Junjie Xu,Lin Ji,Yuelong Liang,Zhe Wan,Wei Zheng ORCID: orcid.org/0000-0003-1034-0757,Xiaomin Song,Kirill Gorshkov ORCID: orcid.org/0000-0002-4652-8818,Qiming Sun ORCID: orcid.org/0000-0003-4988-9886,Hui Lin,Xueyong Zheng,Jiang Chen,Ren-an Jin,Xiao Liang &…Xiujun Cai ORCID: orcid.org/0000-0002-6457-0577

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.

https://doi.org/10.1038/s41392-020-00375-5

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