Hepatitis B virus X protein induces RHAMM-dependent motility in hepatocellular carcinoma cells via PI3K-Akt-Oct-1 signaling

Chronic hepatitis B virus (HBV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC), which represents one of the most common cancers worldwide. Recent studies suggest that HBV's protein X (HBx) plays a crucial role in HCC development and progression. Earlier, genome-wide analysis identified that the receptor for hyaluronan-mediated motility (RHAMM) represents a putative oncogene and is overexpressed in many human cancers, including HCC. However, the mechanism underlying RHAMM upregulation and its role in tumorigenesis remain unclear. Here, we show that ectopic expression of HBx activates the PI3K/Akt/Oct-1 pathway and upregulates RHAMM expression in HCC cells. HBx overexpression leads to dissociation of C/EBPβ from the RHAMM gene promoter, thereby inducing RHAMM upregulation. RHAMM knockdown attenuates HBx induced cell migration and invasion in vitro. In mice, HBx promotes cancer cell colonization via RHAMM upregulation, resulting in enhanced metastasis. Analysis of gene expression datasets reveals that RHAMM mRNA level is upregulated in patients with HCC with poor prognosis.