Connective Tissue Growth Factor Is Overexpressed in Esophageal Squamous Cell Carcinoma and Promotes Tumorigenicity through β-Catenin-T-cell Factor/Lef Signaling

Deng, Yue; Chen, Ping Ping; Wang, Yan; Ding, Yin; Koeffler, H. Phillip; Li, Baojie; Xiang, Tong; Xie, Dong

doi:10.1074/jbc.m704141200

Cited by 112 publications

(112 citation statements)

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“…CTGF can directly bind to cell surface integrin complexes thus activating ILK signaling (13,14). CTGF can also directly bind to LRP5/6, coreceptors of Wnt (15,16). Activation of ILK and LRP5/6 can lead to nuclear translocation of β-catenin and subsequent activation of target gene transcription.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, we have also found that CTGFinduced lung pathology is associated with activation of β-catenin signaling, whereas treatment with CTGF antibody inhibits hyperoxia-activated β-catenin signaling. It is known that CTGF can activate β-catenin signaling by binding to cell surface integrins and lipoprotein receptor-related protein (LRP) 5/6, coreceptors of wingless/Int (Wnt) (13)(14)(15)(16). It is unknown, however, whether activation of β-catenin signaling mediates CTGF-induced alveolar and vascular pathology in neonatal mice.…”

Section: Introductionmentioning

confidence: 97%

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Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

et al. 2016

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Background: Bronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease of premature infants. Connective tissue growth factor (CTGF) plays an important role in tissue development and remodeling. We have previously shown that targeted overexpression of CTGF in alveolar type II epithelial cells results in BPD-like pathology and activates β-catenin in neonatal mice. Methods: Utilizing this transgenic mouse model and ICG001, a specific pharmacological inhibitor of β-catenin, we tested the hypothesis that β-catenin signaling mediates the effects of CTGF in the neonatal lung. Newborn CTGF mice and control littermates received ICG001 (10 mg/kg/dose) or placebo (dimethyl sulfoxide, equal volume) by daily i.p. injection from postnatal day 5 to 15. Alveolarization, vascular development, and pulmonary hypertension (PH) were analyzed. results: Administration of ICG001 significantly downregulated expression of cyclin D1, collagen 1a1, and fibronectin, which are the known target genes of β-catenin signaling in CTGF lungs. Inhibition of β-catenin signaling improved alveolar and vascular development and decreased pulmonary vascular remodeling. More importantly, the improved vascular development and vascular remodeling led to a decrease in PH. conclusion: β-Catenin signaling mediates the autocrine and paracrine effects of CTGF in the neonatal lung. Inhibition of CTGF-β-catenin signaling may provide a novel therapy for BPD. INTRODUCTIONBronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease of premature infants (1). Over the past four decades, the incidence of this disease has significantly increased as a result of improved survival of extremely-low-birthweight infants (2). The pathology of BPD is increasingly being recognized as a developmental arrest of the immature lung caused by injurious stimuli such as mechanical ventilation, oxygen exposure, and intrauterine or postnatal infections. Larger and simplified alveoli, decreased vascular growth, and variable interstitial fibrosis are the key pathological features observed in lungs of infants who died of BPD (1). The combination of decreased vascular growth and excessive pulmonary vascular remodeling leads to pulmonary hypertension (PH) which significantly contributes to the morbidity and mortality of these infants (3). Yet, the underlying cellular and molecular mechanisms are poorly defined, and there is no effective therapy.Connective tissue growth factor (CTGF) is a matricellular protein that plays an important role in tissue development and remodeling (4). Recent studies have highlighted the potential role of CTGF in BPD development and progression. The clinical association of CTGF with BPD is best established by studies demonstrating increased CTGF concentrations in bronchoalveolar lavage fluid from preterm infants developing BPD (5) and increased CTGF expression in lung tissues of infants who died of BPD (6). Multiple studies have examined the potential role of CTGF in experimental BPD and demonstrated that increased CTG...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

et al. 2016

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“…The primer pairs used for real-time PCR are as follows: ephrinA5: F: 5 0 -GCAATCCCAGATAATGGAAGAA-3 0 , R: 5 0 -TCGGCT GACTCATGTACGGT-3 0 ; EGFR: F: 5 0 -CGGGACATAGT CAGCAGTG-3 0 , R: 5 0 -GCTGGGCACAGATGATTTTG-3 0 ; b-actin: F: 5 0 -GATCATTGCTCCTCCTGAGC-3 0 , R: 5 0 -ACTCCTGCTTGCTGATCCAC-3 0 . Amplification reactions were performed as described earlier (Deng et al, 2007).…”

Section: Antibodies and Reagentsmentioning

confidence: 99%

EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor

et al. 2009

Oncogene

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Eph receptors, the largest subfamily of receptor tyrosine kinases, and their ephrin ligands play important roles in nervous system development. Recently, they have been implicated in tumorigenesis of different cancers. In this study, we showed that the expression of ephrinA5 was dramatically downregulated in primary gliomas compared with normal tissues. Forced expression of ephrinA5 reduced tumorigenicity of human glioma U373 cells. Epidermal growth factor receptor (EGFR), which frequently acts as an oncoprotein in glioma, was greatly decreased in ephrinA5-transfected glioma cells, and the two molecules exhibited a mutually exclusive expression pattern in primary glioma samples. We found that ephrinA5 enhanced c-Cbl binding to EGFR, thus promoted ubiquitylation and degradation of the receptor. Either ephrinA5-Fc or EphA2-Fc treatment simulating bidirectional signaling of Eph/ephrin system resulted in EGFR decrease. This study discovered that ephrinA5 acted as a tumor suppressor in glioma, and its negative regulation of EGFR contributed to the suppressive effects. In addition to identifying a novel mechanism underlying tumor suppressor activity of ephrinA5, we also showed cross-talk between different receptor tyrosine kinase families in glioma. These findings may improve therapeutic strategies for glioma.

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“…Briefly, triplicate plates of cells were trypsinized and stained with Trypan blue, and unstained cells were counted using a haemocytometer. Colony-survival assay was performed as previously described 46 . Briefly, cells were seeded sparsely (2,000 cells per well for 6-well plates, 1,000 cells per well for 12-well plates) and were grown for 10 days with normal medium.…”

Section: Methodsmentioning

confidence: 99%

BCLAF1 and its splicing regulator SRSF10 regulate the tumorigenic potential of colon cancer cells

et al. 2014

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Bcl-2-associated transcription factor 1 (BCLAF1) is known to be involved in multiple biological processes. Although several splice variants of BCLAF1 have been identified, little is known about how BCLAF1 splicing is regulated or the contribution of alternative splicing to its developmental functions. Here we find that inclusion of alternative exon5a was significantly increased in colorectal cancer (CRC) samples. Knockdown of the BCLAF1 protein isoform resulting from exon5a inclusion inhibited growth and that its overexpression increased tumorigenic potential. We also found that the splicing factor SRSF10 stimulates inclusion of exon5a and has growth-inducing activity. Importantly, the upregulation of SRSF10 expression observed in clinical CRC samples parallels the increased inclusion of BCLAF1 exon5a, both of which are associated with higher tumour grade. These findings identify SRSF10 as a key regulator of BCLAF1 pre-mRNA splicing and the maintenance of oncogenic features in human colon cancer cells.

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Connective Tissue Growth Factor Is Overexpressed in Esophageal Squamous Cell Carcinoma and Promotes Tumorigenicity through β-Catenin-T-cell Factor/Lef Signaling

Cited by 112 publications

References 44 publications

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

Inhibition of β-catenin signaling protects against CTGF-induced alveolar and vascular pathology in neonatal mouse lung

EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor

BCLAF1 and its splicing regulator SRSF10 regulate the tumorigenic potential of colon cancer cells

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