Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, T Campanella Cancer Center, Salvatore Venuta University Campus; Pathology Unit, Magna Graecia University, Catanzaro, Italy.
Clin Cancer Res. 2012 Nov 15;18(22):6260-70. doi: 10.1158/1078-0432.CCR-12-1708. Epub 2012 Oct 3.
Deregulated expression of miRNAs has been shown in multiple myeloma (MM). A promising strategy to achieve a therapeutic effect by targeting the miRNA regulatory network is to enforce the expression of miRNAs that act as tumor suppressor genes, such as miR-34a.
Here, we investigated the therapeutic potential of synthetic miR-34a against human MM cells in vitro and in vivo.
Either transient expression of miR-34a synthetic mimics or lentivirus-based miR-34a-stable enforced expression triggered growth inhibition and apoptosis in MM cells in vitro. Synthetic miR-34a downregulated canonic targets BCL2, CDK6, and NOTCH1 at both the mRNA and protein level. Lentiviral vector-transduced MM xenografts with constitutive miR-34a expression showed high growth inhibition in severe combined immunodeficient (SCID) mice. The anti-MM activity of lipidic-formulated miR-34a was further shown in vivo in two different experimental settings: (i) SCID mice bearing nontransduced MM xenografts; and (ii) SCID-synth-hu mice implanted with synthetic 3-dimensional scaffolds reconstituted with human bone marrow stromal cells and then engrafted with human MM cells. Relevant tumor growth inhibition and survival improvement were observed in mice bearing TP53-mutated MM xenografts treated with miR-34a mimics in the absence of systemic toxicity.
Our findings provide a proof-of-principle that formulated synthetic miR-34a has therapeutic activity in preclinical models and support a framework for development of miR-34a-based treatment strategies in MM patients.
已经在多发性骨髓瘤（MM）中显示 miRNA 的表达失调。通过靶向 miRNA 调控网络来实现治疗效果的一种很有前途的策略是强制表达作为肿瘤抑制基因的 miRNA，例如 miR-34a。
在这里，我们研究了合成 miR-34a 对体外和体内人类 MM 细胞的治疗潜力。
miR-34a 合成模拟物的瞬时表达或基于慢病毒的 miR-34a 稳定表达均可在体外触发 MM 细胞的生长抑制和凋亡。合成 miR-34a 下调了 BCL2、CDK6 和 NOTCH1 的 mRNA 和蛋白水平的典型靶标。具有组成型 miR-34a 表达的慢病毒载体转导的 MM 异种移植物在严重联合免疫缺陷（SCID）小鼠中表现出高生长抑制。脂质制剂的 miR-34a 的抗 MM 活性在两种不同的实验设置中在体内进一步得到证明：（i）未转导 MM 异种移植物的 SCID 小鼠；和（ii）植入了由人骨髓基质细胞重建的合成 3 维支架并随后植入人 MM 细胞的 SCID-synth-hu 小鼠。在没有全身毒性的情况下，用 miR-34a 模拟物处理携带 TP53 突变的 MM 异种移植物的小鼠观察到相关的肿瘤生长抑制和生存改善。
我们的研究结果提供了一个原理证明，即配方合成 miR-34a 在临床前模型中具有治疗活性，并为开发基于 miR-34a 的治疗策略提供了框架，用于 MM 患者。
