The Key Laboratory of Experimental Teratology of Ministry of Education, Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China; Key Laboratory of Urinary Precision Diagnosis and Treatment, Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
Key Laboratory of Urinary Precision Diagnosis and Treatment, Department of Urology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
Biochem Pharmacol. 2021 Jun;188:114575. doi: 10.1016/j.bcp.2021.114575. Epub 2021 Apr 20.
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.
信号转导子和转录激活子 3（STAT3）的过度激活与癌症的发生、进展、转移、化疗耐药和免疫逃逸密切相关；因此，STAT3 一直被作为癌症治疗的治疗靶点进行深入研究。小檗碱（BBR）是从黄连中提取的一种有效成分，已在多种肿瘤中显示出抗肿瘤作用。然而，其潜在机制尚未完全阐明。在本研究中，我们研究了 BBR 对膀胱癌（BCa）细胞的作用及其潜在机制。我们发现，BBR 对 BCa 细胞系在体内和体外均表现出显著的细胞毒性作用，而对人正常尿路上皮细胞系 SV-HUC-1 的细胞毒性作用要低得多。BBR 处理诱导 DNA 复制缺陷和细胞周期停滞，导致细胞凋亡或衰老，具体取决于 p53 状态。在机制上，BBR 通过上调 miR-17-5p 抑制 Janus 激酶 1（JAK1）-STAT3 信号通路，从而发挥对 BCa 细胞的抗肿瘤作用，miR-17-5p 直接结合 JAK1 和 STAT3 的 3'UTR，下调它们的表达。总之，我们的研究结果表明，BBR 通过上调 miR-17-5p 干扰 BCa 细胞中的 JAK1-STAT3 信号通路发挥抗肿瘤作用，BBR 可能成为治疗膀胱癌的潜在治疗选择。
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