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

The hepatitis B virus X protein (HBx) of the hepatitis B virus (HBV) has be en involved in the development of hepatocellular carcinoma (HCC). However, its possible contribution to the metastatic spreading of liver tumors has n ot 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 mi gratory phenotype in transformed cells. HBx altered the cellular morphology by inducing the formation of pseudopodial protrusions and cytoskeletal rea rrangements, which was accompanied by the polarization of cell-surface adhe sion 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-depende nt 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-CD-44 monoclonal antibody (mAb), suggesting that the HBx-ind uced cell motility is partially mediated by CD44. Interestingly, HBx-bearin g cells showed increased HA-interaction efficiency as assessed under lamina r flow conditions, which was the result, at least in part, of an enhanced b inding affinity of CD44. HBx may therefore contribute to the acquisition of metastatic properties by modifying the migratory behavior of transformed h epatocytes and by increasing their ability to bind KA in the outer margin o f the tumors or in secondary target organs.