MiR-146a promotes the asymmetric division and inhibits the self-renewal ability of breast cancer stem-like cells via indirect upregulation of Let-7
MiR-146a promotes the asymmetric division and inhibits the self-renewal ability of breast cancer stem-like cells via indirect upregulation of Let-7
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MiR-146a通过间接上调Let-7促进乳腺癌干细胞样细胞的不对称分裂并抑制自我更新能力
DOI：
10.1080/15384101.2018.1489176
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发表时间：
2018-01-01
期刊：
影响因子：
4.3
通讯作者：
Ren, Hong
中科院分区：
文献类型：
--
作者：
Liang, Rui;Li, Yuan;Ren, Hong
MiR-146a在系统性恶性肿瘤中可以刺激肿瘤生长或阻断肿瘤增殖，这是指其特异的下游靶基因。然而，它在乳腺癌干细胞（BrCSCs）中的作用却鲜为人知。为了挖掘其机制功能，我们在临床前研究中探讨了miR-146在激素受体状态下的指示性作用，证实miR-146与预后良好呈正相关，与Let-7c相关。为了揭示相关机制，我们首先确定了miR-146a在干细胞更新中的抑制作用，这是通过促进BrCSCs的不对称分裂来实现的。Let-7c先前被发现在干细胞样细胞扩增中具有抑制功能，miR-146被预测并成功证明可以结合并降解Let-7家族的成熟阻断剂LIN28的3'UTR。结果进一步表明，miR-146a通过降解LIN28提高了Let-7c水平，miR-146a诱导不对称干细胞分裂需要抑制LIN28。此外，Let-7控制的Wnt信号通路活性可因miR146对H19的抑制而增强，H19在具有Wnt信号功能存在的干细胞组中经常被激活。H19自身又与Let-7形成正反馈调节。我们的研究结果提示miR-146a/LIN28/Wnt信号圈抑制细胞对称分裂，具体指的是控制Let-7c和H19的小圈，这两个双轴可以共同抑制干细胞的扩增。
ABSTRACT MiR-146a could stimulate tumor growth or block tumor proliferation in systemic malignancies, referring to the specific downstream targeted gene. However, its roles in breast cancer stem-like cells (BrCSCs) are barely known. To dig out its mechanistic functions, we explored the indicative roles of miR-146 in preclinical study, regardless of the hormone receptor status, and the positive correlation between miR-146 and better prognosis was proved, as its correlation to Let-7c was. To uncover the implicated mechanisms, we first identified the suppressive role of miR-146a in stem cells’ renewal, which was achieved by promoting the asymmetric division of BrCSCs. Let-7c was previously revealed with its suppressive functions in stem-like cells expansion, and miR-146 was predicated and successfully proved to bind to and degrade the 3’UTR of LIN28, a maturation blocker of Let-7 family. Results further showed that miR-146a increased the Let-7c level through degrading LIN28, and LIN28 inhibition is required for miR-146a induction of asymmetric stem cells’ division. Moreover, Let-7 controlled Wnt signaling pathway activity could be strengthened due to the miR146 inhibition of H19, later of which was often activated in stem cells group with functional existence of Wnt signaling. H19 itself in turn formed the positive feedback regulation with Let-7. Our results suggested the miR-146a/LIN28/Wnt signaling circle in restraining the symmetric cells division, which was specifically referred to the controlling of the small circle of Let-7c and H19, and together, this dual axis could help to prohibit the stem cells expansion.