期刊
SIGNAL TRANSDUCTION AND TARGETED THERAPY
卷 5, 期 1, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41392-020-00375-5
关键词
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资金
- National Natural Science Foundation of China [81772546, 81827804, 81902367]
- Zhejiang Provincial Natural Science Foundation of China [LQ19H160026, LGF18H160011]
- China Postdoctoral Science Foundation [2020M671755]
- Key Research and Development Project of Zhejiang Province [2018C03083]
- Zhejiang Clinical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases [2018E50003]
- Special fund for basic scientific research operating expenses of Zhejiang University [2019XZZX005-4-05]
- Hepatobiliary and Pancreatic Cancer Research of Hubei Chen Xiaoping Science and Technology Development Foundation [CXPJJH11900001-2019308, CXPJJH11900001-2019209, CXPJJH11900009-03]
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [ZIATR000018] Funding Source: NIH RePORTER
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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