[show abstract][hide abstract] ABSTRACT: Hepatitis B virus X protein (HBx) plays an important role in the development of hepatocellular carcinoma (HCC). However, the mechanism remains unclear. Recently, we have reported that HBx promotes hepatoma cell migration through the upregulation of calpain small subunit 1 (Capn4). In addition, several reports have revealed that osteopontin (OPN) plays important roles in tumor cell migration. In this study, we investigated the signaling pathways involving the promotion of cell migration mediated by HBx. We report that HBx stimulates several factors in a network manner to promote hepatoma cell migration. We showed that HBx was able to upregulate the expression of osteopontin (OPN) through 5-lipoxygenase (5-LOX) in HepG2-X/H7402-X (stable HBx-transfected cells) cells. Furthermore, we identified that HBx could increase the expression of 5-LOX through nuclear factor-κB (NF-κB). We also found that OPN could upregulate Capn4 through NF-κB. Interestingly, we showed that Capn4 was able to upregulate OPN through NF-κB in a positive feedback manner, suggesting that the OPN and Capn4 proteins involving cell migration affect each other in a network through NF-κB. Importantly, NF-κB plays a crucial role in the regulation of 5-LOX, OPN and Capn4. Thus, we conclude that HBx drives multiple cross-talk cascade loops involving NF-κB, 5-LOX, OPN and Capn4 to promote cell migration. This finding provides new insight into the mechanism involving the promotion of cell migration by HBx.
PLoS ONE 01/2012; 7(2):e31458. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hepatitis B virus (HBV) X (HBx) gene multi-site mutations are a frequent event in the clinical hepatocellular carcinoma (HCC) tissues. It has been reported that the mutation of the HBx plays a crucial role in the development of HBV-related HCC. To identify the novel mutations of HBx in the HCC tissues, we examined and analyzed the sequences of HBx gene in 60 cases of HCC tumor tissues and paratumor tissues from China by polymerase chain reaction (PCR). The mutation patterns of HBx were analyzed by comparing the tumor tissues with non-tumor tissues. The data showed that 44 cases of tissues out of 60 patients were HBV-positive. Our results showed that the mutations at amino acid 30, 88, 144 from tumor samples and at amino acid 31, 43, 87, 94 from non-tumor samples were highly frequent events. Interestingly, we found that a novel type of HBx linked-mutations, such as at aa L30F/S144A, was 29.5% (13/44) positive in the tumor tissues. However, the role of HBx gene mutations at aa L30F/S144A relative to wild type HBx gene is unclear in hepatocarcinogenesis. The novel HBx linked-mutations may be significant in the development of HCC.