CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1.
CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1.
复制标题
CircRNA-SORE 通过稳定 YBX1 介导肝细胞癌中索拉非尼耐药
DOI：
10.1038/s41392-020-00375-5
复制
发表时间：
2020-12-26
影响因子：
39.3
通讯作者：
Cai X
中科院分区：
文献类型：
--
作者：
Xu J;Ji L;Liang Y;Wan Z;Zheng W;Song X;Gorshkov K;Sun Q;Lin H;Zheng X;Chen J;Jin RA;Liang X;Cai X
索拉非尼是晚期肝细胞癌（HCC）的一线化疗药物。然而，索拉非尼耐药严重限制了其治疗效果，耐药的机制尚未完全阐明。在这里，我们报告了一种环状RNA，circRNA-SORE（一种在索拉非尼耐药HCC细胞中上调的环状RNA），在HCC的索拉非尼耐药中起着重要作用。我们发现，circRNA-SORE在索拉非尼耐药HCC细胞中上调，并且circRNA-SORE的消耗显著增加了索拉非尼的细胞杀伤能力。进一步的研究表明，circRNA-SORE结合细胞质中的主致癌蛋白YBX 1，这阻止了YBX 1与E3泛素连接酶PRP 19的核相互作用，从而阻断了PRP 19介导的YBX 1降解。此外，我们的体外和体内结果表明，circRNA-SORE由外来体转运，以在HCC细胞中传播索拉非尼耐药性。使用不同的HCC小鼠模型，我们证明了通过注射siRNA沉默circRNA-SORE可以基本上克服索拉非尼抗性。我们的研究为通过靶向circRNA-SORE或YBX 1克服HCC患者中索拉非尼耐药性的潜在策略提供了概念验证。
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.
登录
查看更多内容
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
外泌体传输的 lncARSR 通过充当竞争性内源性 RNA 促进肾癌舒尼替尼耐药
影响因子：
50.3
作者：
Qu, Le;Ding, Jin;Wang, Lin-Hui
通讯作者：
Wang, Lin-Hui
影响因子：
168.9
作者：
Bruix, Jordi;Qin, Shukui;Han, Guohong
通讯作者：
Han, Guohong
索拉非尼对亚太地区晚期肝细胞癌患者的疗效和安全性：一项 III 期随机、双盲、安慰剂对照试验
影响因子：
51.1
作者：
Cheng, Ann-Lii;Kang, Yoon-Koo;Guan, Zhongzhen
通讯作者：
Guan, Zhongzhen
影响因子：
4.1
作者：
Löscher, M;Fortschegger, K;Grillari, J
通讯作者：
Grillari, J