MicroRNA-Based Therapeutic Strategies for Targeting Mutant and Wild Type RAS in Cancer.
MicroRNA-Based Therapeutic Strategies for Targeting Mutant and Wild Type RAS in Cancer.
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DOI：
10.1002/ddr.21270
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发表时间：
2015-09
影响因子：
3.8
通讯作者：
Ruppert JM
中科院分区：
文献类型：
--
作者：
Sharma SB;Ruppert JM
微小RNA（miR）与多种癌症的进展和发展有因果关系。miR通过调节途径组分蛋白的翻译来调节关键细胞信号传导网络的活性。因此，通过促进（使用miR补充）或通过抑制（使用基于反义寡核苷酸的策略）miR活性来调节癌细胞信号传导网络的miR的药理学靶向是密集研究的领域。RAS-细胞外信号调节激酶（ERK）途径代表赋予细胞一些经典癌症标志的主要miR调节的信号传导网络，并且通常在恶性肿瘤中通过点突变或基因拷贝数改变的体细胞遗传改变而被不适当地激活。此外，最近的进展表明，由于致癌microRNA的协同作用，许多肿瘤可能缺乏GTP酶激活蛋白（GAP）。最近的研究还表明，在携带突变型RAS等位基因的肿瘤中，野生型RAS蛋白在决定整体RAS-ERK通路活性方面具有关键作用。这两项进展共同构成了治疗干预的新机会。在这篇综述中，我们评估了基于miR的治疗策略，用于调节癌症中的RAS-ERK信号传导，特别是更直接地调节RAS-GTP水平，并有可能补充当前的策略，以产生更持久的治疗反应。为此，我们讨论了基于miR的治疗的潜力，重点是三个突出的miR，包括泛RAS调节因子let-7和由miR-206和miR-21组成差距调节因子（miR-206/21）。
MicroRNAs (miRs) have been causally implicated in the progression and development of a wide variety of cancers. miRs modulate the activity of key cell signaling networks by regulating the translation of pathway component proteins. Thus, the pharmacological targeting of miRs that regulate cancer cell signaling networks, either by promoting (using miR-supplementation) or by suppressing (using anti-sense oligonucleotide based strategies) miR activity is an area of intense research. The RAS-Extracellular signal regulated kinase (ERK) pathway represents a major miR-regulated signaling network that endows cells with some of the classical hallmarks of cancer, and is often inappropriately activated in malignancies by somatic genetic alteration through point mutation or alteration of gene copy number. In addition, recent progress indicates that many tumors may be deficient in GTPase activating proteins (GAPs) due to the collaborative action of oncogenic microRNAs. Recent studies also suggest that in tumors harboring a mutant RAS allele there is a critical role for wild type RAS proteins in determining overall RAS-ERK pathway activity. Together, these two advances comprise a new opportunity for therapeutic intervention. In this review, we evaluate miR-based therapeutic strategies for modulating RAS-ERK signaling in cancers, in particular for more direct modulation of RAS-GTP levels, with the potential to complement current strategies in order to yield more durable treatment responses. To this end, we discuss the potential for miR-based therapies focused on three prominent miRs including the pan-RAS regulator let-7 and the GAP regulator comprised of miR-206 and miR-21 (miR-206/21).