LAUSR

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 beenintenselystudiedasatherapeutictargetfor 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.