Drug Design, Development and Therapy (May 2021)
Exosomal Circ-XIAP Promotes Docetaxel Resistance in Prostate Cancer by Regulating miR-1182/TPD52 Axis
Abstract
Hui Zhang,1 Minghui Li,1 Jing Zhang,1 Yanbing Shen,2 Qi Gui2 1College of Medical, Huanghuai University, Zhumadian, Henan, People’s Republic of China; 2Department of Urology, The Central Hospital of Zhumadian, Zhumadian, Henan, People’s Republic of ChinaCorrespondence: Hui ZhangCollege of Medical, Huanghuai University, No. 2628, Mountain Panlong Road, Zhumdian, 463000, Henan, People’s Republic of ChinaTel +86-0396-2853503Email [email protected]: Exosomal circular RNAs (circRNAs) are involved in the pathogenesis of prostate cancer (PCa) and chemotherapy resistance. This research aimed to explore the function and molecular mechanism of circRNA X-linked inhibitor of apoptosis (circ-XIAP) in docetaxel (DTX) resistance of PCa.Methods: The expression of circ-XIAP, microRNA-1182 (miR-1182), tumor protein D52 (TPD52) was measured by quantitative real-time polymerase chain reaction (qRT-PCR). Exosomes were detected with transmission electron microscopy (TEM). Cluster of differentiation 63 (CD63), cluster of differentiation 9 (CD9) and TPD52 protein levels were detected by Western blot (WB). FIfty percent inhibitory concentration (IC50) of DTX and cell viability were determined using Cell Counting Kit-8 (CCK-8) assay. Colony formation assay was applied to assess colony-forming ability. Cell cycle distribution and apoptosis were analyzed by flow cytometry. Transwell assay was used for measuring cell migration and invasion. Dual-reporter luciferase assay was performed to confirm the interaction between miR-1182 and circ-XIAP or TPD52. The role of circ-XIAP in vivo was confirmed via the mice xenograft model.Results: Circ-XIAP and TPD52 were upregulated and miR-1182 was downregulated in DTX-resistant PCa tissue specimens and cell lines. Circ-XIAP was also overexpressed in exosomes from DTX-resistant cells and could be transmitted via exosomes. Circ-XIAP knockdown enhanced DTX sensitivity by suppressing DTX-resistant cell proliferation, migration and invasion and inducing cell cycle arrest and apoptosis. Circ-XIAP directly targeted miR-1182, and the effects of circ-XIAP knockdown were reversed by downregulating miR-1182 in DTX-resistant cells. TPD52 was the target of miR-1182, and its upregulation weakened the promotive effect of miR-1182 on DTX sensitivity. Importantly, circ-XIAP depletion inhibited tumor growth and increased DTX sensitivity in vivo.Conclusion: Exosomal circ-XIAP promoted DTX resistance of PCa by regulating miR-1182/TPD52 axis, providing a promising therapeutic target for PCa chemotherapy.Keywords: prostate cancer, exosomes, circ-XIAP, miR-1182, TPD52
