing human wild-type Mst1 gene to transfect human non-small cell lung cancer (NSCLC) A549 cells in vitro and in vivo. The results showed that Mst1 overexpression inhibited cell proliferation and induced apoptosis of A549 cells, promoted Yes-associated protein (YAP) (Ser127) phosphorylation and downregulated the transcriptional level of Cystein-rich protein connective tissue growth factor (CTGF), amphiregulin (AREG) and Survivin. In human NSCLC-cell-A549-xenograft models, Mst1 gene or cisplatin alone suppressed the growth of tumors and increased the cytoplasm-positive expression levels of YAP and Phospho-YAP (Ser127) proteins; however, their combination had the strongest anticancer effects. Overall, Mst1 has an important role in inhibiting the growth of NSCLC in vitro and in vivo; its antiproliferative effect is associated with induction of apoptosis through promotion of the cytoplasmic localization and phosphorylation of YAP protein at Ser127 site, indicating that Mst1 may be developed as a promising therapeutic target for NSCLC.

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