Liu Xiaoqiang, Zhou Zhengtao, Wang Yibing, Zhu Ke, Deng Wen, Li Yulei, Zhou Xiaochen, Chen Luyao, Li Yu, Xie An, Zeng Tao, Wang Gongxian, Fu Bin
Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
Jiangxi Institute of Urology, Nanchang, China.
Front Oncol. 2020 May 12;10:589. doi: 10.3389/fonc.2020.00589. eCollection 2020.
MicroRNAs (miRNAs) have been implicated in regulating the development and metastasis of human cancers. MiR-221 is reported to be an oncogene in multiple cancers, including bladder cancer (BC). Deregulation of autophagy is associated with multiple human malignant cancers. Whether and how miR-221 regulates autophagy and how miR-221 has been regulated in BC are poorly understood. This study explored the potential functions and mechanisms of miR-221 in the autophagy and tumorigenesis of BC. We showed that the downregulation of miR-221 induces autophagy via increasing TP53INP1 (tumor protein p53 inducible nuclear protein 1) and inhibits migration and invasion of BC cells through suppressing activation of extracellular signal-regulated kinase (ERK). Furthermore, the expression of miR-221 is regulated by high-mobility group AT-hook 1 (HMGA1) which is overexpressed in BC. And both miR-221 and HMGA1 are correlated with poor patient survival in BC. Finally, the downregulation of HMGA1 suppressed the proliferative, migrative, and invasive property of BC by inducing toxic autophagy via miR-221/TP53INP1/p-ERK axis. Collectively, our findings demonstrate that the downregulation of miR-221 and HMGA1 mediates autophagy in BC, and both of them are valuable therapeutic targets for BC.
微小RNA（miRNA）已被证实参与调控人类癌症的发生发展与转移。据报道，miR-221在包括膀胱癌（BC）在内的多种癌症中是一种癌基因。自噬失调与多种人类恶性肿瘤相关。miR-221是否以及如何调控自噬，以及在膀胱癌中miR-221是如何被调控的，目前尚不清楚。本研究探讨了miR-221在膀胱癌自噬和肿瘤发生中的潜在功能及机制。我们发现，miR-221的下调通过增加TP53INP1（肿瘤蛋白p53诱导核蛋白1）诱导自噬，并通过抑制细胞外信号调节激酶（ERK）的激活来抑制膀胱癌细胞的迁移和侵袭。此外，miR-221的表达受高迁移率族AT钩蛋白1（HMGA1）调控，HMGA1在膀胱癌中过表达。而且miR-221和HMGA1均与膀胱癌患者的不良预后相关。最后，HMGA1的下调通过miR-221/TP53INP1/p-ERK轴诱导毒性自噬，从而抑制膀胱癌的增殖、迁移和侵袭特性。总之,我们的研究结果表明，miR-221和HMGA1的下调介导了膀胱癌中的自噬，它们都是膀胱癌有价值的治疗靶点。
