Exosomal Circ-XIAP Promotes Docetaxel Resistance in Prostate Cancer by Regulating miR-1182/TPD52 Axis

Abstract

Background 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.

The Emerging Role of Circular RNAs in Prostate Cancer: A Systematic Review

“…In addition, suppressing hsa_circ_0000735 promoted docetaxel sensitivity and suppressed tumor growth in vivo . Zhang et al reported that exosomal circ-XIAP promoted docetaxel resistance in PCa by altering miR-1182/TPD52 axis (Zhang et al, 2021 ).…”

“…However, this study did not investigate whether exosomal circRNAs could be taken up by cells and function. Zhang et al discovered that circ-XIAP was up-regulated in exosomes from docetaxel-resistant cell lines and could be transmitted via exosomes (Zhang et al, 2021 ). Adding exosomes from docetaxel-resistant cells increased circ-XIAP level in prostate cancer cell lines, suggesting that exosomes containing circ-XIAP could be absorbed.…”

Targeting Apoptosis to Overcome Chemotherapy Resistance

“…Specific delivery of chemotherapeutic agents to the tumor cells can be improved with exosome or nanoparticle conjugations. For instance, exosome-mediated transfer of apoptosis inducers such as circRNA and miRNA may help overcome chemotherapy resistance (91,136). Cancerspecific, pro-apoptotic drug-drug conjugate for SMAC and doxorubicin suppressed tumor growth in drug-resistant lung cancer model (137).…”

“…Transmission of exosomal circular RNA of XIAP (Circ-XIAP) to the docetaxel-resistant prostate cancer cells acted as a miRNA sponge for miR-1182 and promoted resistance (91). A recent report showed that anti-apoptotic proteins FLICE-like inhibitory protein (FLIP) and XIAP are downregulated after hydrogen peroxide in the imatinib-resistant CML cells (92).…”

Potential Clinical Applications of Exosomal Circular RNAs: More than Diagnosis

“…Exo-circRNAs have also demonstrated to function in drug resistance regulation through miRNA sponging. For instance, exosomal circ_0072083 promoted TMZ resistance via increasing Nanoghomeobox (NANOG) and administering miR-1252-5p mediated degradation and demethylation in glioma ( Ding C. Y. et al, 2021 ) and additionally exosomal circ-XIAP stimulated DTX resistance of PC through the regulation of miR-1182/TPD52 axis further providing a promising therapeutic mark for PC chemotherapy ( Zhang et al, 2021 ). In another study, exosomal mmu_circ_0000250 modified adipose derived mesynchymal stem cells advanced wound healing in diabetic mice by inducing miR-128-3p/SIRT1 mediated autophagy ( Shi et al, 2020 ).…”