Berberine suppresses bladder cancer cell proliferation by inhibiting JAK1-STAT3 signaling via upregulation of miR-17-5p

Jianfeng Cui,Yangli Shen,Benkang Shi,Wenfu Wang,Shouzhen Chen,Li Gong,Shuna Sun,Yangyang Xia,Yaofeng Zhu,Yongxin Zou,Xuewen Jiang,Jiangxia Li,Yong Wang,Xiaochen Liu

doi:10.1016/j.bcp.2021.114575

Abstract

Hyperactivation of signal transducer and activator of transcription 3 (STAT3) is strongly associated with cancer initiation, progression, metastasis, chemoresistance, and immune evasion; thus, STAT3 has been intensely studied as a therapeutic target for cancer treatment. Berberine (BBR), an active component extracted from Coptis chinensis, has shown anti-tumor effects in multiple tumors. However, its underlying mechanisms have not yet been fully elucidated. In this study, we investigated the effects and the underlying mechanisms of BBR on bladder cancer (BCa) cells. We found that BBR showed significant cytotoxic effects against BCa cell lines both in vivo and in vitro, with much lower cytotoxic effects on the human normal urothelial cell line SV-HUC-1. BBR treatment induced DNA replication defects and cell cycle arrest, resulting in apoptosis or cell senescence, depending on p53 status, in BCa cells. Mechanistically, BBR exerted anti-tumor effects on BCa cells by inhibiting Janus kinase 1 (JAK1)-STAT3 signaling through the upregulation of miR-17-5p, which directly binds to the 3′UTR of JAK1 and STAT3, downregulating their expressions. Collectively, our results demonstrate that BBR exerts anti-tumor effects by perturbing JAK1-STAT3 signaling through the upregulation of miR-17-5p in BCa cells, and that BBR may serve as a potential therapeutic option for BCa treatment.

Highlights

Berberine (BBR), an active component extracted from Coptis chinensis, has shown antitumor effects in multiple tumors
Our results demonstrate that BBR exerts anti-tumor effects through perturbing Janus kinase 1 (JAK1)-signal transducer and activator of transcription 3 (STAT3) signaling via upregulating expression of miR-17-5p in bladder cancer (BCa) cells, and BBR may serve as a potential therapeutic option for BCa treatment
Our results demonstrated that BBR induced apoptosis in p53 deficient while caused senescence in p53 proficient BCa cells via targeting JAK1-STAT3 signaling

Summary

Introduction

Berberine (BBR), an active component extracted from Coptis chinensis, has shown antitumor effects in multiple tumors. Approximately half of NMIBC cases recur and 10–15% would progress to muscle-invasive bladder cancer (MIBC) or metastasis within 5 years[2]. For those patients with MIBC, radical cystectomy with lymphadenectomy is still considered as standard treatment. Checkpoint blockade immunotherapy (ICI) and FGFR2/3 target therapy have emerged as potential therapeutic strategies for BCa treatment[4]. These medicines are applicable for certain patients and the objective response rate (ORR) is limited[5,6,7]. It is vital to explore novel therapeutic drugs for BCa

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Conclusion