通过对原代细胞基因谱分析揭示 v-Src 转化的细胞过程--对人类癌症的影响。
Cellular processes of v-Src transformation revealed by gene profiling of primary cells--implications for human cancer.
机构信息
Department of Biology, McMaster University, 1280 Main street West, Hamilton, ON, L8S 4K1, Canada.
出版信息
BMC Cancer. 2010 Feb 12;10:41. doi: 10.1186/1471-2407-10-41.
BACKGROUND
Cell transformation by the Src tyrosine kinase is characterized by extensive changes in gene expression. In this study, we took advantage of several strains of the Rous sarcoma virus (RSV) to characterize the patterns of v-Src-dependent gene expression in two different primary cell types, namely chicken embryo fibroblasts (CEF) and chicken neuroretinal (CNR) cells. We identified a common set of v-Src regulated genes and assessed if their expression is associated with disease-free survival using several independent human tumor data sets.
METHODS
CEF and CNR cells were infected with transforming, non-transforming, and temperature sensitive mutants of RSV to identify the patterns of gene expression in response to v-Src-transformation. Microarray analysis was used to measure changes in gene expression and to define a common set of v-Src regulated genes (CSR genes) in CEF and CNR cells. A clustering enrichment regime using the CSR genes and two independent breast tumor data-sets was used to identify a 42-gene aggressive tumor gene signature. The aggressive gene signature was tested for its prognostic value by conducting survival analyses on six additional tumor data sets.
RESULTS
The analysis of CEF and CNR cells revealed that cell transformation by v-Src alters the expression of 6% of the protein coding genes of the genome. A common set of 175 v-Src regulated genes (CSR genes) was regulated in both CEF and CNR cells. Within the CSR gene set, a group of 42 v-Src inducible genes was associated with reduced disease- and metastasis-free survival in several independent patient cohorts with breast or lung cancer. Gene classes represented within this group include DNA replication, cell cycle, the DNA damage and stress responses, and blood vessel morphogenesis.
CONCLUSION
By studying the v-Src-dependent changes in gene expression in two types of primary cells, we identified a set of 42 inducible genes associated with poor prognosis in breast and lung cancer. The identification of these genes provides a set of biomarkers of aggressive tumor behavior and a framework for the study of cancer cells characterized by elevated Src kinase activity.
背景
Src 酪氨酸激酶引起的细胞转化的特征是基因表达的广泛改变。在这项研究中，我们利用几种劳斯肉瘤病毒（RSV）株来描述两种不同原代细胞类型（鸡胚成纤维细胞（CEF）和鸡神经视网膜（CNR）细胞）中 v-Src 依赖性基因表达的模式。我们确定了一组共同的 v-Src 调控基因，并使用几个独立的人类肿瘤数据集评估它们的表达与无病生存的相关性。
方法
将转化、非转化和温度敏感的 RSV 突变体感染 CEF 和 CNR 细胞，以鉴定 v-Src 转化后基因表达的模式。使用微阵列分析来测量基因表达的变化，并在 CEF 和 CNR 细胞中定义一组共同的 v-Src 调控基因（CSR 基因）。使用 CSR 基因和两个独立的乳腺癌数据集的聚类富集方案，鉴定出一个由 42 个基因组成的侵袭性肿瘤基因特征。通过对六个额外的肿瘤数据集进行生存分析，对侵袭性基因特征进行了预后价值的测试。
结果
CEF 和 CNR 细胞的分析表明，v-Src 引起的细胞转化改变了基因组中 6%的蛋白质编码基因的表达。CEF 和 CNR 细胞中共同调节了一组 175 个 v-Src 调控基因（CSR 基因）。在 CSR 基因集中，一组 42 个 v-Src 诱导基因与乳腺癌或肺癌患者的几个独立队列的疾病和无转移生存时间缩短有关。该组中包含的基因类别包括 DNA 复制、细胞周期、DNA 损伤和应激反应以及血管形态发生。
结论
通过研究两种类型的原代细胞中 v-Src 依赖性基因表达的变化，我们鉴定出一组与乳腺癌和肺癌不良预后相关的 42 个诱导基因。这些基因的鉴定提供了一组侵袭性肿瘤行为的生物标志物，并为研究具有高 Src 激酶活性的癌细胞提供了一个框架。
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