Updated February 05, 2008

Xin Wei Wang, Ph.D.
Molecular Biologist
Principal Investigator

Biography:

Dr. Wang is a trained cancer biologist with a special interest in the molecular biology and genetics of human liver cancer. He holds a BachelorÕs degree from Shanghai Medical University (1982), a MasterÕs degree from the Chinese Academia of Science (1985) and a Ph.D. degree from New York University (1991). He completed postdoctoral fellowships at the Roche Institute of Molecular Biology (1991-1992) and at NCI (1992-1995) with studies on molecular carcinogenesis and signal transduction. He then served as a Senior Staff Fellow at NCI (1995-1998). He was recruited as a tenure-track investigator in the Laboratory of Human Carcinogenesis, NCI in 1998, and received tenure as a Senior Investigator in 2005. Currently, he serves as the Head of the Liver Carcinogenesis Section in Laboratory of Human Carcinogenesis, NCI, and as an Adjunct Associate Professor at the University Of Maryland School Of Medicine. He has published over 72 manuscripts and book chapters, and has been frequently invited to give lectures both nationally and internationally. He provides numerous editorial services and grant reviews.

Research Program and Goals:

Our laboratory is interested in studying the genetic and biochemical pathways involved in human carcinogenesis. Currently, we are exploring molecular mechanisms related to human hepatocellular carcinoma to address the multistage process of this disease. The dogma for tumor evolution is that a tumor is derived from a clonal expansion of an initiating cell with a mutation in a tumor suppressor gene or an oncogene followed by an acquisition of sequential multiple genetic changes. Human hepatocellular carcinoma is an excellent model system to explore this problem because its underlying etiologies can be identified in most cases. We are focusing on two areas of research, namely initiation and metastasis. For example, we have used state-of-the-art technologies, such as SAGE and cDNA microarray, to identify molecular signatures that are unique to the development of human hepatocellular carcinoma 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 SAGE and 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. Currently, we are exploring the roles of these genes in liver cancer initiation and 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. 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/IkBa 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. Moreover, we have revealed nucleophosmin as a novel substrate for Ran/Crm1 to negatively regulate unnecessary centrosome duplication (Wang et al, Nat Cell Biol 2005). These findings let us to generate a new hypothesis in which the Ran/Crm1 complex acts as a Ôloading dockÕ 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.