Molecular profiling of human hepatocellular cancer

人类肝细胞癌的分子谱分析

• 批准号: 6951273
• 负责人: XIN WEI WANG
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6951273
• 关键词: clinical research; complementary DNA; early diagnosis; gene expression; genetic library; genetic mapping; genetic markers; genetic transcription; hepatitis B virus group; hepatitis C virus; hepatocellular carcinoma; human genetic material tag; human tissue; liver cells; liver neoplasms; metastasis; microarray technology; molecular genetics; neoplasm /cancer genetics; northern blottings; oncoproteins; osteopontin; protein degradation; protein structure; ribosomal proteins; serial analysis of gene expression; transfection /expression vector

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.

在美国，人类肝癌的发生越来越大，是世界上第五大最普遍的恶性疾病。这是癌症死亡率的第四个主要原因，每年估计死亡100万。肝细胞癌（HCC）是原发性肝癌的主要类型。 HCC被认为是一种疾病，目前，在发现有效疗法导致回归方面几乎没有进展。这主要是由于缺乏早期诊断方法以及缺乏与HCC发展相关的表型变化的信息。我们的目标是确定负责HCC起源的常见基因簇，并发现对病毒肝炎介导的HCC至关重要的新基因以及转移所需的基因。这些研究将有助于建立具有潜在诊断和预后价值的新颖标记物，对这些基因的分析将进一步了解肝癌的起源，并为直接临床干预该疾病提供潜在的治疗靶标。 我们已经制定了一种通过基因表达分析定义HCC进展的分子特征的策略。我们的策略是确定通常通过HBV或HCV在原发性人肝细胞，肿瘤前慢性肝脏疾病和HCC中的HBV或HCV表达而改变的细胞基因。我们已经使用SAGE和微阵列免费技术来定义全球基因表达谱，并确定了几种可能在病毒肝炎介导的HCC中发挥作用的候选基因。通过检查患有各种病因因素的慢性肝病患者的肝样本，我们已经确定了一个独特的表达基因小组，这些基因可能可用于诊断患者早期发作HCC。通过比较带有或没有伴随转移的初级HCC，我们还确定了一个可以预测HCC患者转移和存活的分子特征。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可用于消除肝癌细胞或停止转移性进展的潜在治疗靶标。这种方法可能使我们能够采用个性化的治疗策略来增强治疗的功效。一个示例包括将骨桥蛋白（OPN）鉴定为诊断标记和转移性HCC的潜在治疗靶标。当前，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协作项目，可以使我们能够扩展基于微阵列的临床使用，以预测HCC或转移的早期发作。