AGO-accessible anticancer siRNAs designed with synergistic miRNA-like activity
| Autor: | Sung Wook Chi, Eun Sook Jang, Sangkyeong Eom, You Kyung Cho, Juyoung Ham, Hye Sook Lee, Dowoon Gu, Dong Ha Lee, Yongjun Koh, Elizaveta Ignatova, Seung Hyun Ahn |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Small interfering RNA cervical cancer Immunoprecipitation Biology RNAi Therapeutics 03 medical and health sciences breast cancer 0302 clinical medicine RNA interference Drug Discovery microRNA AGO CLIP Gene miRNA lcsh:RM1-950 RNA Argonaute lcsh:Therapeutics. Pharmacology ovarian cancer 030104 developmental biology siRNA 030220 oncology & carcinogenesis Cancer research Molecular Medicine Original Article |
| Zdroj: | Molecular Therapy. Nucleic Acids Molecular Therapy: Nucleic Acids, Vol 23, Iss, Pp 1172-1190 (2021) |
| ISSN: | 2162-2531 |
| Popis: | Small interfering RNAs (siRNAs) therapeutically induce RNA interference (RNAi) of disease-causing genes, but they also silence hundreds of seed-matched off-targets as behaving similar to microRNAs (miRNAs). miRNAs control the pathophysiology of tumors, wherein their accessible binding sites can be sequenced by Argonaute crosslinking immunoprecipitation (AGO CLIP). Herein, based on AGO CLIP, we develop potent anticancer siRNAs utilizing miRNA-like activity (mi/siRNAs). The mi/siRNAs contain seed sequences (positions 2–7) of tumor-suppressive miRNAs while maintaining perfect sequence complementarity to the AGO-accessible tumor target sites. Initially, host miRNA interactions with human papillomavirus 18 (HPV18) were identified in cervical cancer by AGO CLIP, revealing tumor-suppressive activity of miR-1/206 and miR-218. Based on the AGO-miRNA binding sites, mi/siRNAs were designed to target E6 and E7 (E6/E7) transcript with seed sequences of miR-1/206 (206/E7) and miR-218 (218/E7). Synergistic anticancer activity of 206/E7 and 218/E7 was functionally validated and confirmed via RNA sequencing and in vivo xenograft models (206/E7). Other mi/siRNA sequences were additionally designed for cervical, ovarian, and breast cancer, and available as an online tool (http://ago.korea.ac.kr/misiRNA); some of the mi/siRNAs were validated for their augmented anticancer activity (206/EphA2 and 206/Her2). mi/siRNAs could coordinate miRNA-like activity with robust siRNA function, demonstrating the potential of AGO CLIP analysis for RNAi therapeutics. Graphical Abstract The gene silencing activity of siRNAs depends on target accessibility of Argonaute (AGO) and has a problem to induce miRNA-like repression of seed-matched off-targets. Based on AGO CLIP sequencing analyses, Gu and colleagues developed a robust strategy to design anticancer siRNAs (mi/siRNAs), which utilize AGO-accessible tumor target sites to augment tumor-suppressive miRNA-like activity. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|