2. Academic Validation
  3. N6-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling

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

  • Mol Cancer. 2020 Nov 23;19(1):163. doi: 10.1186/s12943-020-01281-8.
Junjie Xu 1 2 3 4 5,  Zhe Wan 1 2 3 4 5,  Minyue Tang 6,  Zhongjie Lin 1 2 3 4 5,  Shi Jiang 1 2 3 4 5,  Lin Ji 1 2 3 4 5,  Kirill Gorshkov 7,  Qijiang Mao 1 2 3 4 5,  Shunjie Xia 1 2 3 4 5,  Dong Cen 1 2 3 4 5,  Junhao Zheng 1 2 3 4 5,  Xiao Liang 8 9 10 11 12,  Xiujun Cai 13 14 15 16 17
Affiliations

Affiliations

  • 1 Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
  • 2 Key Laboratory of Laparoscopic Technology of Zhejiang Province, Hangzhou, China.
  • 3 Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, China.
  • 4 Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, China.
  • 5 Zhejiang University Cancer Center, Hangzhou, China.
  • 6 Department of Reproductive Endocrinology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
  • 7 National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD, 20892, USA.
  • 8 Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China. srrshlx@zju.edu.cn.
  • 9 Key Laboratory of Laparoscopic Technology of Zhejiang Province, Hangzhou, China. srrshlx@zju.edu.cn.
  • 10 Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, China. srrshlx@zju.edu.cn.
  • 11 Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, China. srrshlx@zju.edu.cn.
  • 12 Zhejiang University Cancer Center, Hangzhou, China. srrshlx@zju.edu.cn.
  • 13 Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China. srrsh_cxj@zju.edu.cn.
  • 14 Key Laboratory of Laparoscopic Technology of Zhejiang Province, Hangzhou, China. srrsh_cxj@zju.edu.cn.
  • 15 Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Hangzhou, China. srrsh_cxj@zju.edu.cn.
  • 16 Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, China. srrsh_cxj@zju.edu.cn.
  • 17 Zhejiang University Cancer Center, Hangzhou, China. srrsh_cxj@zju.edu.cn.
PMID: 33222692 DOI: 10.1186/s12943-020-01281-8
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.

Keywords

Circular RNA; Hepatocellular carcinoma; Sorafenib resistance; m6A.

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