H19/let-7/LIN28 reciprocal negative regulatory circuit promotes breast cancer stem cell maintenance.
H19/let-7/LIN28 reciprocal negative regulatory circuit promotes breast cancer stem cell maintenance.
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H19/let-7/LIN28相互负调节电路促进乳腺癌干细胞维持
DOI：
10.1038/cddis.2016.438
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发表时间：
2017-01-19
影响因子：
9
通讯作者：
Liu Q
中科院分区：
文献类型：
--
作者：
Peng F;Li TT;Wang KL;Xiao GQ;Wang JH;Zhao HD;Kang ZJ;Fan WJ;Zhu LL;Li M;Cui B;Zheng FM;Wang HJ;Lam EW;Wang B;Xu J;Liu Q
长链非编码RNA-H19（H19）是一种印记癌胚基因，在肿瘤发生中起着重要作用。H19调节癌症干细胞的机制仍然难以捉摸。在这里，我们发现乳腺癌干细胞（BCSCs）表达高水平的H19，H19的异位过表达显著促进乳腺癌细胞的克隆形成，迁移和乳腺球形成能力。相反，H19的沉默抑制这些BCSC特性。一致地，敲低H19显著抑制裸鼠中的肿瘤生长并抑制肿瘤发生。从机制上讲，我们发现H19作为竞争性内源性RNA与海绵状miRNA let-7竞争，导致let-7靶点（核心多能性因子LIN 28）表达增加，其在BCSC群体和乳腺患者样本中富集。有趣的是，这种LIN 28表达的增加也可以反馈以逆转H19损失介导的BCSC性质的抑制。我们的数据还表明，LIN 28阻断成熟let-7的产生，从而解除乳腺癌细胞中H19表达的抑制。适当地，H19和LIN 28表达在原发性乳腺癌中表现出强相关性。总的来说，这些发现揭示了lncRNA H19、miRNA let-7和转录因子LIN 28形成了一个双负反馈环，该环在BCSC的维持中具有关键作用。因此，破坏这一途径为乳腺癌提供了一种新的治疗策略。
Long noncoding RNA-H19 (H19), an imprinted oncofetal gene, has a central role in carcinogenesis. Hitherto, the mechanism by which H19 regulates cancer stem cells, remains elusive. Here we show that breast cancer stem cells (BCSCs) express high levels of H19, and ectopic overexpression of H19 significantly promotes breast cancer cell clonogenicity, migration and mammosphere-forming ability. Conversely, silencing of H19 represses these BCSC properties. In concordance, knockdown of H19 markedly inhibits tumor growth and suppresses tumorigenesis in nude mice. Mechanistically, we found that H19 functions as a competing endogenous RNA to sponge miRNA let-7, leading to an increase in expression of a let-7 target, the core pluripotency factor LIN28, which is enriched in BCSC populations and breast patient samples. Intriguingly, this gain of LIN28 expression can also feedback to reverse the H19 loss-mediated suppression of BCSC properties. Our data also reveal that LIN28 blocks mature let-7 production and, thereby, de-represses H19 expression in breast cancer cells. Appropriately, H19 and LIN28 expression exhibits strong correlations in primary breast carcinomas. Collectively, these findings reveal that lncRNA H19, miRNA let-7 and transcriptional factor LIN28 form a double-negative feedback loop, which has a critical role in the maintenance of BCSCs. Consequently, disrupting this pathway provides a novel therapeutic strategy for breast cancer.