br Discussion Using HBV transgenic mice Kim et al

Discussion Using HBV transgenic mice, Kim, et al. first reported that the HBx gene caused HCC [34]. Since then, transgenic mice have become a useful experimental model for defining the molecular events of HBV hepatitis, and HBV-related hepatocarcinogenesis. In the present study, we first confirmed viral persistence in the mice, which was reflected by positive expression of HBV mRNA and viral proteins (HBsAg+, HBeAg+). Chronic HBV infection in patients is associated with chronic hepatitis and liver fibrosis, which is characterized by leukocyte infiltration and collagen deposition in portal/periportal regions of the liver [35]. Attack towards liver by HBV virus will lead to its damage. Fibrosis represents early damage in the liver while cirrhosis is resulted from severe damage with scar in the liver tissue. In this model, liver injury and degeneration, including elevated serum ALT and AST levels, ballooning of hepatocytes, fatty changes, fibrosis, inflammation and hyperplastic nodules were noticeable in the late stage of HBV-mediated liver pathogenesis (around 10 months of age). Importantly, we also observed different responses of oval cells and hepatocytes upon HBV infections at the cellular and molecular level. To the best of our knowledge, this is the first report to identify oval cell activation induced by HBV expression in rodent model. We believe oval cells activation may be involved in HBV induced pathogenesis and carcinogenesis. The HBV x protein (HBx) is involved in numerous biological progresses by either interacting with cellular proteins or serving as a coactivator for various transcription factors [36]. For example, HBx is preferentially recruited to the promoters or distal enhancers of certain genes which contain consensus Erismodegib australia for NFĸB, AP1 and CREB [36]. Here, we found that HBV had minimal effects on the apoptosis of oval cells while induced higher levels of cell death of hepatocytes. On the contrary, a higher proliferation rate was observed in oval cells compared to hepatocytes in HBV transgene mice. The possible explanation is that the HBx binding transcription factors are differentially expressed between oval cells and hepatocytes so that the participation of HBx into transcriptional regulation or signaling transduction varies in these two types of cells. In addition, HBV DNA integration into genome also causes dysregulation of gene expression which is attributable to the interruption of gene transcription resulted from the insertion of HBV DNA into the active transcriptional sites. The difference on the accessibility of HBV DNA into the chromatin between oval cells and normal hepatocytes probably results in different molecular responses, leading to the differential response of oval cells and hepatocytes upon HBV infection. The active response of oval cells indicates that they can survive from HBV-induced injury and persist for a sufficient length of time to acquire genetic alterations for neoplastic development. HBV related diseases is a complex disease with a multi-step process from preneoplastic lesions. Although we failed to detect the HCC in this model, precancerous lesion and hyperplastic nodules were present in livers expressing HBV. So we deemed this model is a valuable tool to explore the underlying molecular mechanisms of HBV-induced hepatitis, cirrhosis and liver tumors. To our knowledge, the molecular pathogenesis of HCC development resulted from simple investigation of liver tissues in rodent models and few genetic alterations within various cell types were explored in the liver upon HBV infection, mainly because of difficulties associated with the isolation and culture of primary adult oval cells. In this manuscript, we successfully isolated and cultured primary adult oval cells from both HBV transgenic mice and healthy controls, which guaranteed us to explore the molecular changes of oval cells after HBV infection. Interestingly, we found there is differential regulation of certain genes between oval cells and hepatocytes in response to HBV infection, suggesting some genes may serve as new progenitor markers or therapeutic targets for oval cells. For instance, our data showed that the TNF, EGF, IFNα, IL6, PPAR, and TGF-β signal pathways were deregulated in HBV-infected oval cells, which was consistent with the results from the previous study [37]. Therefore, inhibitors specific to these pathways may be an ideal treatments for HCC development.