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肿瘤。它是癌症死亡的第四大原因，估计每年有100万人死于癌症。肝细胞癌是原发性肝癌的一种主要类型。肝细胞癌被认为是一种晚期疾病，目前，在发现导致消退的有效治疗方法方面进展甚微。这在很大程度上是由于缺乏早期诊断的方法，以及缺乏与肝细胞癌发展相关的表型变化的信息。我们的目标是确定共同的基因簇，负责肝癌的发生，并发现新的对病毒性肝炎介导的肝癌至关重要的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的标记，对这些基因的分析将有助于进一步了解肝癌的发生机制，并为临床直接干预肝癌提供潜在的治疗靶点。 我们开发了一种策略，通过基因表达谱来定义肝细胞癌进展的分子特征。我们的策略是确定在原代人类肝细胞、癌前慢性肝病和肝细胞癌中通常因乙肝病毒或丙型肝炎的表达而改变的细胞基因。我们使用SAGE和微阵列互补技术来定义全球基因表达谱，并确定了几个可能在病毒性肝炎介导的肝细胞癌中发挥作用的候选基因。通过检测具有各种病因的慢性肝病患者的肝脏样本，我们已经确定了一组独特的表达基因，这些基因可能有助于诊断患者的早期肝细胞癌。通过比较有无转移的原发性肝细胞癌，我们还确定了一个可以预测肝细胞癌患者转移和生存的分子标志。这项研究还揭示了转移进展的新机制。我们已经确定了几个潜在的治疗靶点，可以用来消除肝癌细胞或阻止转移进展。这种方法可能允许我们应用个体化的治疗策略来提高治疗的有效性。一个例子包括确定骨桥蛋白(OPN)作为转移性肝癌的诊断标记物和潜在的治疗靶点。目前，我们正在探索OPN和其他基因的功能作用。此外，我们已经建立了两个合作项目，这可能使我们能够将基于微阵列的签名扩展到临床使用，以预测肝癌或转移的早期发病。

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.