The hepatitis B virus X protein (HBx) induces a migratory phenotype in a CD44-dependent manner: Possible role of HBx in invasion and metastasis

• Published in: Hepatology (Baltimore, Md.) Vol. 33; no. 5; pp. 1270 - 1281
• Main Authors: Lara-Pezzi, Enrique, Serrador, Juan M., Montoya, Marı́a C., Zamora, David, Yáñez-Mó, Marı́a, Carretero, Marta, Furthmayr, Heinz, Sánchez-Madrid, Francisco, López-Cabrera, Manuel
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Elsevier Inc 01.05.2001; W.B. Saunders; Wiley
• Subjects: Actins - metabolism; Adaptor Proteins, Signal Transducing; Biological and medical sciences; Carrier Proteins - metabolism; Carrier Proteins - pharmacology; Carrier Proteins - physiology; Cell Adhesion Molecules - metabolism; Cell Membrane - metabolism; Cell Movement - drug effects; Cell Movement - physiology; Cell Polarity - physiology; Cytoskeleton - ultrastructure; Gastroenterology. Liver. Pancreas. Abdomen; HeLa Cells - cytology; HeLa Cells - ultrastructure; Humans; Hyaluronan Receptors - physiology; Hyaluronic Acid - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Neoplasm Invasiveness - physiopathology; Neoplasm Metastasis - physiopathology; Phenotype; Pseudopodia - metabolism; rho GTP-Binding Proteins - physiology; Tissue Distribution - drug effects; Tumors; Viral Nonstructural Proteins - pharmacology; Viral Nonstructural Proteins - physiology; Human; Pathogenesis; Migration; Hepatic disease; Hepatocellular carcinoma; Malignant tumor; Metastasis; Experimental study; Infection; Viral hepatitis B; Cell line; Viral disease; Digestive diseases; Complication; Mechanism of action; Tumor cell
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1053/jhep.2001.1270

The hepatitis B virus X protein (HBx) of the hepatitis B virus (HBV) has been involved in the development of hepatocellular carcinoma (HCC). However, its possible contribution to the metastatic spreading of liver tumors has not been explored so far. We report here the ability of HBx to enhance cell motility, both alone and in synergy with growth factors, and to induce a migratory phenotype in transformed cells. HBx altered the cellular morphology by inducing the formation of pseudopodial protrusions and cytoskeletal rearrangements, which was accompanied by the polarization of cell-surface adhesion molecules, including the hyaluronan (HA) receptor, CD44. Furthermore, HBx induced the redistribution to the pseudopodial tips of F-actin–binding proteins of the ezrin/radixin/moesin (ERM) family in a Rho- and Rac-dependent manner and increased the association of CD44 with moesin. The migration of HBx-bearing cells in response to HA and growth factors was impaired by a blocking anti-CD44 monoclonal antibody (mAb), suggesting that the HBx-induced cell motility is partially mediated by CD44. Interestingly, HBx-bearing cells showed increased HA-interaction efficiency as assessed under laminar flow conditions, which was the result, at least in part, of an enhanced binding affinity of CD44. HBx may therefore contribute to the acquisition of metastatic properties by modifying the migratory behavior of transformed hepatocytes and by increasing their ability to bind HA in the outer margin of the tumors or in secondary target organs. (HEPATOLOGY 2001;33:1270-1281.)