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

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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 insorafenib-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 N6-methyladenosine (m6A) 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.
Funding Information
  • National Natural Science Foundation of China (81772546, 81827804, 81902367)
  • Natural Science Foundation of Zhejiang Province (LQ19H160026)
  • Zhejiang Clinical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases (2018E50003)
  • Key Research and Development Project of Zhejiang Province (2018C03083)
  • Hepatobiliary and Pancreatic Cancer Research of Hubei Chen Xiaoping Science and Technology Development Foundation (CXPJJH11900001-2019308, CXPJJH11900009-03, CXPJJH11900001-2019209)

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