Targeting of G-Quadruplex Harboring Pre-miRNA 92b by LNA Rescues PTEN Expression in NSCL Cancer Cells,ACS Chemical Biology

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Targeting of G-Quadruplex Harboring Pre-miRNA 92b by LNA Rescues PTEN Expression in NSCL Cancer Cells
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-03-12 00:00:00 , DOI: 10.1021/acschembio.7b00749
Gayan Mirihana Arachchilage ₁ , Prakash Kharel ₁ , Joshua Reid ₁ , Soumitra Basu ₁

Affiliation

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 IC₅₀ 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.

中文翻译：

LNA靶向G-四链体含Pre-miRNA 92b挽救PTEN在NSCL癌细胞中的表达

由于microRNA（miRNA）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策略仅限于靶向成熟miRNA，因为由于存在稳定的pre-miRNA茎环结构，用寡核苷酸进行miRNA成熟的上游靶向具有挑战性。先前，我们报道了大约16％的已知人类pre-miRNA具有替代经典茎环采用G-四链体（GQ）结构的潜力。在这里，我们表明，合理设计的锁定核酸（LNA）可以特异性结合pre-miRNA 92b的GQ构象，并抑制pre-miRNA的成熟。此外，我们发现LNA治疗可挽救非小细胞肺癌（NSCLC）细胞中的PTEN表达，这被miRNA 92b的水平升高所抑制。LNA的治疗可显着降低IC₅₀的阿霉素用于NSCLC细胞。可以将这种策略开发为靶向miGs的目标GQ的新型抗miRNA治疗方法。与靶向成熟miRNA相比，这可能是一种更强大的方法，因为它是上游靶向，可以同时降低3'和5'成熟miRNA的水平。

更新日期：2018-03-12

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