Our research is centered on hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatocellular carcinoma (HCC). HBV and HCV are two important pathogens that can both cause severe liver diseases including hepatitis, liver cirrhosis and HCC. Approximately 2 billion people in the world had been exposed to these two viruses and nearly 500 million people are chronic carriers of either one of these two viruses or sometimes both. The following is a summary of our current research interests:


  1. Hepatitis B Virus

HBV We are interested in understanding the molecular and cellular biology of this virus and how it replicates and establishes chronic infection in patients. Our recent studies indicated that HBV could induce autophagy to stimulate its own replication, and this effect of autophagy on HBV was at the step of viral DNA replication. We had also discovered that interferons could stimulate HBV gene expression when viral load was low, and suppress HBV replication when viral load was high. This raised the possibility that HBV might use the host interferon response to stimulate its own replication in the early stage of viral infection to enhance its spread. We had also developed mouse models to study how HBV establishes persistent infection after the vertical transmission of the virus from the mother to her children. We found that the maternal HBV e antigen (HBeAg) could condition the Kupffer cells of the offspring to suppress the HBV-specific CD8+ T cell activity, resulting in HBV persistence in the offspring. We are currently trying to understand how maternal HBeAg conditions Kupffer cells.


  1. Hepatitis C Virus

hcvOur research on HCV is centered on the HCV-host interactions. We found that the binding of HCV to its receptor CD81 and claudin-1 could activate the PI3K-AKT signaling pathway to enhance viral entry. We also found that hepatocytes in response to HCV infection could produce tumor necrosis factor α (TNF-α) via toll-like receptors 7 and 8. TNF-α thus produced was required to support type I interferon signaling in HCV-infected cells, as in the absence of TNF-α, the type I interferon receptor IFNAR2 would be depleted by HCV. We also discovered that HCV could induce the endoplasmic reticulum (ER) stress and the unfolded protein response to perturb the autophagic pathway. We also found that HCV could temporally regulate the maturation of autophagosomes and use autophagosomal membranes as the platform for its RNA replication, and that HCV could use autophagy to deplete TRAF6, an important signaling molecule that mediates the production of pro-inflammatory cytokines. We are currently further investigating the relationship between HCV and autophagy to understand how HCV controls this important cellular pathway for its own replication.


  1. Mechanisms of Hepatocarcinogenesis

mechanisms-of-hepatocarcinogenesisHBV and HCV are responsible for approximately 8 0% of the hepatocellular carcinoma (HCC) incidence in the world. We had studied the mechanism of HBV-induced hepatocarcinogenesis and found that HBV could perturb the redox status in hepatocytes and sensitize hepatocytes to oxidative DNA damage and hepatocarcinogenesis. We also found that HCV could impair oxidative DNA-damage repair in hepatocytes. More recently, we also discovered that autophagy played dual roles in hepatocarcinogenesis. We found that autophagy could suppress the initiation of hepatocarcinogenesis by removing dysfunctional mitochondria to reduce oxidative stress and DNA damage. However, we also found that once hepatocarcinogenesis had been initiated, autophagy was also required for the progression of benign hepatic tumors into malignant HCC, due to the need of autophagy to suppress the expression of tumor suppressors, maintain the population of hepatic cancer stem cells, enhance cellular proliferation and alleviate metabolic stress.