Regulation of hepatic stellate cells by connective tissue growth factor.
ABSTRACT Connective tissue growth factor (CTGF/CCN2) regulates cell proliferation, differentiation, adhesion, chemotaxis, migration, apoptosis and extracellular matrix production. Through these diverse actions, CTGF/CCN2 plays a major role in important physiological and pathophysiological processes such as embryogenesis, implantation, angiogenesis, chondrogenesis, tumorigenesis, differentiation, wound healing and fibrosis. Whereas hepatic levels of CTGF/CCN2 are usually low, elevated levels of hepatic CTGF/CCN2 occur in patients with liver fibrosis and in experimental animal models of liver fibrosis. In fibrotic liver, CTGF/CCN2 is produced by multiple cell types but its sustained expression by and action on hepatic stellate cells is particularly important because these cells assume an activated phenotype during fibrosing injury and are principally responsible for the excessive production of fibrillar collagens, a process that is driven by CTGF/CCN2. Through its direct actions and interactions with other molecules such as fibronectin or transforming growth factor beta-1, CTGF/CCN2 promotes proliferation, survival, migration, adhesion, and extracellular matrix production in activated hepatic stellate cells, thereby promoting hepatic fibrogenic pathways. This review focuses on the regulation of hepatic stellate cell function by CTGF/CCN2.
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ABSTRACT: To determine the expression characteristics of connective tissue growth factor (CTGF/CCN2) in human hepatocellular carcinoma (HCC) in histology and to elucidate the roles of CCN2 on hepatoma cell cycle progression and metastasis in vitro. Liver samples from 36 patients (who underwent hepatic resection for the first HCC between 2006 and 2011) and 6 normal individuals were examined for transforming growth factor β1 (TGF-β1) or CCN2 mRNA by in situ hybridization. Computer image analysis was performed to measure integrated optimal density of CCN2 mRNA-positive cells in carcinoma foci and the surrounding stroma. Fibroblast-specific protein-1 (FSP-1) and E-cadherin were examined to evaluate the process of epithelial to mesenchymal transition, α-smooth muscle actin and FSP-1 were detected to identify hepatic stellate cells, and CD34 was measured to evaluate the extent of vascularization in liver tissues by immunohistochemical staining. CCN2 was assessed for its stimulation of HepG2 cell migration and invasion using commercial kits while flow cytometry was used to determine CCN2 effects on HepG2 cell-cycle. In situ hybridization analysis showed that TGF-β1 mRNA was mainly detected in connective tissues and vasculature around carcinoma foci. In comparison to normal controls, CCN2 mRNA was enhanced 1.9-fold in carcinoma foci (12.36 ± 6.08 vs 6.42 ± 2.35) or 9.4-fold in the surrounding stroma (60.27 ± 28.71 vs 6.42 ± 2.35), with concomitant expression of CCN2 and TGF-β1 mRNA in those areas. Epithelial-mesenchymal transition phenotype related with CCN2 was detected in 12/36 (33.3%) of HCC liver samples at the edges between carcinoma foci and vasculature. Incubation of HepG2 cells with CCN2 (100 ng/mL) resulted in more of the cells transitioning into S phase (23.85 ± 2.35 vs 10.94 ± 0.23), and induced a significant migratory (4.0-fold) and invasive (5.7-fold) effect. TGF-β1-induced cell invasion was abrogated by a neutralizing CCN2 antibody showing that CCN2 is a downstream mediator of TGF-β1-induced hepatoma cell invasion. These data support a role for CCN2 in the growth and metastasis of HCC and highlight CCN2 as a potential novel therapeutic target.World Journal of Gastroenterology 12/2012; 18(47):7070-8. · 2.55 Impact Factor
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ABSTRACT: Wound healing, cardiac fibrosis, and infarct scar development, while possessing distinct features, share a number of key functional similarities, including extracellular matrix synthesis and remodeling by fibroblasts and myofibroblasts. Understanding the underlying mechanisms that are common to these processes may suggest novel therapeutic approaches for pathologic situations such as fibrosis, or defective wound healing such as hypertrophic scarring or keloid formation. This manuscript will briefly review the major steps of wound healing, and will contrast this process with how cardiac infarct scar formation or interstitial fibrosis occurs. The feasibility of targeting common pro-fibrotic growth factor signaling pathways will be discussed. Finally, the potential exploitation of novel regulators of wound healing and fibrosis (ski and scleraxis), will be examined.Fibrogenesis & Tissue Repair 11/2012; 5(1):19.