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Abstract：
BACKGROUND: 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.
METHODS: 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).
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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).
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：癌症干细胞（CSCs）在其发生中起着至关重要的作用，维护,和实体瘤的复发。虽然,miR-145-5p可以抑制CSCs的存活,对潜在机制的理解不足阻碍了患者进一步的治疗优化.慢病毒具有显著的转导效率,是研究中最常用的RNA载体,但显示出有限的肿瘤靶向能力。
方法：我们已经应用脂质体来修饰慢病毒表面，从而产生基于脂质体-慢病毒杂交体的载体，称为miR-145-5p-慢病毒纳米脂质体（MRL145），并系统分析了它们对肝脏CSCs（LCSCs）的潜在治疗作用。
结果:MRL145在体外和体内表现出高的递送效率和有效的抗肿瘤功效。机械上,过表达的miR-145-5p可以显著抑制自我更新，迁移,通过靶向IV型胶原α3链（COL4A3）和LCSC的侵袭能力。重要的是,COL4A3可以促进ser9磷酸化GSK-3β（p-GSK-3βS9）使GSK3β失活，并促进β-catenin易位进入细胞核以激活Wnt/β-catenin通路，从而促进自我更新，迁移,和LCSC的侵袭。有趣的是,COL4A3可通过调节GSK3β/Gli3/VMP1轴减弱细胞自噬,促进细胞自我更新,迁移,和LCSC的侵袭。
结论：这些发现为miR-145-5p在LCSC治疗中的作用模式提供了新的见解，并表明脂质体-病毒杂交载体在miRNA递送中具有巨大的前景。
方法：我们已经应用脂质体来修饰慢病毒表面，从而产生基于脂质体-慢病毒杂交体的载体，称为miR-145-5p-慢病毒纳米脂质体（MRL145），并系统分析了它们对肝脏CSCs（LCSCs）的潜在治疗作用。
结果:MRL145在体外和体内表现出高的递送效率和有效的抗肿瘤功效。机械上,过表达的miR-145-5p可以显著抑制自我更新，迁移,通过靶向IV型胶原α3链（COL4A3）和LCSC的侵袭能力。重要的是,COL4A3可以促进ser9磷酸化GSK-3β（p-GSK-3βS9）使GSK3β失活，并促进β-catenin易位进入细胞核以激活Wnt/β-catenin通路，从而促进自我更新，迁移,和LCSC的侵袭。有趣的是,COL4A3可通过调节GSK3β/Gli3/VMP1轴减弱细胞自噬,促进细胞自我更新,迁移,和LCSC的侵袭。
结论：这些发现为miR-145-5p在LCSC治疗中的作用模式提供了新的见解，并表明脂质体-病毒杂交载体在miRNA递送中具有巨大的前景。
