Department of Chemistry and Biochemistry , Kent State University , Kent , Ohio 44242 , United States.
ACS Chem Biol. 2018 Apr 20;13(4):909-914. doi: 10.1021/acschembio.7b00749. Epub 2018 Mar 19.
Since the elevated levels of microRNAs (miRNAs) often cause various diseases, selective inhibition of miRNA maturation is an important therapeutic strategy. Commonly used anti-miRNA strategies are limited to targeting of mature miRNAs, as the upstream targeting of miRNA maturation with an oligonucleotide is challenging due to the presence of a stable pre-miRNA stem-loop structure. Previously, we reported that about 16% of known human pre-miRNAs have the potential to adopt G-quadruplex (GQ) structures alternatively to canonical stem-loops. Herein, we showed that a rationally designed locked nucleic acid (LNA) binds specifically the GQ conformation of pre-miRNA 92b and inhibits pre-miRNA maturation. Further, we showed that the LNA treatment rescues PTEN expression in non-small-cell lung cancer (NSCLC) cells, which is suppressed by the elevated level of miRNA 92b. Treatment of LNA significantly decreases the IC of doxorubicin for NSCLC cells. This strategy can be developed as a novel anti-miRNA therapeutic approach to target GQ harboring miRNAs. This can potentially be a more powerful approach than targeting of the mature miRNA, as it is an upstream targeting and can reduce both 3' and the 5' mature miRNA levels at once.
由于 miRNA（microRNAs）水平升高通常会导致各种疾病，因此选择性抑制 miRNA 成熟是一种重要的治疗策略。常用的抗 miRNA 策略仅限于针对成熟 miRNA，因为由于存在稳定的 pre-miRNA 茎环结构，寡核苷酸对 miRNA 成熟的上游靶向具有挑战性。以前，我们报道说，已知的人类 pre-miRNA 中约有 16%有可能采用 G-四链体（GQ）结构替代规范的茎环。在这里，我们表明，经过合理设计的锁核酸（LNA）特异性结合 pre-miRNA 92b 的 GQ 构象并抑制 pre-miRNA 成熟。此外，我们表明，LNA 处理可挽救非小细胞肺癌（NSCLC）细胞中 PTEN 表达的抑制，该表达被 miRNA 92b 水平升高所抑制。LNA 的治疗显着降低了 NSCLC 细胞对阿霉素的 IC。这种策略可以作为一种针对含有 GQ 的 miRNA 的新型抗 miRNA 治疗方法进行开发。与针对成熟 miRNA 相比，这可能是一种更强大的方法，因为它是一种上游靶向，并且可以同时降低 3'和 5'成熟 miRNA 水平。
