Institute of Animal Sciences and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, 250000, China.
School of Life Sciences, Tsinghua University, Beijing, 100084, China.
J Nanobiotechnology. 2024 Jun 10;22(1):329. doi: 10.1186/s12951-024-02534-0.
Cancer stem cells (CSCs) play a vital role in the occurrence, maintenance, and recurrence of solid tumors. Although, miR-145-5p can inhibit CSCs survival, poor understanding of the underlying mechanisms hamperes further therapeutic optimization for patients. Lentivirus with remarkable transduction efficiency is the most commonly used RNA carrier in research, but has shown limited tumor-targeting capability.
We have applied liposome to decorate lentivirus surface thereby yielding liposome-lentivirus hybrid-based carriers, termed miR-145-5p-lentivirus nanoliposome (MRL145), and systematically analyzed their potential therapeutic effects on liver CSCs (LCSCs).
MRL145 exhibited high delivery efficiency and potent anti-tumor efficacy under in vitro and in vivo. Mechanistically, the overexpressed miR-145-5p can significantly suppress the self-renewal, migration, and invasion abilities of LCSCs by targeting Collagen Type IV Alpha 3 Chain (COL4A3). Importantly, COL4A3 can promote phosphorylating GSK-3β at ser 9 (p-GSK-3β S9) to inactivate GSK3β, and facilitate translocation of β-catenin into the nucleus to activate the Wnt/β-catenin pathway, thereby promoting self-renewal, migration, and invasion of LCSCs. Interestingly, COL4A3 could attenuate the cellular autophagy through modulating GSK3β/Gli3/VMP1 axis to promote self-renewal, migration, and invasion of LCSCs.
These findings provide new insights in mode of action of miR-145-5p in LCSCs therapy and indicates that liposome-virus hybrid carriers hold great promise in miRNA delivery.
癌症干细胞（CSCs）在实体瘤的发生、维持和复发中起着至关重要的作用。尽管 miR-145-5p 可以抑制 CSCs 的存活，但对其潜在机制的理解不足阻碍了患者的进一步治疗优化。具有显著转导效率的慢病毒是研究中最常用的 RNA 载体，但显示出有限的肿瘤靶向能力。
我们应用脂质体来修饰慢病毒表面，从而产生基于脂质体-慢病毒混合的载体，称为 miR-145-5p-慢病毒纳米脂质体（MRL145），并系统地分析了它们对肝 CSCs（LCSCs）的潜在治疗效果。
MRL145 在体外和体内均表现出高递送效率和强大的抗肿瘤功效。在机制上，过表达的 miR-145-5p 通过靶向Ⅳ型胶原α 3 链（COL4A3），可显著抑制 LCSCs 的自我更新、迁移和侵袭能力。重要的是，COL4A3 可以促进 GSK-3β 在丝氨酸 9 位（p-GSK-3β S9）的磷酸化，从而使 GSK3β 失活，并促进 β-连环蛋白向核内易位，激活 Wnt/β-连环蛋白通路，从而促进 LCSCs 的自我更新、迁移和侵袭。有趣的是，COL4A3 可以通过调节 GSK3β/Gli3/VMP1 轴来减弱细胞自噬，从而促进 LCSCs 的自我更新、迁移和侵袭。
这些发现为 miR-145-5p 在 LCSCs 治疗中的作用机制提供了新的见解，并表明脂质体-病毒混合载体在 miRNA 传递方面具有广阔的应用前景。
