Cargando…
AGO-accessible anticancer siRNAs designed with synergistic miRNA-like activity
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 s...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900643/ https://www.ncbi.nlm.nih.gov/pubmed/33664996 http://dx.doi.org/10.1016/j.omtn.2021.01.018 |
_version_ | 1783654251062362112 |
---|---|
author | Gu, Dowoon Ahn, Seung Hyun Eom, Sangkyeong Lee, Hye-Sook Ham, Juyoung Lee, Dong Ha Cho, You Kyung Koh, Yongjun Ignatova, Elizaveta Jang, Eun-Sook Chi, Sung Wook |
author_facet | Gu, Dowoon Ahn, Seung Hyun Eom, Sangkyeong Lee, Hye-Sook Ham, Juyoung Lee, Dong Ha Cho, You Kyung Koh, Yongjun Ignatova, Elizaveta Jang, Eun-Sook Chi, Sung Wook |
author_sort | Gu, Dowoon |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7900643 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-79006432021-03-03 AGO-accessible anticancer siRNAs designed with synergistic miRNA-like activity Gu, Dowoon Ahn, Seung Hyun Eom, Sangkyeong Lee, Hye-Sook Ham, Juyoung Lee, Dong Ha Cho, You Kyung Koh, Yongjun Ignatova, Elizaveta Jang, Eun-Sook Chi, Sung Wook Mol Ther Nucleic Acids Original Article 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. American Society of Gene & Cell Therapy 2021-01-26 /pmc/articles/PMC7900643/ /pubmed/33664996 http://dx.doi.org/10.1016/j.omtn.2021.01.018 Text en © 2021 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Gu, Dowoon Ahn, Seung Hyun Eom, Sangkyeong Lee, Hye-Sook Ham, Juyoung Lee, Dong Ha Cho, You Kyung Koh, Yongjun Ignatova, Elizaveta Jang, Eun-Sook Chi, Sung Wook AGO-accessible anticancer siRNAs designed with synergistic miRNA-like activity |
title | AGO-accessible anticancer siRNAs designed with synergistic miRNA-like activity |
title_full | AGO-accessible anticancer siRNAs designed with synergistic miRNA-like activity |
title_fullStr | AGO-accessible anticancer siRNAs designed with synergistic miRNA-like activity |
title_full_unstemmed | AGO-accessible anticancer siRNAs designed with synergistic miRNA-like activity |
title_short | AGO-accessible anticancer siRNAs designed with synergistic miRNA-like activity |
title_sort | ago-accessible anticancer sirnas designed with synergistic mirna-like activity |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900643/ https://www.ncbi.nlm.nih.gov/pubmed/33664996 http://dx.doi.org/10.1016/j.omtn.2021.01.018 |
work_keys_str_mv | AT gudowoon agoaccessibleanticancersirnasdesignedwithsynergisticmirnalikeactivity AT ahnseunghyun agoaccessibleanticancersirnasdesignedwithsynergisticmirnalikeactivity AT eomsangkyeong agoaccessibleanticancersirnasdesignedwithsynergisticmirnalikeactivity AT leehyesook agoaccessibleanticancersirnasdesignedwithsynergisticmirnalikeactivity AT hamjuyoung agoaccessibleanticancersirnasdesignedwithsynergisticmirnalikeactivity AT leedongha agoaccessibleanticancersirnasdesignedwithsynergisticmirnalikeactivity AT choyoukyung agoaccessibleanticancersirnasdesignedwithsynergisticmirnalikeactivity AT kohyongjun agoaccessibleanticancersirnasdesignedwithsynergisticmirnalikeactivity AT ignatovaelizaveta agoaccessibleanticancersirnasdesignedwithsynergisticmirnalikeactivity AT jangeunsook agoaccessibleanticancersirnasdesignedwithsynergisticmirnalikeactivity AT chisungwook agoaccessibleanticancersirnasdesignedwithsynergisticmirnalikeactivity |