Department of Pharmacology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-Ku, Tokyo, 113-8602, Japan.
Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-Ku, Tokyo, 113-8602, Japan.
Mol Neurobiol. 2024 Sep;61(9):7168-7180. doi: 10.1007/s12035-024-04017-7. Epub 2024 Feb 19.
Oxaliplatin, a platinum-based chemotherapeutic agent, frequently causes acute and chronic peripheral sensory neuropathy, for which no effective treatment has been established. In particular, chronic neuropathy can persist for years even after treatment completion, thus worsening patients' quality of life. To avoid the development of intractable adverse effects, a predictive biomarker early in treatment is awaited. In this study, we explored extracellular long non-coding RNAs (lncRNAs) released from primary sensory neurons as biomarker candidates for oxaliplatin-induced peripheral neuropathy. Because many human-specific lncRNA genes exist, we induced peripheral sensory neurons from human induced pluripotent stem cells. Oxaliplatin treatment changed the levels of many lncRNAs in extracellular vesicles (EVs) released from cultured primary sensory neurons. Among them, the levels of release of lncRNAs that were considered to be selectively expressed in dorsal root ganglia were correlated with those of lncRNAs in plasma EV obtained from healthy individuals. Several lncRNAs in plasma EVs early after the initiation of treatment showed greater changes in patients who did not develop chronic neuropathy that persisted for more than 1 year than in those who did. Therefore, these extracellular lncRNAs in plasma EVs may represent predictive biomarkers for the development of chronic peripheral neuropathy induced by oxaliplatin.
奥沙利铂是一种基于铂的化疗药物,常引起急性和慢性周围感觉神经病,目前尚未确立有效的治疗方法。特别是慢性神经病在治疗完成后甚至可以持续多年,从而降低了患者的生活质量。为避免产生难治性的不良反应,人们期待在治疗早期就可以使用预测性生物标志物。在这项研究中,我们探索了从原代感觉神经元释放的细胞外长链非编码 RNA(lncRNA),作为奥沙利铂诱导的周围神经病的生物标志物候选物。因为存在许多人类特异性 lncRNA 基因,所以我们从人诱导多能干细胞诱导产生周围感觉神经元。奥沙利铂处理改变了培养的原代感觉神经元释放的细胞外囊泡(EV)中许多 lncRNA 的水平。其中,被认为在背根神经节中特异性表达的 lncRNA 的释放水平与从健康个体获得的血浆 EV 中的 lncRNA 水平相关。在治疗开始后早期,血浆 EV 中的几种 lncRNA 在未发展为持续 1 年以上的慢性神经病的患者中变化更大。因此,这些血浆 EV 中的细胞外 lncRNA 可能代表奥沙利铂诱导的慢性周围神经病发展的预测性生物标志物。
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