聚焦超声联合 miR-1208 装载的外泌体抑制神经胶质瘤的恶性进展。
Focused ultrasound combined with miR-1208-equipped exosomes inhibits malignant progression of glioma.
机构信息
Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
出版信息
Br J Cancer. 2023 Oct;129(7):1083-1094. doi: 10.1038/s41416-023-02393-w. Epub 2023 Aug 14.
BACKGROUND
Exosomes (Exos) can safely and effectively deliver therapeutic substances to glioma cells; however, their blood-brain barrier (BBB) crossing capacity remains limited. Focused ultrasound (FUS) can transiently, reversibly, and locally open the BBB, while the effects of FUS combined with Exos-miRNA on the treatment of glioma have not been explored to date.
METHODS
Exos were extracted by differential centrifugation and the efficacy of miR-1208-loaded Exos combined with FUS in the treatment of glioma was detected by CCK-8, colony formation, flow cytometry, transwell and tumour xenografts assays. The METTL3-mediated regulation of IGF2BP2 on mRNA stability of NUP214 was determined by MeRIP-qPCR, half-life and RIP assays.
RESULTS
We used Exos secreted by mesenchymal stem cells as carriers for the tumour suppressor gene miR-1208, and following FUS irradiation, more Exos carrying miR-1208 were allowed to pass through the BBB, and the uptake of miR-1208 in Exos by glioma cells was promoted, thereby achieving high-efficiency tumour-suppressive effects. Furthermore, the molecular mechanism underlying this effect was elucidated that miR-1208 downregulated the mA methylation level of NUP214 mRNA by negatively regulating the expression of METTL3, thereby NUP214 expression and TGF-β pathway activity were suppressed.
CONCLUSIONS
MiR-1208-loaded Exos combined with FUS is expected to become an effective glioma treatment and deserves further clinical evaluation.
背景
外泌体 (Exos) 可以安全有效地将治疗物质递送至神经胶质瘤细胞；然而，其血脑屏障 (BBB) 穿透能力仍然有限。聚焦超声 (FUS) 可以瞬时、可逆、局部地打开 BBB，而 FUS 联合 Exos-miRNA 对神经胶质瘤治疗的影响迄今尚未得到探索。
方法
通过差速离心提取 Exos，并通过 CCK-8、集落形成、流式细胞术、Transwell 和肿瘤异种移植实验检测载 miR-1208 的 Exos 联合 FUS 治疗神经胶质瘤的疗效。MeRIP-qPCR、半衰期和 RIP 实验确定 METTL3 介导的 IGF2BP2 对 NUP214 mRNA 稳定性的调节作用。
结果
我们使用间充质干细胞分泌的 Exos 作为肿瘤抑制基因 miR-1208 的载体，经 FUS 照射后，更多携带 miR-1208 的 Exos 可以通过 BBB，促进 miR-1208 在 Exos 中的摄取神经胶质瘤细胞，从而达到高效的肿瘤抑制作用。此外，还阐明了这种作用的分子机制，即 miR-1208 通过负调控 METTL3 的表达下调 NUP214 mRNA 的 mA 甲基化水平，从而抑制 NUP214 的表达和 TGF-β 通路活性。
结论
载 miR-1208 的 Exos 联合 FUS 有望成为一种有效的神经胶质瘤治疗方法，值得进一步临床评估。
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