miR-221 Augments TRAIL-Mediated Apoptosis in Prostate Cancer Cells by Inducing Endogenous TRAIL Expression and Targeting the Functional Repressors SOCS3 and PIK3R1
miR-221 Augments TRAIL-Mediated Apoptosis in Prostate Cancer Cells by Inducing Endogenous TRAIL Expression and Targeting the Functional Repressors SOCS3 and PIK3R1
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DOI：
10.1155/2019/6392748
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发表时间：
2019-11-14
影响因子：
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通讯作者：
Kneitz, Burkhard
中科院分区：
文献类型：
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作者：
Krebs, Markus;Behrmann, Christoph;Kneitz, Burkhard
miR-221 被认为是许多恶性肿瘤中的致癌基因，miR-221 介导的 TRAIL 抗性是这种小非编码 RNA 最早显示的致癌作用之一。相反，miR-221在前列腺癌（PCa）中下调，从而暗示肿瘤抑制功能。通过使用增殖和凋亡测定，我们在 PCa 细胞中展示了 miR-221 的一个新特征：miR-221 不是诱导 TRAIL 抗性，而是使细胞对 TRAIL 诱导的增殖抑制和凋亡诱导敏感。造成这种效应的部分原因是干扰素介导的基因特征，其中包括 TRAIL 编码基因 TNFSF10 的内源性过度表达。这种 TRAIL 友好的环境是由已建立的 miR-221 靶基因 SOCS3 的下调引起的。此外，我们在 PCa 细胞中引入 PIK3R1 作为 miR-221 的靶基因。增殖测定表明，siRNA 介导的 SOCS3 和 PIK3R1 下调模拟了 miR-221 对 TRAIL 敏感性的影响。最后，蛋白质印迹实验证实，在 PC3 细胞中 siRNA 介导的 PIK3R1 下调后，磷酸化 Akt 的含量较低。我们的结果进一步支持 miR-221 在 PCa 中的肿瘤抑制作用，因为它通过调节癌基因 SOCS3 和 PIK3R1 的表达使 PCa 细胞对 TRAIL 敏感。鉴于 miR-221 在各种癌症实体中的 TRAIL 抑制作用，我们的结果表明 miR-221 对 TRAIL 介导的细胞凋亡的影响高度依赖于背景和实体。
miR-221 is regarded as an oncogene in many malignancies, and miR-221-mediated resistance towards TRAIL was one of the first oncogenic roles shown for this small noncoding RNA. In contrast, miR-221 is downregulated in prostate cancer (PCa), thereby implying a tumour suppressive function. By using proliferation and apoptosis assays, we show a novel feature of miR-221 in PCa cells: instead of inducing TRAIL resistance, miR-221 sensitized cells towards TRAIL-induced proliferation inhibition and apoptosis induction. Partially responsible for this effect was the interferon-mediated gene signature, which among other things contained an endogenous overexpression of the TRAIL encoding gene TNFSF10. This TRAIL-friendly environment was provoked by downregulation of the established miR-221 target gene SOCS3. Moreover, we introduced PIK3R1 as a target gene of miR-221 in PCa cells. Proliferation assays showed that siRNA-mediated downregulation of SOCS3 and PIK3R1 mimicked the effect of miR-221 on TRAIL sensitivity. Finally, Western blotting experiments confirmed lower amounts of phospho-Akt after siRNA-mediated downregulation of PIK3R1 in PC3 cells. Our results further support the tumour suppressing role of miR-221 in PCa, since it sensitises PCa cells towards TRAIL by regulating the expression of the oncogenes SOCS3 and PIK3R1. Given the TRAIL-inhibiting effect of miR-221 in various cancer entities, our results suggest that the influence of miR-221 on TRAIL-mediated apoptosis is highly context- and entity-dependent.