Monroig Paloma Del C, Chen Lu, Zhang Shuxing, Calin George A
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; University of Puerto Rico School of Medicine, San Juan 00936, Puerto Rico.
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Adv Drug Deliv Rev. 2015 Jan;81:104-16. doi: 10.1016/j.addr.2014.09.002. Epub 2014 Sep 17.
One of the most fascinating discoveries in molecular oncology has been that cancer represents a disease in which genetic alterations in protein-coding, but also in non-coding genes complement each other. MicroRNAs (miRNAs) are a type of non-coding RNA (ncRNA) transcripts that can regulate gene expression primarily by disrupting messenger RNA (mRNA) translation and/or stability, or alternatively by modulating the transcription of target mRNAs. For the last decade, miRNAs have shown to be pivotal characters of every single one of the cancer hallmarks. Profiling studies have proven the significance of identifying over-expressed miRNAs (oncomiRs) causative of the activation of oncogenic pathways that lead to malignancy. Due to their crucial role in cancer, it has become a challenge to develop efficient miRNA-inhibiting strategies such as antagomiRs, locked nucleic acids or antisense oligonucleotides. However, to this date, the accessible delivery agents and their pharmacokinetic/pharmacodynamic properties are not ideal. Thus there is an urgent, unmet need to develop miRNA-based inhibitory therapeutics. Herein we present a novel therapeutic strategy that is only at the tip of the iceberg: the use of small molecule inhibitors to target specific miRNAs (SMIRs). Furthermore we describe several high-throughput techniques to screen for SMIRs both in vitro and in silico. Finally we take you through the journey that has led to discovering the handful of SMIRs that have been validated to this date.
分子肿瘤学中最引人入胜的发现之一是，癌症是一种疾病，其中蛋白质编码基因以及非编码基因中的基因改变相互补充。微小RNA（miRNA）是一类非编码RNA（ncRNA）转录本，主要通过破坏信使RNA（mRNA）的翻译和/或稳定性，或者通过调节靶mRNA的转录来调节基因表达。在过去十年中，miRNA已被证明是癌症各个标志特征中的关键因素。分析研究已经证明，鉴定导致致癌途径激活并导致恶性肿瘤的过表达miRNA（致癌miRNA）具有重要意义。由于它们在癌症中的关键作用，开发有效的miRNA抑制策略，如抗miRNA、锁核酸或反义寡核苷酸，已成为一项挑战。然而，迄今为止，可用的递送剂及其药代动力学/药效学性质并不理想。因此，迫切需要开发基于miRNA的抑制性疗法。在此，我们提出一种新颖的治疗策略，而这仅仅是冰山一角：使用小分子抑制剂靶向特定的miRNA（SMIR）。此外，我们描述了几种在体外和计算机模拟中筛选SMIR的高通量技术。最后，我们带您了解导致发现至今已得到验证的少数SMIR的历程。
