通过外泌体载体介导的circ_0017636细胞间转移通过ARRB1介导的信号通路恢复克服胶质母细胞瘤化疗耐药性
Intercellular transfer of circ_0017636 via exosomal vehicles overcomes glioblastoma chemoresistance through ARRB1-mediated signaling restoration.
摘要(中文译文)
替莫唑胺（TMZ）耐药是胶质母细胞瘤（GBM）治疗失败和预后不良的主要原因。外泌体介导的细胞间通讯日益被认为是驱动化疗耐药传播的关键机制；然而，外泌体环状RNA货物在这一适应性过程中的具体贡献仍不清楚。本研究系统表征了外泌体circ_0017636在重塑TMZ耐药微环境中的生物学功能。我们发现circ_0017636在TMZ耐药组织中显著下调，并与不良预后相关。在机制上，circ_0017636作为竞争性内源RNA，通过物理海绵吸附miR-665来解除对β-抑制蛋白1（ARRB1）的抑制。关键的是，我们从敏感细胞中分离了外泌体，并通过透射电子显微镜（TEM）和标志物分析确认了其身份。利用CD63-GFP荧光追踪，我们直观地展示了这些囊泡被耐药受体细胞高效内化，证实circ_0017636作为可转移货物被物理包装进这些外泌体中。摄取后，这些负载circ_0017636的外泌体有效传播了化疗敏感性信号，显著降低了增殖标志物Ki-67和多药耐药蛋白P-糖蛋白（P-gp）的表达，从而抑制了恶性表型。此外，体内实验证实，瘤内递送富含circ_0017636的外泌体显著延缓了异种移植瘤的生长并克服了TMZ耐药。总之，本研究阐明了一条新的基于外泌体的通讯轴，其中circ_0017636作为可转移的肿瘤抑制因子发挥作用。我们的发现表明，利用外泌体作为天然载体递送circ_0017636是一种有前景的治疗策略，同时也提示其作为诊断生物标志物的潜力。
Abstract
Temozolomide (TMZ) resistance represents a primary cause of treatment failure and poor outcomes in glioblastoma (GBM). Exosome-mediated intercellular communication is increasingly recognized as a pivotal mechanism driving the dissemination of chemoresistance; however, the specific contribution of exosomal circular RNA cargos to this adaptive process remains elusive. This study systematically characterized the biological function of exosomal circ_0017636 in remodeling the TMZ-resistant microenvironment. We identified that circ_0017636 was significantly downregulated in TMZ-resistant tissues and correlated with poor prognosis. Mechanistically, circ_0017636 functions as a competing endogenous RNA that physically sponges miR-665 to de-repress Arrestin Beta 1 (ARRB1). Crucially, we isolated exosomes from sensitive cells and confirmed their identity via transmission electron microscopy (TEM) and marker analysis. Utilizing CD63-GFP fluorescent tracking, we visually demonstrated the efficient internalization of these vesicles by resistant recipient cells, confirming that circ_0017636 is physically packaged into these exosomes as a transferable cargo. Upon uptake, these circ_0017636-loaded exosomes effectively propagated chemosensitivity signals, significantly reducing the expression of the proliferation marker Ki-67 and the multidrug resistance protein P-glycoprotein (P-gp), thereby suppressing malignant phenotypes. Furthermore, vivo experiments confirmed that intratumoral delivery of circ_0017636-enriched exosomes significantly retarded xenograft tumor growth and overcame TMZ resistance. Collectively, this study elucidates a novel exosome-based communication axis, wherein circ_0017636 acts as a transferable tumor suppressor. Our findings suggest that leveraging exosomes as natural vehicles to deliver circ_0017636 represents a promising therapeutic strategy, while also indicating its potential as a diagnostic biomarker.
如何引用
AMA
Qiang Li, Jianglong Xu, Bin Ye, Peikan Jin, Diana Bee-Lan Ong, Kein Seong Mun, et al. Intercellular transfer of circ_0017636 via exosomal vehicles overcomes glioblastoma chemoresistance through ARRB1-mediated signaling restoration.. Cellular signalling. 2026; doi:10.1016/j.cellsig.2026.112432.
APA
Qiang Li, Jianglong Xu, Bin Ye, Peikan Jin, Diana Bee-Lan Ong, Kein Seong Mun, et al (2026). Intercellular transfer of circ_0017636 via exosomal vehicles overcomes glioblastoma chemoresistance through ARRB1-mediated signaling restoration.. Cellular signalling. https://doi.org/10.1016/j.cellsig.2026.112432
GB/T 7714
Qiang Li, Jianglong Xu, Bin Ye, Peikan Jin, Diana Bee-Lan Ong, Kein Seong Mun, et al. Intercellular transfer of circ_0017636 via exosomal vehicles overcomes glioblastoma chemoresistance through ARRB1-mediated signaling restoration.[J]. Cellular signalling, 2026 doi:10.1016/j.cellsig.2026.112432.
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