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N(6)-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling

BACKGROUND AND AIMS: Accumulating evidence suggests that the primary and acquired resistance of hepatocellular carcinoma (HCC) to sorafenib is mediated by multiple molecular, cellular, and microenvironmental mechanisms. Understanding these mechanisms will enhance the likelihood of effective sorafeni...

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Autores principales: Xu, Junjie, Wan, Zhe, Tang, Minyue, Lin, Zhongjie, Jiang, Shi, Ji, Lin, Gorshkov, Kirill, Mao, Qijiang, Xia, Shunjie, Cen, Dong, Zheng, Junhao, Liang, Xiao, Cai, Xiujun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681956/
https://www.ncbi.nlm.nih.gov/pubmed/33222692
http://dx.doi.org/10.1186/s12943-020-01281-8
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author Xu, Junjie
Wan, Zhe
Tang, Minyue
Lin, Zhongjie
Jiang, Shi
Ji, Lin
Gorshkov, Kirill
Mao, Qijiang
Xia, Shunjie
Cen, Dong
Zheng, Junhao
Liang, Xiao
Cai, Xiujun
author_facet Xu, Junjie
Wan, Zhe
Tang, Minyue
Lin, Zhongjie
Jiang, Shi
Ji, Lin
Gorshkov, Kirill
Mao, Qijiang
Xia, Shunjie
Cen, Dong
Zheng, Junhao
Liang, Xiao
Cai, Xiujun
author_sort Xu, Junjie
collection PubMed
description BACKGROUND AND AIMS: Accumulating evidence suggests that the primary and acquired resistance of hepatocellular carcinoma (HCC) to sorafenib is mediated by multiple molecular, cellular, and microenvironmental mechanisms. Understanding these mechanisms will enhance the likelihood of effective sorafenib therapy. METHODS: In vitro and in vivo experiments were performed and clinical samples and online databases were acquired for clinical investigation. RESULTS: In this study, we found that a circular RNA, circRNA-SORE, which is up-regulated in sorafenib-resistant HCC cells, was necessary for the maintenance of sorafenib resistance, and that silencing circRNA-SORE substantially increased the efficacy of sorafenib-induced apoptosis. Mechanistic studies determined that circRNA-SORE sequestered miR-103a-2-5p and miR-660-3p by acting as a microRNA sponge, thereby competitively activating the Wnt/β-catenin pathway and inducing sorafenib resistance. The increased level of circRNA-SORE in sorafenib-resistant cells resulted from increased RNA stability. This was caused by an increased level of N(6)-methyladenosine (m(6)A) at a specific adenosine in circRNA-SORE. In vivo delivery of circRNA-SORE interfering RNA by local short hairpin RNA lentivirus injection substantially enhanced sorafenib efficacy in animal models. CONCLUSIONS: This work indicates a novel mechanism for maintaining sorafenib resistance and is a proof-of-concept study for targeting circRNA-SORE in sorafenib-treated HCC patients as a novel pharmaceutical intervention for advanced HCC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-020-01281-8.
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spelling pubmed-76819562020-11-23 N(6)-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling Xu, Junjie Wan, Zhe Tang, Minyue Lin, Zhongjie Jiang, Shi Ji, Lin Gorshkov, Kirill Mao, Qijiang Xia, Shunjie Cen, Dong Zheng, Junhao Liang, Xiao Cai, Xiujun Mol Cancer Research BACKGROUND AND AIMS: Accumulating evidence suggests that the primary and acquired resistance of hepatocellular carcinoma (HCC) to sorafenib is mediated by multiple molecular, cellular, and microenvironmental mechanisms. Understanding these mechanisms will enhance the likelihood of effective sorafenib therapy. METHODS: In vitro and in vivo experiments were performed and clinical samples and online databases were acquired for clinical investigation. RESULTS: In this study, we found that a circular RNA, circRNA-SORE, which is up-regulated in sorafenib-resistant HCC cells, was necessary for the maintenance of sorafenib resistance, and that silencing circRNA-SORE substantially increased the efficacy of sorafenib-induced apoptosis. Mechanistic studies determined that circRNA-SORE sequestered miR-103a-2-5p and miR-660-3p by acting as a microRNA sponge, thereby competitively activating the Wnt/β-catenin pathway and inducing sorafenib resistance. The increased level of circRNA-SORE in sorafenib-resistant cells resulted from increased RNA stability. This was caused by an increased level of N(6)-methyladenosine (m(6)A) at a specific adenosine in circRNA-SORE. In vivo delivery of circRNA-SORE interfering RNA by local short hairpin RNA lentivirus injection substantially enhanced sorafenib efficacy in animal models. CONCLUSIONS: This work indicates a novel mechanism for maintaining sorafenib resistance and is a proof-of-concept study for targeting circRNA-SORE in sorafenib-treated HCC patients as a novel pharmaceutical intervention for advanced HCC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12943-020-01281-8. BioMed Central 2020-11-23 /pmc/articles/PMC7681956/ /pubmed/33222692 http://dx.doi.org/10.1186/s12943-020-01281-8 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Xu, Junjie
Wan, Zhe
Tang, Minyue
Lin, Zhongjie
Jiang, Shi
Ji, Lin
Gorshkov, Kirill
Mao, Qijiang
Xia, Shunjie
Cen, Dong
Zheng, Junhao
Liang, Xiao
Cai, Xiujun
N(6)-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling
title N(6)-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling
title_full N(6)-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling
title_fullStr N(6)-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling
title_full_unstemmed N(6)-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling
title_short N(6)-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling
title_sort n(6)-methyladenosine-modified circrna-sore sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681956/
https://www.ncbi.nlm.nih.gov/pubmed/33222692
http://dx.doi.org/10.1186/s12943-020-01281-8
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