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首页> 外文期刊>Biochemistry >Rationally Induced RNA:DNA G?Quadruplex Structures Elicit an Anticancer Effect by Inhibiting Endogenous eIF-4E Expression
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Rationally Induced RNA:DNA G?Quadruplex Structures Elicit an Anticancer Effect by Inhibiting Endogenous eIF-4E Expression

机译：理性诱导的RNA：DNA g？四驱结构通过抑制内源性EIF-4E表达引发抗癌效果

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摘要

RNA G-quadruplex (GQ) structures act as regulators of a diverse array of cellular processes including translation, premRNA processing, and mRNA targeting. We report here a strategy of harnessing the natural ability of RNA GQs to inhibit translation by rationally inducing a GQ on a targeted mRNA to knockdown endogenous gene expression. We chose to target eIF-4E because of its key role in translation initiation and overexpression in multiple cancers and with the expectation that downregulation of eIF-4E would result in antiproliferation of cancer cells. Targeted hybrid (RNA:DNA) GQ structures were induced at the 5′-untranslated region (UTR) and the protein coding region of the eIF-4E mRNA by rationally designed and partially modified extraneous DNA sequences and their effect on eIF-4E expression was determined. The formation of a stable induced G-quadruplex was established by biophysical and biochemical methods. Thermodynamic parameters calculated from CD melting indicate formation of a stable induced GQ at a physiologically relevant salt concentration. We established the specificity and efficacy of the induced GQ formation by monitoring the targeted repression of a reporter gene. Most importantly we have demonstrated that inducing GQ in the 5′-UTR and the protein coding region of eIF-4E mRNA in human cancer cells results in 30% and 60% inhibition of the endogenous protein expression, respectively. Treating with the GQ inducing oligonucleotide sequences resulted in a decrease in the viability of human cancer cells in a dose-dependent manner. The above concept opens up a new strategy for targeted modulation of endogenous gene expression.
机译：RNA G-Quadruplex（GQ）结构充当多种细胞过程的调节因子，包括翻译，premRNA处理和mRNA靶向。我们在此报告通过合理诱导靶向mRNA对靶向基因表达的GQ来抑制RNA GQs的天然能力来抑制转化的策略。我们选择瞄准EIF-​​4E，因为它在多种癌症中的翻译开始和过表达中的关键作用，并且期望EIF-4E的下调将导致癌细胞的抗溶解。靶向杂化（RNA：DNA）GQ结构在5'-未转过来的区域（UTR）和EIF-4E mRNA的蛋白质编码区，通过合理设计和部分修饰的外来DNA序列及其对EIF-4E表达的影响是决定。通过生物物理和生物化学方法建立稳定诱导的G-QUADRuplex的形成。从CD熔化计算的热力学参数表明在生理相关的盐浓度下形成稳定的诱导GQ。通过监测报告基因的靶向抑制，我们建立了诱导GQ形成的特异性和疗效。最重要的是，我们已经证明，在5'-UTR中诱导GQ和人类癌细胞中EIF-4E mRNA的蛋白质编码区分别导致内源蛋白表达的30％和60％抑制。用GQ诱导寡核苷酸序列治疗，以剂量依赖性方式降低人癌细胞的活力。上述概念为内源基因表达的有针对性调节开辟了一种新的策略。

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