Department of Urology, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, China.
Cancer Biol Ther. 2020 May 3;21(5):452-462. doi: 10.1080/15384047.2020.1727700. Epub 2020 Feb 23.
Drug resistance limits the efficacy of chemotherapy in human cancers. Previous studies reported that long noncoding RNA colon cancer-associated transcript 1 (CCAT1) regulated progression of prostate cancer (PCa). However, the potential role of CCAT1 in the sensitivity of paclitaxel (PTX) in PCa and its mechanism remain largely unknown. The PTX-resistant PCa cells were established in PC3 and DU145 cells by increasing concentrations of PTX. The expressions of CCAT1, microRNA-24-3p (miR-24-3p) and fascin1 (FSCN1) were measured by quantitative real-time polymerase chain reaction. The viability and apoptosis were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay, flow cytometry and western blot, respectively. The interaction among CCAT1, miR-24-3p and FSCN1 was explored by luciferase activity, RNA immunoprecipitation, RNA pull-down and western blot, respectively. Results showed that the expressions of CCAT1 were up-regulated and miR-24-3p was down-regulated in PCa and PTX-resistant PCa cells (PC3-TXR and DU145-TXR). Knockdown of CCAT1 or overexpression of miR-24-3p inhibited survival rate, half maximal inhibitory concentration (IC50) of PTX but increased apoptosis in PC3-TXR and DU145-TXR cells after treatment of PTX. miR-24-3p was bound to CCAT1 and its abrogation reversed knockdown of CCAT1-mediated increase of PTX sensitivity in PC3-TXR and DU145-TXR cells. Moreover, FSCN1 restoration attenuated miR-24-3p-mediated inhibition of PTX resistance. Besides, FSCN1 level was enhanced in PCa and PTX-resistant PCa cells and regulated by CCAT1 and miR-24-3p. Our data suggested interference of CCAT1 contributed to PTX sensitivity in PCa by regulating miR-24-3p and FSCN1, indicating a novel avenue for treatment of PCa through regulating chemoresistance.
耐药性限制了化疗在人类癌症中的疗效。先前的研究报道，长链非编码 RNA 结肠癌相关转录本 1（CCAT1）调节前列腺癌（PCa）的进展。然而，CCAT1 在 PCa 中对紫杉醇（PTX）敏感性的潜在作用及其机制在很大程度上仍然未知。通过增加 PTX 的浓度，在 PC3 和 DU145 细胞中建立了 PTX 耐药的 PCa 细胞。通过实时定量聚合酶链反应测量 CCAT1、microRNA-24-3p（miR-24-3p）和 fascin1（FSCN1）的表达。通过 3-（4,5-二甲基-2-噻唑基）-2,5-二苯基-2-H-四唑溴盐测定法、流式细胞术和 Western blot 分别检测细胞活力和细胞凋亡。通过荧光素酶活性、RNA 免疫沉淀、RNA 下拉和 Western blot 分别探索了 CCAT1、miR-24-3p 和 FSCN1 之间的相互作用。结果表明，CCAT1 在 PCa 和 PTX 耐药的 PCa 细胞（PC3-TXR 和 DU145-TXR）中表达上调，miR-24-3p 表达下调。CCAT1 敲低或 miR-24-3p 过表达抑制了 PC3-TXR 和 DU145-TXR 细胞在 PTX 处理后的存活率、PTX 的半最大抑制浓度（IC50），但增加了细胞凋亡。miR-24-3p 与 CCAT1 结合，其缺失逆转了 CCAT1 介导的 PC3-TXR 和 DU145-TXR 细胞中 PTX 敏感性的增加。此外，FSCN1 恢复减弱了 miR-24-3p 对 PTX 耐药性的抑制作用。此外，FSCN1 水平在 PCa 和 PTX 耐药的 PCa 细胞中增强，并受 CCAT1 和 miR-24-3p 调节。我们的数据表明，通过调节 miR-24-3p 和 FSCN1，干扰 CCAT1 有助于 PCa 中的 PTX 敏感性，这表明通过调节化疗耐药性治疗 PCa 的新途径。
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