Molecular signatures for liver cancer diagnosis and treatment stratification

我们正在使用一种基于最先进技术的全球基因表达谱分析方法， 微阵列技术来分析与不同阶段相关的临床标本， 肝脏疾病例如，通过比较慢性肝病患者的肝脏样本， 有不同程度的发展为肝细胞癌的风险，我们已经确定了一个 独特的签名，可能有助于诊断早期肝癌患者。 几种血清蛋白已被确定为肝细胞癌的潜在诊断标志物 早期或甲胎蛋白阴性的癌症。我们 还开发了一种独特的基于mRNA基因表达的分子标记， 转移性原发性肝细胞癌标本预测预后和转移 肝癌患者。由于肝细胞癌通常存在于 肝脏发炎，由于纤维化，肝硬化和/或慢性肝炎，我们还开发了一个 基于肝脏mRNA基因表达的独特分子预后特征 肝癌患者的微环境。我们发现一种主要的体液免疫 细胞因子谱发生在转移性肝脏微环境中， 抗炎/免疫抑制反应可能促进肝细胞癌 转移因此，这些研究表明局部组织的重要作用 肝细胞癌转移的微环境。有趣的是，肿瘤的特征是 主要不同于肝脏微环境。此外，我们还使用了分子 分析，以确定五个基因，可能作为生物标志物的早期发病， 肝细胞癌，尤其是甲胎蛋白阴性的患者。我们 他们还探索了小的非编码RNA，称为microRNA，在肝细胞中的作用， 癌转移和存活。我们发现，某些microRNA表达的变化， 与转移相关，甚至可以显著预测患者的生存和复发， 在疾病早期。这些microRNA可以提供一种简单的分析方法， 识别可能发生转移的HCC患者。此外，功能 对这些microRNA的分析可能会增强我们对肝细胞癌的生物学理解， 癌转移我们的研究成果非常丰硕，并提供了有用的工具， 患者管理，也挑战了当前的肿瘤演变模式。很明显吉恩 表达谱分析扩大了我们对肝脏中发生的整体变化的认识， 癌症，并为这种疾病的分子机制提供了许多见解。在 此外，这些研究无疑将有助于建立新的标记物， 潜在的诊断和预后价值，以及潜在的治疗靶点， 临床干预。

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.