Lawlor Elizabeth R, Soucek Laura, Brown-Swigart Lamorna, Shchors Ksenya, Bialucha C Uli, Evan Gerard I
Cancer Research Institute, University of California San Francisco Comprehensive Cancer Center, San Francisco, California 94143, USA.
Cancer Res. 2006 May 1;66(9):4591-601. doi: 10.1158/0008-5472.CAN-05-3826.
Deregulated expression of the Myc transcription factor is a frequent causal mutation in human cancer. Thousands of putative Myc target genes have been identified in in vitro studies, indicating that Myc exerts highly pleiotropic effects within cells and tissues. However, the complexity and diversity of Myc gene targets has confounded attempts at identifying which of these genes are the critical targets mediating Myc-driven tumorigenesis in vivo. Acute activation of Myc in a reversibly switchable transgenic model of Myc-mediated beta cell tumorigenesis induces rapid tumor onset, whereas subsequent Myc deactivation triggers equally rapid tumor regression. Thus, sustained Myc activity is required for tumor maintenance. We have used this reversibly switchable kinetic tumor model in combination with high-density oligonucleotide microarrays to develop an unbiased strategy for identifying candidate Myc-regulated genes responsible for maintenance of Myc-dependent tumors. Consistent with known Myc functions, some Myc-regulated genes are involved in cell growth, cycle, and proliferation. In addition, however, many Myc-regulated genes are specific to beta cells, indicating that a significant component of Myc action is cell type specific. Finally, we identify a very restricted cadre of genes with expression that is inversely regulated upon Myc activation-induced tumor progression and deactivation-induced tumor regression. By definition, such genes are candidates for tumor maintenance functions. Combining reversibly switchable, transgenic models of tumor formation and regression with genomic profiling offers a novel strategy with which to deconvolute the complexities of oncogenic signaling pathways in vivo.
Myc转录因子的失调表达是人类癌症中常见的致病变异。在体外研究中已鉴定出数千个假定的Myc靶基因，这表明Myc在细胞和组织内发挥着高度多效性作用。然而，Myc基因靶标的复杂性和多样性使得确定这些基因中哪些是介导Myc驱动的体内肿瘤发生的关键靶标变得困难。在Myc介导的β细胞肿瘤发生的可逆性可切换转基因模型中急性激活Myc会诱导肿瘤快速发生，而随后Myc失活则会引发同样快速的肿瘤消退。因此，肿瘤维持需要持续的Myc活性。我们已将这种可逆性可切换的动力学肿瘤模型与高密度寡核苷酸微阵列相结合，以开发一种无偏见的策略来鉴定负责维持Myc依赖性肿瘤的候选Myc调控基因。与已知的Myc功能一致，一些Myc调控基因参与细胞生长、周期和增殖。然而，此外，许多Myc调控基因是β细胞特有的，这表明Myc作用的一个重要组成部分是细胞类型特异性的。最后，我们鉴定出一小部分基因，其表达在Myc激活诱导的肿瘤进展和失活诱导的肿瘤消退时受到反向调节。根据定义，这些基因是肿瘤维持功能的候选基因。将肿瘤形成和消退的可逆性可切换转基因模型与基因组分析相结合，提供了一种新的策略，用于在体内解析致癌信号通路的复杂性。
