Molecular profiling of human hepatocellular cancer

人类肝癌在美国的发病率越来越高，是世界上第五大最常见的恶性疾病。它是导致癌症死亡的第四大原因，每年约有100万人死于癌症。肝细胞癌（HCC）是原发性肝癌的主要类型。HCC被认为是一种绝症，目前在发现有效的治疗方法方面进展甚微。这主要是由于缺乏早期诊断的方法和缺乏与HCC发展相关的表型变化的信息。我们的目标是确定负责HCC发生的常见基因簇，发现对病毒性肝炎介导的HCC至关重要的新基因以及转移所必需的基因。这些研究将有助于建立具有潜在诊断和预后价值的新标志物，对这些基因的分析将进一步了解肝癌的发生机制，并为直接临床干预肝癌提供潜在的治疗靶点。

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.