Department of Urology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Anticancer Drugs. 2022 Oct 1;33(9):871-882. doi: 10.1097/CAD.0000000000001365. Epub 2022 Sep 14.
Exosomal circular RNA was found to mediate cancer chemoresistance. However, whether exosomal circRNA Scm-like with four malignant brain tumor domains 2 (circ-SFMBT2) was involved in the chemoresistance of prostate cancer (PCa) remains unclear. The docetaxel (DTX) resistance of PCa cells was analyzed by Cell Counting Kit 8 assay. Quantitative real-time PCR was used to measure circSFMBT2, microRNA (miR)-136-5p and tribbles homolog 1 (TRIB1) expression. Cell proliferation, apoptosis, migration and invasion were analyzed by 5-ethynyl-2'-deoxyuridine (EdU) assay, flow cytometry, wound-healing assay and transwell assay. RNA interaction was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Protein expression was measured by western blot analysis. Exosomes-extracted from cells were identified by transmission electron microscope, nanoparticles tracking analysis and western blot. Xenograft mice models were constructed to analyze the effect of exosomal circSFMBT2 on the DTX sensitivity of PCa tumors in vivo. CircSFMBT2 was upregulated in DTX-resistant PCa cells, and its knockdown enhanced the DTX sensitivity of DTX-resistant PCa cells by suppressing cell proliferation, migration, invasion and enhancing apoptosis. CircSFMBT2 severed as miR-136-5p sponge to positively regulate TRIB1. The regulation of circSFMBT2 knockdown on the DTX sensitivity of DTX-resistant PCa cells could be reversed by miR-136-5p inhibitor or TRIB1 overexpression. Exosomal circSFMBT2 from DTX-resistant PCa could increase the DTX resistance of normal PCa cells. In addition, exosomal circSFMBT2 also enhanced the DTX resistance of PCa tumors in vivo, and it was highly expressed in the serum of DTX-resistance PCa patients. Exosomal circSFMBT2 enhanced the DTX resistance of PCa by miR-136-5p/TRIB1 axis, indicating that circSFMBT2 might be a potential target for the treatment of PCa chemoresistance.
外泌体环状 RNA 被发现介导癌症化疗耐药性。然而，是否存在具有四个恶性脑肿瘤结构域 2 的外泌体环状 RNA Scm 样（circ-SFMBT2）参与前列腺癌（PCa）的化疗耐药性仍不清楚。通过细胞计数试剂盒 8 测定分析 PCa 细胞的多西紫杉醇（DTX）耐药性。使用实时定量 PCR 测定 circSFMBT2、微小 RNA（miR）-136-5p 和 tribbles 同源物 1（TRIB1）的表达。通过 5-乙炔基-2'-脱氧尿苷（EdU）测定、流式细胞术、划痕愈合测定和 Transwell 测定分析细胞增殖、凋亡、迁移和侵袭。通过双荧光素酶报告基因测定和 RNA 免疫沉淀（RIP）测定验证 RNA 相互作用。通过 Western blot 分析测定蛋白表达。通过透射电子显微镜、纳米颗粒跟踪分析和 Western blot 鉴定细胞提取的外泌体。构建异种移植小鼠模型以分析外泌体 circSFMBT2 对体内 PCa 肿瘤 DTX 敏感性的影响。circSFMBT2 在 DTX 耐药性 PCa 细胞中上调，其敲低通过抑制细胞增殖、迁移、侵袭和增强凋亡来增强 DTX 耐药性 PCa 细胞的 DTX 敏感性。circSFMBT2 作为 miR-136-5p 的海绵正向调节 TRIB1。miR-136-5p 抑制剂或 TRIB1 过表达可逆转 circSFMBT2 敲低对 DTX 耐药性 PCa 细胞 DTX 敏感性的调节。来自 DTX 耐药性 PCa 的外泌体 circSFMBT2 可增加正常 PCa 细胞对 DTX 的耐药性。此外，外泌体 circSFMBT2 还增强了体内 PCa 肿瘤的 DTX 耐药性，并且在 DTX 耐药性 PCa 患者的血清中高表达。外泌体 circSFMBT2 通过 miR-136-5p/TRIB1 轴增强 PCa 的 DTX 耐药性，表明 circSFMBT2 可能是治疗 PCa 化疗耐药性的潜在靶点。
