CircRNA-SORE mediates sorafenib resistance inhepatocellular carcinoma by stabilizing YBX1  

作　　者：Junjie Xu Lin Ji Yuelong Liang Zhe Wan Wei Zheng Xiaomin Song Kirill Gorshkov Qiming Sun Hui Lin Xueyong Zheng Jiang Chen Ren-an Jin Xiao Liang Xiujun Cai 

机构地区：[1]Key Laboratory of Laparoscopic Technology of Zhejiang Province,Department of General Surgery,Sir Run-Run Shaw Hospital,Zhejiang University School of Medicine,310016Hangzhou,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

出　　处：《Signal Transduction and Targeted Therapy》2021年第1期117-130,共14页信号转导与靶向治疗（英文）

基　　金：This research was supported by the National Natural Science Foundation of China under Grant No.81772546(to X.C.),No.81827804(to X.C.)and No.81902367(to J.X.);Zhejiang Provincial Natural Science Foundation of China under Grant No.LQ19H160026(to J.X.)and LGF18H160011(to Y.L.);China Postdoctoral Science Foundation under Grant No.2020M671755(to J.X.);Key Research and Development Project of Zhejiang Province under Grant No.2018C03083(to X.C.);Zhejiang Clinical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases under Grant No.2018E50003(to X.C.);Special fund for basic scientific research operating expenses of Zhejiang University under Grant No.2019XZZX005-4-05(to Y.L.);Hepatobiliary and Pancreatic Cancer Research of Hubei Chen Xiaoping Science and Technology Development Foundation under Grant No.CXPJJH11900001-2019308(to J.X.),CXPJJH11900001-2019209(to X.L.)and CXPJJH11900009-03(to X.L.).

摘　　要：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.

关 键 词：SORAFENIB HEPATOCELLULAR RESISTANCE 

分 类 号：R735.7[医药卫生—肿瘤]