Updated July 22, 2008

Xin Wei Wang, Ph.D.
Head of Liver Carcinogenesis Section
Senior Investigator

Biography:

Dr. Wang grew up in Shanghai, China where he received a Bachelor's degree from Shanghai First Medical College in 1982 and a Master's degree from Chinese Academia of Science in 1984. He moved to United States in mid-80 and attended New York University School of Medicine for his Ph.D. studies under the guidance of Dr. Max Costa. He joined Dr. Michael Newman's group at Roche Institute of Molecular Biology and subsequently Dr. Curtis Harris' group at NCI for his post-doctoral fellowships. He was recruited to NCI as a tenure track investigator in 1998 and was subsequently promoted as a tenured Senior Investigator in 2005. Dr. Wang is an internationally recognized researcher on cancer genetics and genomics studies, particularly on liver cancer. He has published over 97 peer-reviewed manuscripts and book chapters, and has been frequently invited to give lectures both nationally and internationally. He serves on many scientific committees and provides numerous editorial services and grant reviews.

Research Program and Goals:

Our laboratory is interested in studying genetics, genomics and biochemical pathways related to human cancers. We are exploring molecular mechanisms related to gastroenterological malignancies including liver cancer, metastatic gastric cancer and colorectal cancer to determine molecular events critical to tumor initiation and progression. Human hepatocellular carcinoma (HCC) has been extensively explored as a model system to examine tumor evolution cascade. We are interested in tumor initiation, progression/metastasis and cellular origins of HCC including cancer stem cells. For example, we are using the state-of-the-art technologies to determine global genomic and transcriptomic profiles including mRNA and microRNA that are unique to different stages of HCC attributed to hepatitis B and C viruses. The overall aims of our research are to learn how cancer cells initiate and metastasize, and to identify biomarkers that are helpful for early diagnosis and molecular targets for effective therapeutic intervention.

Current Research Projects:

1. Molecular profiling of human hepatocarcinogenesis:

Identification of molecular fingerprints is a vital step in helping to elucidate the molecular mechanisms of human cancer and to provide molecular diagnostic tools to guild individualized care for patients with cancer. Our strategy is to identify cellular genes that are commonly changed by the expression of HBV or HCV in primary human hepatocytes, preneoplastic chronic liver diseases and hepatocellular carcinoma. We have used microarray, and have identified several candidate genes that may play a role in initiating liver cancer. By comparing liver samples from chronic liver disease patients with varying degrees of risk for developing hepatocellular carcinoma, we have identified unique fingerprints that may be useful in diagnosing patients with liver cancer (Kim et al, Hepatology 2004). By comparing hepatocellular carcinoma with or without accompanying metastasis, we have identified a molecular signature that can be used to predict liver cancer patients with potential to develop metastasis or recurrence (Ye et al, Nature Medicine 2003). We have also identified several potential therapeutic targets that can be used to eliminate liver cancer cells or stop metastatic progression. For example, osteopontin has been identified as the lead gene that plays a significant role in liver cancer metastasis. In addition, we are examining the role of the liver microenvironment in metastasis and recurrence by focusing particularly on the functions of immune cells and the inflammatory process in liver cancer progression (Budhu et al, Cancer Cell 2006). Recently, we also identified a unique microRNA signature that is correlated with HCC metastasis and survival (Budhu et al, Hepatology 2008). These approaches will allow us to apply an individualized therapeutic strategy to enhance the efficacy of treatment.

2. Role of the Crm1/Ran complex in early stages of hepatocarcinogenesis:

The Ran/Crm1 complex is essential in nucleocytoplasmic transport of cellular proteins. This complex is often utilized by mammalian viruses to efficiently transport their own viral proteins intracellularly. We have recently demonstrated that the HBV-encoded HBx protein not only contains a functional nuclear export signal that utilizes the Ran/Crm1 pathway, but also alters Ran/Crm1-dependent nuclear export of the NFkB/IkB complex (Forgues et al, J Biol Chem 2001). This finding implicates the Ran/Crm1 complex in the molecular pathogenesis of HBV. More recently, we have uncovered a new role of the Ran/Crm1 complex, namely that it is involved in regulating cellular proteins that control centrosome duplication and mitotic spindle assembly (Forgues et al, Mol Cell Biol 2003). We have shown that inactivation of the Ran/Crm1 complex by HBx or by a specific inhibitor can result in multipolar spindles and abnormal mitoses. These findings let us to generate a new hypothesis in which the Ran/Crm1 complex acts as a 'loading dock' in controlling cellular homeostasis, and disruption of this complex may result in genomic instability that serves as an early step in viral hepatitis-mediated hepatocarcinogenesis. Currently, we are exploring other potential partners associated with this complex that may regulate spindle assembly.