Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype
Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype
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DOI：
10.1172/jci27236
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发表时间：
2006-06-01
影响因子：
15.9
通讯作者：
Thorgeirsson, Snorri S.
中科院分区：
文献类型：
--
作者：
Kaposi-Novak, Pal;Lee, Ju-Seog;Thorgeirsson, Snorri S.
识别致癌途径的特异性基因表达特征是人类恶性肿瘤分子分类的重要一步。Met信号通路的异常激活通常与肿瘤进展和转移相关。在这项研究中，我们使用WT和Met缺陷原代小鼠肝细胞的全局基因表达谱来定义Met依赖性基因表达特征。新鉴定的Met途径的转录靶点包括参与氧化应激反应调节以及细胞运动性、细胞骨架组织和血管生成的基因。为了评估Met调控基因表达特征的重要性，将比较功能基因组学方法应用于242例人肝细胞癌（HCC）和7例转移性肝病变。聚类分析显示，一个子集的人肝癌和所有的肝转移共享Met诱导的表达签名。此外，Met标记的存在显示出与增加的血管浸润率和微血管密度以及HCC患者的平均生存时间降低显著相关。我们的结论是，基因定义的基因表达签名与比较功能基因组学相结合，构成了一个有吸引力的范例定义致癌途径的功能和临床相关的人类癌症亚组。
Identification of specific gene expression signatures characteristic of oncogenic pathways is an important step toward molecular classification of human malignancies. Aberrant activation of the Met signaling pathway is frequently associated with tumor progression and metastasis. In this study, we defined the Met-dependent gene expression signature using global gene expression profiling of WT and Met-deficient primary mouse hepatocytes. Newly identified transcriptional targets of the Met pathway included genes involved in the regulation of oxidative stress responses as well as cell motility, cytoskeletal organization, and angiogenesis. To assess the importance of a Met-regulated gene expression signature, a comparative functional genomic approach was applied to 242 human hepatocellular carcinomas (HCCs) and 7 metastatic liver lesions. Cluster analysis revealed that a subset of human HCCs and all liver metastases shared the Met-induced expression signature. Furthermore, the presence of the Met signature showed significant correlation with increased vascular invasion rate and microvessel density as well as with decreased mean survival time of HCC patients. We conclude that the genetically defined gene expression signatures in combination with comparative functional genomics constitute an attractive paradigm for defining both the function of oncogenic pathways and the clinically relevant subgroups of human cancers.