AGO-accessible anticancer siRNAs designed with synergistic miRNA-like activity

Dowoon Gu; Seung Hyun Ahn; Sangkyeong Eom; Hye Sook Lee; Juyoung Ham; Dong Ha Lee; You Kyung Cho; Yongjun Koh; Elizaveta Ignatova; Eun Sook Jang; Sung Wook Chi

doi:10.1016/j.omtn.2021.01.018

AGO-accessible anticancer siRNAs designed with synergistic miRNA-like activity

Dowoon Gu, Seung Hyun Ahn, Sangkyeong Eom, Hye Sook Lee, Juyoung Ham, Dong Ha Lee, You Kyung Cho, Yongjun Koh, Elizaveta Ignatova, Eun Sook Jang, Sung Wook Chi

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1172-1190
Number of pages	19
Journal	Molecular Therapy - Nucleic Acids
Volume	23
DOIs	https://doi.org/10.1016/j.omtn.2021.01.018
Publication status	Published - 2021 Mar 5

Keywords

AGO CLIP
breast cancer
cervical cancer
miRNA
ovarian cancer
siRNA

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.omtn.2021.01.018

Cite this

@article{b9c66297ec274035955418843460bc13,

title = "AGO-accessible anticancer siRNAs designed with synergistic miRNA-like activity",

abstract = "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.",

keywords = "AGO CLIP, breast cancer, cervical cancer, miRNA, ovarian cancer, siRNA",

author = "Dowoon Gu and Ahn, {Seung Hyun} and Sangkyeong Eom and Lee, {Hye Sook} and Juyoung Ham and Lee, {Dong Ha} and Cho, {You Kyung} and Yongjun Koh and Elizaveta Ignatova and Jang, {Eun Sook} and Chi, {Sung Wook}",

note = "Funding Information: We thank members of the Chi Laboratory for discussion, and H. Seok and J. Park for critical review of the manuscript. We are grateful to the late Y.S. Lee for his help on this work. We also thank Samsung Medical Center for the bioluminescence images, J.H. Choi for providing the A2780 cell line, and K.K. Kim for initial help with bioinformatics analyses. This work was supported by the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea ( HI15C3137 ) and by the Korea University Research Grant . Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = mar,

day = "5",

doi = "10.1016/j.omtn.2021.01.018",

language = "English",

volume = "23",

pages = "1172--1190",

journal = "Molecular Therapy - Nucleic Acids",

issn = "2162-2531",

publisher = "Nature Publishing Group",

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T1 - AGO-accessible anticancer siRNAs designed with synergistic miRNA-like activity

AU - Gu, Dowoon

AU - Ahn, Seung Hyun

AU - Eom, Sangkyeong

AU - Lee, Hye Sook

AU - Ham, Juyoung

AU - Lee, Dong Ha

AU - Cho, You Kyung

AU - Koh, Yongjun

AU - Ignatova, Elizaveta

AU - Jang, Eun Sook

AU - Chi, Sung Wook

N1 - Funding Information: We thank members of the Chi Laboratory for discussion, and H. Seok and J. Park for critical review of the manuscript. We are grateful to the late Y.S. Lee for his help on this work. We also thank Samsung Medical Center for the bioluminescence images, J.H. Choi for providing the A2780 cell line, and K.K. Kim for initial help with bioinformatics analyses. This work was supported by the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea ( HI15C3137 ) and by the Korea University Research Grant . Publisher Copyright: © 2021 The Authors

PY - 2021/3/5

Y1 - 2021/3/5

N2 - 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.

AB - 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.

KW - AGO CLIP

KW - breast cancer

KW - cervical cancer

KW - miRNA

KW - ovarian cancer

KW - siRNA

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U2 - 10.1016/j.omtn.2021.01.018

DO - 10.1016/j.omtn.2021.01.018

M3 - Article

AN - SCOPUS:85101039613

SN - 2162-2531

VL - 23

SP - 1172

EP - 1190

JO - Molecular Therapy - Nucleic Acids

JF - Molecular Therapy - Nucleic Acids

ER -

AGO-accessible anticancer siRNAs designed with synergistic miRNA-like activity

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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