Department of Urology, Shengjing Hospital of China Medical University, NO. 36 Sanhao Street, Heping District, Shenyang City, 110004, Liaoning Province Shenyang, China.
Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
BMC Cancer. 2022 Mar 23;22(1):313. doi: 10.1186/s12885-022-09419-1.
Bladder cancer (BC) is one of the most common malignant tumors of the urinary system, and cisplatin (CDDP) is a critical chemical drug for the treatment of BC. However, CDDP-resistance seriously limits the therapeutic efficacy of this drug for clinical utilization. Thus, identification of pivotal molecule targets that regulate CDDP-resistance in BC become urgent and necessary. In this study, we firstly identified a novel BC-associated circular RNA circ_0058063 that participates in the regulation of CDDP-resistance in BC. Specifically, circ_0058063 was significantly overexpressed in CDDP-resistant tissue and cells, in contrast with the corresponding CDDP-sensitive counterparts. Further loss-of-function experiments validated that downregulation of circ_0058063 suppressed cell proliferation and tumor growth, whereas induced cell apoptosis in the CDDP-resistant BC cells in vitro and in vivo. In addition, we disclosed that circ_0058063 acts as a sponge for miR-335-5p to positively regulate B2M expression, and further rescuing experiments verified that the enhancing effects of sh-circ_0058063 on CDDP-sensitivity in the CDDP-resistant BC cells were abrogated by silencing miR-335-5p. Taken together, our results demonstrated that circ_0058063 contributed to CDDP resistance of bladder cancer cells via sponging miR-335-5p, and B2M might be the downstream effector gene. This study firstly evidenced that targeting circ_0058063 might be an effective strategy to improve CDDP-sensitivity in BC.
膀胱癌（BC）是泌尿系统最常见的恶性肿瘤之一，顺铂（CDDP）是治疗 BC 的关键化疗药物。然而，CDDP 耐药严重限制了该药物在临床应用中的治疗效果。因此，鉴定调控 BC 中 CDDP 耐药的关键分子靶标变得紧迫和必要。在本研究中，我们首先鉴定了一种新型与 BC 相关的环状 RNA circ_0058063，它参与调节 BC 中的 CDDP 耐药性。具体而言，circ_0058063 在 CDDP 耐药组织和细胞中显著过表达，与相应的 CDDP 敏感对照物相反。进一步的功能丧失实验验证了下调 circ_0058063 抑制了 CDDP 耐药性 BC 细胞的增殖和肿瘤生长，而在体外和体内诱导了细胞凋亡。此外，我们揭示了 circ_0058063 作为 miR-335-5p 的海绵正向调节 B2M 表达，进一步的挽救实验验证了 sh-circ_0058063 对 CDDP 耐药性 BC 细胞中 CDDP 敏感性的增强作用被沉默 miR-335-5p 所取消。总之，我们的研究结果表明 circ_0058063 通过海绵吸附 miR-335-5p 促进膀胱癌细胞对 CDDP 的耐药性，B2M 可能是下游效应基因。本研究首次证明，针对 circ_0058063 可能是提高 BC 中 CDDP 敏感性的有效策略。
