Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy.
Int J Mol Sci. 2022 May 13;23(10):5484. doi: 10.3390/ijms23105484.
Among the surrounding cells influencing tumor biology, platelets are recognized as novel players as they release microvesicles (MVs) that, once delivered to cancer cells, modulate signaling pathways related to cell growth and dissemination. We have previously shown that physiological delivery of platelet MVs enriched in miR-126 exerted anti-tumor effects in different breast cancer (BC) cell lines. Here, we seek further insight by identifying AKT2 kinase as a novel miR-126-3p direct target, as assessed by bioinformatic analysis and validated by luciferase assay. Both ectopic expression and platelet MV-mediated delivery of miR-126-3p downregulated AKT2 expression, thus suppressing proliferating and invading properties, in either triple negative (BT549 cells) or less aggressive Luminal A (MCF-7 cells) BC subtypes. Accordingly, as shown by bioinformatic analysis, both high miR-126 and low AKT2 levels were associated with favorable long-term prognosis in BC patients. Our results, together with the literature data, indicate that miR-126-3p exerts suppressor activity by specifically targeting components of the PIK3/AKT signaling cascade. Therefore, management of platelet-derived MV production and selective delivery of miR-126-3p to tumor cells may represent a useful tool in multimodal therapeutic approaches in BC patients.
在影响肿瘤生物学的周围细胞中，血小板被认为是新的参与者，因为它们释放的微小囊泡（MVs）一旦递送到癌细胞中，就会调节与细胞生长和扩散相关的信号通路。我们之前已经表明，富含 miR-126 的血小板 MV 的生理传递对不同的乳腺癌（BC）细胞系发挥了抗肿瘤作用。在这里，我们通过生物信息学分析评估 AKT2 激酶为 miR-126-3p 的新的直接靶标，并通过荧光素酶测定进行验证，从而进一步深入了解这一点。外源性表达和血小板 MV 介导的 miR-126-3p 传递均可下调 AKT2 表达，从而抑制增殖和侵袭特性，无论是在三阴性（BT549 细胞）还是侵袭性较低的 Luminal A（MCF-7 细胞）BC 亚型中。因此，正如生物信息学分析所示，高 miR-126 和低 AKT2 水平与 BC 患者的长期预后良好相关。我们的结果与文献数据一起表明，miR-126-3p 通过特异性靶向 PI3K/AKT 信号级联的组成部分发挥抑制活性。因此，管理血小板衍生的 MV 产生和 miR-126-3p 的选择性递送到肿瘤细胞可能是 BC 患者多模式治疗方法中的有用工具。
