2. Academic Validation
  3. CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1

CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1

  • Signal Transduct Target Ther. 2020 Dec 26;5(1):298. doi: 10.1038/s41392-020-00375-5.
Junjie Xu 1 2 3,  Lin Ji 1 2 3,  Yuelong Liang 1 2 3,  Zhe Wan 1 2 3,  Wei Zheng 4,  Xiaomin Song 5,  Kirill Gorshkov 4,  Qiming Sun 6,  Hui Lin 1 2 3,  Xueyong Zheng 1 2 3,  Jiang Chen 1 2 3,  Ren-An Jin 1 2 3,  Xiao Liang 7 8 9,  Xiujun Cai 10 11 12
Affiliations

Affiliations

  • 1 Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, 310016, Hangzhou, China.
  • 2 Zhejiang University Cancer Center, 310016, Hangzhou, China.
  • 3 Zhejiang Minimal Invasive Diagnosis and Treantment Thechnology Research Center of Severe Hepatobiliary Disease, 310016, Hangzhou, China.
  • 4 National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD, 20892, USA.
  • 5 State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 200031, Shanghai, China.
  • 6 Department of Biochemistry, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China.
  • 7 Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, 310016, Hangzhou, China. srrshlx@zju.edu.cn.
  • 8 Zhejiang University Cancer Center, 310016, Hangzhou, China. srrshlx@zju.edu.cn.
  • 9 Zhejiang Minimal Invasive Diagnosis and Treantment Thechnology Research Center of Severe Hepatobiliary Disease, 310016, Hangzhou, China. srrshlx@zju.edu.cn.
  • 10 Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, 310016, Hangzhou, China. srrsh_cxj@zju.edu.cn.
  • 11 Zhejiang University Cancer Center, 310016, Hangzhou, China. srrsh_cxj@zju.edu.cn.
  • 12 Zhejiang Minimal Invasive Diagnosis and Treantment Thechnology Research Center of Severe Hepatobiliary Disease, 310016, Hangzhou, China. srrsh_cxj@zju.edu.cn.
PMID: 33361760 DOI: 10.1038/s41392-020-00375-5
Abstract

Sorafenib is the first-line chemotherapeutic therapy for advanced hepatocellular carcinoma (HCC). However, sorafenib resistance significantly limits its therapeutic efficacy, and the mechanisms underlying resistance have not been fully clarified. Here we report that a circular RNA, circRNA-SORE (a circular RNA upregulated in sorafenib-resistant HCC cells), plays a significant role in sorafenib resistance in HCC. We found that circRNA-SORE is upregulated in sorafenib-resistant HCC cells and depletion of circRNA-SORE substantially increases the cell-killing ability of sorafenib. Further studies revealed that circRNA-SORE binds the master oncogenic protein YBX1 in the cytoplasm, which prevents YBX1 nuclear interaction with the E3 ubiquitin Ligase PRP19 and thus blocks PRP19-mediated YBX1 degradation. Moreover, our in vitro and in vivo results suggest that circRNA-SORE is transported by exosomes to spread sorafenib resistance among HCC cells. Using different HCC mouse models, we demonstrated that silencing circRNA-SORE by injection of siRNA could substantially overcome sorafenib resistance. Our study provides a proof-of-concept demonstration for a potential strategy to overcome sorafenib resistance in HCC patients by targeting circRNA-SORE or YBX1.

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