Molecular signatures for liver cancer diagnosis and treatment stratification

我们正在使用一种基于最先进的微阵列技术的全球基因表达谱方法来分析与肝脏疾病不同阶段相关的临床标本。例如，通过比较患有不同程度肝细胞癌的慢性肝病患者的肝脏样本，我们已经确定了一个独特的特征，该特征可能对诊断早期肝癌患者有用。几种血清蛋白已被确定为肝细胞癌的潜在诊断标记物，这些标记物存在于早期或甲胎蛋白阴性者中。我们还开发了一种基于转移性原发性肝细胞癌标本mRNA基因表达的独特分子标志物来预测肝细胞癌患者的预后和转移。由于肝细胞癌通常存在于炎症的肝脏中，由于纤维化、肝硬变和/或慢性肝炎，我们还开发了基于肝细胞癌患者肝脏微环境的mRNA基因表达的独特的分子预后标志。我们发现在转移性肝微环境中存在主要的体液细胞因子，并且向抗炎/免疫抑制反应的转变可能促进肝细胞癌的转移。因此，这些研究表明，局部组织微环境在肝细胞癌转移中起着重要作用。有趣的是，肿瘤的征象与肝脏微环境的征象有很大不同。此外，我们还利用分子图谱鉴定了五个可作为早期肝细胞癌生物标志物的基因，特别是那些甲胎蛋白阴性的基因。我们还探索了小的非编码RNA，称为microRNAs，在肝细胞癌转移和生存中的作用。我们发现，某些微小RNA的表达变化与转移有关，甚至在早期疾病中也可以显着预测患者的生存和复发。这些microRNAs可能提供一种简单的分析方法来帮助识别可能发生转移的肝细胞癌患者。此外，对这些microRNAs的功能分析可能会增强我们对肝细胞癌转移的生物学理解。我们的发现非常有成效，为患者管理提供了有用的工具，也挑战了当前的肿瘤进化范式。显然，基因表达谱扩大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大量的见解。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标记物，以及直接临床干预的潜在治疗靶点。

We are using a global gene expression profiling approach based on 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 hepatocellular carcinoma that are present at 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 hepatocellular carcinoma specimens to predict prognosis and metastasis of hepatocellular carcinoma patients. Since hepatocellular carcinoma 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 hepatocellular carcinoma patients. We found that a predominant humoral cytokine profile occurs in the metastatic liver microenvironment and that a shift toward anti-inflammatory/immune-suppressive responses may promote hepatocellular carcinoma metastases. These studies therefore suggest an important role of the local tissue microenvironment in hepatocellular carcinoma metastasis. Interestingly, the tumor signature is principally different from that of liver microenvironment. In addition, we have used molecular profiling to identify five genes that may serve as biomarkers for early onset of hepatocellular carcinoma, especially for those that are negative for alpha-fetoprotein. We have also explored the role of small non-coding RNAs, termed microRNAs, in hepatocellular carcinoma metastasis and survival. We found that certain microRNA expression changes are associated with metastasis and could significantly predict patient survival and relapse even in early stage disease. These microRNAs may provide a simple profiling method to assist in identifying HCC patients who are likely to develop metastases. In addition, functional analysis of these microRNAs may enhance our biological understanding of hepatocellular carcinoma metastasis. Our findings have been extremely fruitful and offer useful tools for patient management and 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.