通过人工 microRNAs 对点突变 KRAS 的选择性靶向。
Selective targeting of point-mutated KRAS through artificial microRNAs.
机构信息
Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210;
Division of Pulmonary Disease and Critical Care Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298.
出版信息
Proc Natl Acad Sci U S A. 2017 May 23;114(21):E4203-E4212. doi: 10.1073/pnas.1620562114. Epub 2017 May 8.
Abstract
Mutated protein-coding genes drive the molecular pathogenesis of many diseases, including cancer. Specifically, mutated KRAS is a documented driver for malignant transformation, occurring early during the pathogenesis of cancers such as lung and pancreatic adenocarcinomas. Therapeutically, the indiscriminate targeting of wild-type and point-mutated transcripts represents an important limitation. Here, we leveraged on the design of miRNA-like artificial molecules (amiRNAs) to specifically target point-mutated genes, such as KRAS, without affecting their wild-type counterparts. Compared with an siRNA-like approach, the requirement of perfect complementarity of the microRNA seed region to a given target sequence in the microRNA/target model has proven to be a more efficient strategy, accomplishing the selective targeting of point-mutated KRAS in vitro and in vivo.
摘要
突变的蛋白编码基因驱动着许多疾病的分子发病机制，包括癌症。具体来说，突变的 KRAS 是恶性转化的有记录的驱动因素，它发生在肺腺癌和胰腺腺癌等癌症的发病早期。在治疗方面，对野生型和点突变转录本的无差别靶向是一个重要的限制。在这里，我们利用 miRNA 样人工分子 (amiRNA) 的设计来特异性地靶向点突变基因，如 KRAS，而不影响其野生型对应物。与 siRNA 样方法相比，miRNA/target 模型中 miRNA 种子区域与给定靶序列完全互补的要求已被证明是一种更有效的策略，可实现在体外和体内选择性靶向点突变的 KRAS。
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