Shi Liang, Liu Boqiang, Shen Dan-Dan, Yan Peijian, Zhang Yanan, Tian Yuanshi, Hou Lidan, Jiang Guangyi, Zhu Yinxin, Liang Yuelong, Liang Xiao, Shen Bo, Yu Hong, Zhang Yan, Wang Yifan, Guo Xing, Cai Xiujun
Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.
Zhejiang Provincial Key Laboratory of Laparoscopic Technology, Hangzhou 310016, China.
Sci Adv. 2021 Mar 24;7(13). doi: 10.1126/sciadv.abe5043. Print 2021 Mar.
Circular RNAs (circRNAs) have emerged as important regulators of various cellular processes and have been implicated in cancer. Previously, we reported the discovery of several dysregulated circRNAs including circPABPC1 (polyadenylate-binding protein 1) in human hepatocellular carcinoma (HCC), although their roles in HCC development remained unclear. Here, we show that circPABPC1 is preferentially lost in tumor cells from clinical samples and inhibits both intrahepatic and distant metastases in a mouse xenograft model. This tumor-suppressive function of circPABPC1 can be attributed to its inhibition of cell adhesion and migration through down-regulating a key member of the integrin family, ITGB1 (β integrin). Mass spectrometry and biochemical evidence demonstrate that circPABPC1 directly links ITGB1 to the 26S proteasome for degradation in a ubiquitination-independent manner. Our data have revealed an uncanonical route for integrin turnover and a previously unidentified mode of action for circRNAs in HCC that can be harnessed for anticancer treatment.
环状RNA（circRNAs）已成为各种细胞过程的重要调节因子，并与癌症有关。此前，我们报道了在人类肝细胞癌（HCC）中发现了几种失调的circRNAs，包括circPABPC1（聚腺苷酸结合蛋白1），尽管它们在HCC发展中的作用仍不清楚。在这里，我们表明circPABPC1在临床样本的肿瘤细胞中优先缺失，并在小鼠异种移植模型中抑制肝内和远处转移。circPABPC1的这种肿瘤抑制功能可归因于它通过下调整合素家族的一个关键成员ITGB1（β整合素）来抑制细胞粘附和迁移。质谱和生化证据表明，circPABPC1以不依赖泛素化的方式直接将ITGB1与26S蛋白酶体连接以进行降解。我们的数据揭示了整合素周转的一条非经典途径以及circRNAs在HCC中一种以前未被识别的作用模式，这可用于抗癌治疗。
