Department of Traditional Chinese medicine, the First Affiliated Hospital of China Medical University, Shenyang, China.
Department of Ultrasonic Diagnosis, the First Affiliated Hospital of China Medical University, Shenyang, China.
J Cell Biochem. 2019 Aug;120(8):12966-12976. doi: 10.1002/jcb.28568. Epub 2019 Apr 18.
Endocrine therapy resistance represents a major challenge to the successful treatment of patients with breast cancer. The development of tamoxifen resistance commonly occurrs during the treatment of patients with breast cancer whereas its underlying mechanisms remain elusive. Here, we found that miR-24-3p regulated tamoxifen sensitivity in breast cancer cells. Forced overexpression of miR-24-3p augmented tamoxifen-induced cell viability inhibition in breast cancer cells, while knockdown of miR-24-3p partially attenuated the cytotoxicity effect of tamoxifen. Moreover, we discovered Bim as a target gene of miR-24-3p in breast cancer cells by RNA immunoprecipitation, quantitative reverse transcription polymerase chain reaction, Western blot, and dual luciferase reporter assay. In our established tamoxifen resistant MCF7 cell line (MCF7/TAM), there was a significant elevation of miR-24-3p and decrease of BIM expression compared with parental MCF7 cells. In addition, the inhibition of miR-24-3p could reverse the tamoxifen resistance of MCF7/TAM cells by the induction of cell apoptosis. Silencing of Bim expression blocked miR-24-3p inhibitor-induced elevation of tamoxifen sensitivity of MCF7/TAM cells. Using tumor tissues from patients with breast cancer, we also found that the expression of miR-24-3p was negatively correlated with Bim mRNA expression. Collectively, our study highlighted the pivotal role of miR-24-3p overexpression in mediating the development of tamoxifen resistance in breast cancer and suggested miR-24-3p might be a predictor or target for patients with breast cancer.
内分泌治疗耐药是乳腺癌患者成功治疗的主要挑战。在乳腺癌患者的治疗过程中，通常会出现他莫昔芬耐药，但其潜在机制尚不清楚。在这里，我们发现 miR-24-3p 调节乳腺癌细胞中的他莫昔芬敏感性。miR-24-3p 的强制过表达增强了乳腺癌细胞中他莫昔芬诱导的细胞活力抑制，而 miR-24-3p 的敲低部分减弱了他莫昔芬的细胞毒性作用。此外，我们通过 RNA 免疫沉淀、定量逆转录聚合酶链反应、Western blot 和双荧光素酶报告基因检测发现，Bim 是乳腺癌细胞中 miR-24-3p 的靶基因。在我们建立的他莫昔芬耐药 MCF7 细胞系（MCF7/TAM）中，与亲本 MCF7 细胞相比，miR-24-3p 显著升高，BIM 表达降低。此外，miR-24-3p 的抑制可通过诱导细胞凋亡来逆转 MCF7/TAM 细胞的他莫昔芬耐药性。Bim 表达的沉默阻止了 miR-24-3p 抑制剂诱导的 MCF7/TAM 细胞他莫昔芬敏感性的升高。使用来自乳腺癌患者的肿瘤组织，我们还发现 miR-24-3p 的表达与 Bim mRNA 表达呈负相关。总之，我们的研究强调了 miR-24-3p 过表达在介导乳腺癌他莫昔芬耐药发展中的关键作用，并表明 miR-24-3p 可能是乳腺癌患者的预测因子或治疗靶点。
