Molecular profiling of human hepatocellular cancer

我们正在使用基于最先进的微阵列技术的全球基因表达谱分析方法来分析与不同阶段肝脏疾病相关的临床标本。例如，通过比较来自具有不同程度的肝细胞癌发生风险的慢性肝病患者的肝脏样本，我们已经确定了一种独特的特征，该特征可能有助于诊断早期肝癌患者。几种血清蛋白已被确定为HCC的潜在诊断标志物，这些标志物出现在早期阶段或甲胎蛋白阴性的患者中。我们还开发了一种基于转移性原发性HCC标本的mRNA基因表达的独特分子标记，以预测HCC患者的预后和转移。骨桥蛋白被鉴定为该标记中的前导基因，并且被发现对HCC的转移表型至关重要。由于HCC通常存在于发炎的肝脏中，由于纤维化、肝硬化和/或慢性肝炎，我们还开发了基于HCC患者肝脏微环境的mRNA基因表达的独特分子预后特征，并表明HCC转移倾向可能由局部组织微环境确定和/或影响。有趣的是，肿瘤特征主要不同于肝脏微环境。我们证明，CSF 1可能是负责转移性肝癌患者的肝脏微环境中呈现的独特签名。我们的研究表明，一个主要的体液细胞因子发生在转移性肝环境中，向抗炎/免疫抑制反应的转变可能会促进肝癌转移。我们已经确定了五个基因可以作为早期肝癌发病的生物标志物，特别是对于那些甲胎蛋白（AFP）阴性的基因。我们还公开了新的预后HCC亚型，其特征在于EpCAM和AFP表达类似于肝发生的某些阶段。我们已经证明，这种分类系统可以通过预测对独特的分子靶向治疗的药理学反应来促进HCC预后。目前，我们正在探索这些基因在肝癌发生和转移中的作用，特别是它们在肝癌干细胞中的作用。我们的研究结果非常富有成效，因为它们不仅可以为患者管理提供实用程序，而且还挑战了当前的肿瘤演变模式。显然，基因表达谱扩展了我们对肝癌发生的全球变化的了解，并为这种疾病的分子机制提供了许多见解。此外，这些研究无疑将有助于建立具有潜在诊断和预后价值的新型标志物，以及直接临床干预的潜在治疗靶点。

We are using global gene expression profiling approach based on the state-of-the-art microarray technology to profile clinical specimens that are associated with different stages of liver diseases. For example, by comparing liver samples from chronic liver disease patients with varying degrees of risk for developing hepatocellular carcinoma, we have identified a unique signature that may be useful in diagnosing patients with early onset of liver cancer. Several serum proteins have been identified as potential diagnostic markers for HCC that are presented in an early stage or in those negative for alpha fetoprotein. We have also developed a unique molecular signature based on the mRNA gene expression of metastatic primary HCC specimens to predict prognosis and metastasis of HCC patients. Osteopontin was identified as a lead gene in this signature and was found to be critical for the metastatic phenotype of HCC. Since HCC is usually present in inflamed liver, due to fibrosis, cirrhosis and/or chronic hepatitis, we also developed a unique molecular prognostic signature based on mRNA gene expression of the liver microenvironment of HCC patients, and suggested that HCC metastatic propensity may be determined and/or influenced by the local tissue microenvironment. Interestingly, the tumor signature is principally different from that of liver microenvironment. We demonstrated that CSF1 may be responsible for the unique signature presented in the liver microenvironment of metastatic HCC patients. Our studies indicate that a predominant humoral cytokine profile occurs in the metastatic liver milieu and that a shift toward anti-inflammatory/immune-suppressive responses may promote HCC metastases. We have identified five genes that may serve as biomarkers for early onset of HCC, especially for those that are negative for alpha-fetoprotein (AFP). We have also disclosed novel prognostic HCC subtypes, characterized by EpCAM and AFP expression that resemble certain stages of hepatogenesis. We have demonstrated that this classification system may facilitate HCC prognosis by enabling the prediction of pharmacological responses to a unique molecular targeted therapy. Currently, we are exploring the roles of these genes in liver cancer initiation and metastasis, particularly their roles in liver cancer stem cells. Our findings have been extremely fruitful as they may not only offer utilities to patient managements, but also challenge the current paradigm of tumor evolution. Clearly, gene expression profiling has expanded our knowledge of the global changes that occur in liver cancer, and has provided numerous insights into the molecular mechanisms of this disease. In addition, these studies will undoubtedly contribute to the establishment of novel markers with potential diagnostic and prognostic value, as well as potential therapeutic targets for direct clinical intervention.