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

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 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. 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.

CircRNAs: a new target for the diagnosis and treatment of digestive system neoplasms

“…Xu et al found that CircRNA-SORE plays an important role in it. It can mediate sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1, and N-methylated CircRNA-SORE can also maintain sorafenib resistance through β-catenin signaling 74 , 75 .…”

N6-methyladenosine-dependent signalling in cancer progression and insights into cancer therapies

“…However, the m6A-mediated HNF3γ reduction will cause liver cancer cells to be resistant to sorafenib [ 188 ]. Interestingly, m6A modification can stabilize CircRNA-SORE; CircRNA-SORE can act as a miRNA sponge, adsorbing miR-103a-2-5p and miR-660-3p, thereby competitively activating the Wnt/β-catenin pathway and inducing sorafenib resistance [ 189 ]. This shows that the response of m6A modification to drugs may not be single and easy to understand.…”

Circular RNAs: Potential Applications as Therapeutic Targets and Biomarkers in Breast Cancer

“…To this end, some circRNAs were described as associated with drug resistance ( Section 3.2.2 ), and therefore may be relevant as biomarkers in this space [ 99 ]. The mechanism of action in drug resistance has been studied for a number of circRNAs in other types of cancer previously [ 101 , 102 , 103 ], but only a handful of candidates were investigated in detail in BC. One example of a circRNA involved in drug resistance in BC is the above discussed circKDM4C [ 64 ].…”