Human liver cancer, with increasing occurrence in the United States, is the 5th most prevalent malignant disease in the world. It is the fourth leading cause of cancer mortality, which accounts for an estimated 1 million deaths annually. Hepatocellular carcinoma (HCC) is a major type of primary liver cancer. HCC is considered to be a terminally ill disease and currently, there is little progress toward the discovery of efficient therapies leading to regression. This is due largely to the lack of a method for early diagnosis and the lack of information on the phenotypic changes associated with the development of HCC. Our goals are to identify common gene clusters that are responsible for the genesis of HCC and to discover new genes critical for viral hepatitis-mediated HCC as well as genes necessary for metastasis. These studies will contribute to the establishment of novel markers with potential diagnostic and prognostic value, and analysis of these genes would provide further understanding of the genesis of liver cancer and provide potential therapeutic targets for direct clinical intervention of this disease. We have developed a strategy to define molecular signatures for HCC progression by gene expression profiling. 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 HCC. We have used SAGE and microarray complimentary techniques to define global gene expression profiles, and have identified several candidate genes that may play a role in viral hepatitis-mediated HCC. By examining liver samples from chronic liver disease patients with various etiological factors, we have identified a unique panel of expressed genes that may be useful in diagnosing patients for early onset of HCC. By comparing primary HCC with or without accompanying metastasis, we have also identified a molecular signature that can predict metastasis and survival of HCC patients. This study also reveals a novel mechanism for metastasis progression. We have identified several potential therapeutic targets that can be used to eliminate liver cancer cells or stop metastatic progression. This approach may allow us to apply an individualized therapeutic strategy to enhance the efficacy of the treatment. An example includes the identification of osteopontin (OPN) as both a diagnostic marker and a potential therapeutic target for metastatic HCC. Currently, we are exploring the functional roles of OPN and other genes. Moreover, we have established two collaborative projects that may allow us to extend the microarray-based signatures for clinical usages in predicting the early onset of HCC or metastasis.