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
  • 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. [email protected].
  • 8. Zhejiang University Cancer Center, 310016, Hangzhou, China. [email protected].
  • 9. Zhejiang Minimal Invasive Diagnosis and Treantment Thechnology Research Center of Severe Hepatobiliary Disease, 310016, Hangzhou, China. [email protected].
  • 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. [email protected].
  • 11. Zhejiang University Cancer Center, 310016, Hangzhou, China. [email protected].
  • 12. Zhejiang Minimal Invasive Diagnosis and Treantment Thechnology Research Center of Severe Hepatobiliary Disease, 310016, Hangzhou, China. [email protected].
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.

Products