Role of hepatitis C virus induced osteopontin in epithelial to mesenchymal transition, migration and invasion of hepatocytes

• Published in: PloS one Vol. 9; no. 1; p. e87464
• Main Authors: Iqbal, Jawed, McRae, Steven, Mai, Thi, Banaudha, Krishna, Sarkar-Dutta, Mehuli, Waris, Gulam
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 31.01.2014; Public Library of Science (PLoS)
• Subjects: Activation; AKT protein; Angiogenesis; Biocompatibility; Biology; Biology and Life Sciences; Boyden chamber; Cancer; Cancer metastasis; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - virology; CD44 antigen; Cell adhesion & migration; Cell culture; Cell surface; Chronic infection; Cytokines; Development and progression; E-cadherin; Epithelial-Mesenchymal Transition; Focal adhesion kinase; Gene expression; Gene Expression Regulation, Neoplastic; Health aspects; Hep G2 Cells; Hepacivirus - metabolism; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatitis C, Chronic - metabolism; Hepatitis C, Chronic - pathology; Hepatocellular carcinoma; Hepatocytes; Hepatocytes - metabolism; Hepatocytes - pathology; Hepatocytes - virology; Humans; Hyaluronan Receptors; Hypoxia; Immunology; Infection; Infections; Inflammation; Integrins; Kinases; Laboratories; Liver; Liver cancer; Liver diseases; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver Neoplasms - virology; Medical research; Medical schools; Medicine; Medicine and Health Sciences; Mesenchyme; Metastases; Metastasis; mRNA; N-Cadherin; Neoplasm Proteins - biosynthesis; Osteopontin; Osteopontin - biosynthesis; Oxidative stress; Pathogenesis; Phosphorylation; Proteins; Research and Analysis Methods; RNA; Rodents; Science; Signal Transduction; Signaling; Stem cells; Studies; Tumors; Viruses; Wound healing; United States > US; North Chicago Illinois; Illinois
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0087464

Osteopontin (OPN) is a secreted phosphoprotein which has been linked to tumor progression and metastasis in a variety of cancers including hepatocellular carcinoma (HCC). Previous studies have shown that OPN is upregulated during liver injury and inflammation. However, the role of OPN in hepatitis C virus (HCV)-induced liver disease pathogenesis is not known. In this study, we determined the induction of OPN, and then investigated the effect of secreted forms of OPN in epithelial to mesenchymal transition (EMT), migration and invasion of hepatocytes. We show the induction of OPN mRNA and protein expression by HCV-infection. Our results also demonstrate the processing of precursor OPN (75 kDa) into 55 kDa, 42 kDa and 36 kDa forms of OPN in HCV-infected cells. Furthermore, we show the binding of secreted OPN to integrin αVβ3 and CD44 at the cell surface, leading to the activation of downstream cellular kinases such as focal adhesion kinase (FAK), Src, and Akt. Importantly, our results show the reduced expression of epithelial marker (E-cadherin) and induction of mesenchymal marker (N-cadherin) in HCV-infected cells. We also show the migration and invasion of HCV-infected cells using wound healing assay and matrigel coated Boyden chamber. In addition, we demonstrate the activation of above EMT markers, and the critical players involved in OPN-mediated cell signaling cascade using primary human hepatocytes infected with Japanese fulminant hepatitis (JFH)-1 HCV. Taken together, these studies suggest a potential role of OPN in inducing chronic liver disease and HCC associated with chronic HCV infection.