N6-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling

作者：Junjie Xu, Zhe Wan, Minyue Tang, Zhongjie Lin, Jiang Shi, Lin Ji, Kirill Gorshkov, Qijiang Mao, Shunjie Xia, Dong Cen, Junhao Zheng, Xiao Liang, Xiujun Cai · 发表于：Molecular Cancer · 年份：2020 · DOI：10.1186/s12943-020-01281-8 · 被引用次数：321 · 研究领域：Circular RNAs in diseases、Cancer Mechanisms and Therapy、RNA Interference and Gene Delivery

Abstract 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 so rafenib-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 HC...