HAb18G/CD147 promotes activation of hepatic stellate cells and is a target for antibody therapy of liver fibrosis

• Published in: Journal of hepatology Vol. 57; no. 6; pp. 1283 - 1291
• Main Authors: Zhang, Da-Wei, Zhao, You-Xu, Wei, Ding, Li, Ya-Lin, Zhang, Yang, Wu, Jiao, Xu, Jing, Chen, Changsheng, Tang, Hao, Zhang, Wei, Gong, Li, Han, Ying, Chen, Zhi-Nan, Bian, Huijie
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.12.2012; Elsevier
• Subjects: Animals; Antibody; Apoptosis; Basigin - physiology; Biological and medical sciences; Carbon Tetrachloride - metabolism; Carbon Tetrachloride - toxicity; Cell Line; EMMPRIN; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Hepatic Stellate Cells - physiology; Humans; Liver cirrhosis; Liver Cirrhosis - etiology; Liver Cirrhosis - therapy; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Mice; Mice, Inbred BALB C; Myofibroblasts; Other diseases. Semiology; TGF-β1; Transforming Growth Factor beta1 - physiology; ALAT; IHC; Antibody; HCC; snc-RNA; EMT; ECM; MMP; α-SMA; FITC; ECOD; HTNV; CYP450; CCl4; TGF-β1; EMMPRIN; HSCs; Myofibroblasts; HBV; Liver cirrhosis; TIMP; 7-ethoxycoumarin O-deethylase; α-smooth muscle actin; hepatitis B virus; alanine aminotransferase; extracellular matrix metalloproteinase inducer; Hantan virus; silencer-negative control siRNA; transforming growth factor-β1; immunohistochemistry; fluorescein isothiocyanate; hepatocellular carcinoma; epithelial–mesenchymal transition; hepatic stellate cells; carbon tetrachloride; cytochrome P450; CCl 4; tissue inhibitor of metalloproteinase; matrix metalloproteinase; extracellular matrix; Spider cell; Hepatic fibrosis; Targeted therapy; Liver; Myofibroblast; Hepatic disease; Activation; Cirrhosis; Treatment; Gastroenterology; Digestive diseases
• ISSN: 0168-8278; 1600-0641; 1600-0641
• DOI: 10.1016/j.jhep.2012.07.042

Activated hepatic stellate cells (HSCs) located in the Disse’s space play a crucial role in liver fibrosis. HAb18G/CD147, a tumor-related glycoprotein, is highly expressed in hepatocellular carcinoma cells and fibroblasts. Whether HAb18G/CD147 plays an important role in the hepatic fibrogenesis is unknown. Immunohistochemistry for HAb18G/CD147 and α-smooth muscle actin expression in diseased liver tissues was used for correlation analysis. The function of HAb18G/CD147 in fibrogenesis was evaluated with the human HSCs LX-2 cell line and carbon tetrachloride-induced mouse liver fibrosis model. The specific antibody HAb18 targeting HAb18G/CD147 was injected intravenously into the mouse to investigate whether HAb18G/CD147 could be a potential target for liver fibrosis treatment. HAb18G/CD147 is highly expressed on activated HSCs in the sinusoid. The positive rates of HAb18G/CD147 expression in human HBV-related liver cirrhosis, liver biopsy with HBV and liver adjacent to hemangioma were 95.6% (65/68), 14.8% (8/54) and 6.4% (8/125), respectively. HAb18G/CD147 expression was significantly correlated with the Child–Pugh grade (r=0.2848, p=0.0186) and with the expression of α-smooth muscle actin in HSCs (r=0.4434, p=0.0002) in liver cirrhosis. Transforming growth factor-β1 upregulated HAb18G/CD147 expression in LX-2 cells. Transfection of HAb18G/CD147 promoted the profibrogenic genes expression. In mouse liver fibrosis model, HAb18G/CD147 expression increased with the development of fibrogenesis and decreased during the liver fibrosis spontaneous recovery. The HAb18 targeting HAb18G/CD147 could attenuate liver fibrosis. These data suggest that HAb18G/CD147 plays a role in HSC activation and is a potential therapeutic target in fibrosis/cirrhosis.