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首页> 外文期刊>Molecular and Cellular Biology >Role of Epidermal Growth Factor Receptor Signaling in RAS-Driven Melanoma
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Role of Epidermal Growth Factor Receptor Signaling in RAS-Driven Melanoma

机译：表皮生长因子受体信号传导在RAS驱动的黑色素瘤中的作用

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The identification of essential genetic elements in pathways governing the maintenance of fully established tumors is critical to the development of effective antioncologic agents. Previous studies revealed an essential role for H-RASV12G in melanoma maintenance in an inducible transgenic model. Here, we sought to define the molecular basis for RAS-dependent tumor maintenance through determination of the H-RASV12G-directed transcriptional program and subsequent functional validation of potential signaling surrogates. The extinction of H-RASV12G expression in established tumors was associated with alterations in the expression of proliferative, antiapoptotic, and angiogenic genes, a profile consistent with the observed phenotype of tumor cell proliferative arrest and death and endothelial cell apoptosis during tumor regression. In particular, these melanomas displayed a prominent RAS-dependent regulation of the epidermal growth factor (EGF) family, leading to establishment of an EGF receptor signaling loop. Genetic complementation and interference studies demonstrated that this signaling loop is essential to H-RASV12G-directed tumorigenesis. Thus, this inducible tumor model system permits the identification and validation of alternative points of therapeutic intervention without neutralization of the primary genetic lesion.
机译：在控制完全成熟的肿瘤的维持途径中，基本遗传成分的鉴定对于有效的抗精神病药物的开发至关重要。先前的研究揭示了H-RAS V12G 在可诱导的转基因模型中在黑色素瘤维持中的重要作用。在这里，我们试图通过确定H-RAS V12G 定向的转录程序并随后对潜在的信号替代物进行功能验证来确定RAS依赖性肿瘤维持的分子基础。 H-RAS V12G 表达在已建立的肿瘤中的消失与增殖，抗凋亡和血管生成基因表达的改变有关，其分布与观察到的肿瘤细胞增殖停滞，死亡和内皮细胞表型一致肿瘤消退期间的细胞凋亡。特别地，这些黑素瘤显示出对表皮生长因子（EGF）家族的突出的RAS依赖性调节，导致建立了EGF受体信号传导环。遗传互补和干扰研究表明，该信号回路对H-RAS V12G 定向的肿瘤发生至关重要。因此，这种可诱导的肿瘤模型系统允许在不中和原发性遗传病变的情况下鉴定和验证治疗干预的替代点。

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