N6-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating \u03b2-catenin signaling

Junjie Xu,Zhe Wan,Dong Cen,Qijiang Mao,Lin Ji,Shunjie Xia,Xiujun Cai,Zhongjie Lin,Kirill Gorshkov,Shi Jiang,Xiao Liang,Junhao Zheng,Minyue Tang

doi:10.1186/s12943-020-01281-8

Abstract

Background and aimsAccumulating 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.MethodsIn vitro and in vivo experiments were performed and clinical samples and online databases were acquired for clinical investigation.ResultsIn 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 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.ConclusionsThis 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.

Highlights

Hepatocellular carcinoma (HCC) is the most common cancer and the leading cause of cancer-associated mortality worldwide
We previously found that circRNA-SORE was upregulated in sorafenib-resistant hepatocellular carcinoma (HCC) and circRNA-SORE was consistently upregulated in the sorafenib-resistant cell lines (Fig. 1b)
We confirmed its upregulation in sorafenib-resistant cell-derived xenograft (CDX) and PDX models (Fig. 1c), indicating the importance of circRNA-SORE in the induction and maintenance of HCC sorafenib resistance

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most common cancer and the leading cause of cancer-associated mortality worldwide. For unresectable HCC, treatment options include transplantation, ablation, transarterial chemoembolization, targeted therapies and immunotherapies. A multikinase inhibitor, is a first-line targeted drug approved by the US Food and Drug Administration for advanced HCC [2]. According to the results of the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial, sorafenib can prolong survival of HCC patients. Understanding the underlying molecular basis of HCC sorafenib resistance and developing mechanism-based therapies are urgently needed. 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

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Conclusion