MiR-208a stimulates the cocktail of SOX2 and β-catenin to inhibit the let-7 induction of self-renewal repression of breast cancer stem cells and formed miR208a/let-7 feedback loop via LIN28 and DICER1.
MiR-208a stimulates the cocktail of SOX2 and β-catenin to inhibit the let-7 induction of self-renewal repression of breast cancer stem cells and formed miR208a/let-7 feedback loop via LIN28 and DICER1.
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DOI：
10.18632/oncotarget.5079
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发表时间：
2015-10-20
期刊：
影响因子：
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通讯作者：
Ren H
中科院分区：
文献类型：
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作者：
Sun X;Jiang S;Liu J;Wang H;Zhang Y;Tang SC;Wang J;Du N;Xu C;Wang C;Qin S;Zhang J;Liu D;Zhang Y;Li X;Wang J;Dong J;Wang X;Xu S;Tao Z;Xu F;Zhou J;Wang T;Ren H
miR-208 a刺激心肌细胞肥大、纤维化和β-MHC（β-myosin heavy chain，β-肌球蛋白重链）表达，参与心血管疾病的发生。尽管已知miR-208 a在心血管疾病中发挥作用，但其在癌症和癌症干细胞（CSC）中的作用仍不确定。我们确定了乳腺癌标本中miR-208 a和let-7a之间的反向关系，并发现SOX 2，β-catenin和LIN 28在晚期乳腺癌患者中高度表达，而不是较低级别。此外，我们从ZR 75 -1和MDA-MB-231（MM-231）乳腺癌细胞系中分离ALDH 1 + CSC以测试miR-208 a在乳腺CSC（BrCSC）中的作用。我们的研究表明，miR-208 a在这些细胞中的过表达强烈地促进了ALDH 1 + BrCSCs的比例，并持续刺激BrCSCs的自我更新能力。通过使用SOX 2和/或β-catenin的siRNA，我们发现miR-208 a通过刺激SOX 2和β-catenin两者来增加LIN 28。SOX 2或β-catenin的敲除仅部分减弱了miR-208 a的功能。在miR-208 a过表达的癌细胞中，Let-7a表达被强烈抑制，这是通过miR-208 a诱导LIN 28来实现的，并且let-7a的恢复显著抑制了miR-208 a诱导的ALDH 1+细胞的数量，抑制了BrCSC的增殖。在let-7a过表达的ZR 75 -1和MM-231细胞中，DICER 1活性显著抑制，miR-208 a减少。Let-7a不能降低DICER 1敲低的ZR 75 -1和MM-231细胞中miR-208 a的表达。我们的研究揭示了miR-208 a在乳腺癌和BrCSC中的作用机制，并确定了miR-208 a-SOX 2/β-catenin-LIN 28-let-7a-DICER 1调节干细胞更新的调节反馈环。
MiR-208a stimulates cardiomyocyte hypertrophy, fibrosis and β-MHC (β-myosin heavy chain) expression, being involved in cardiovascular diseases. Although miR-208a is known to play a role in cardiovascular diseases, its role in cancer and cancer stem cells (CSCs) remains uncertain. We identified an inverse relationship between miR-208a and let-7a in breast cancer specimens, and found that SOX2, β-catenin and LIN28 are highly expressed in patients with advanced breast cancer opposed to lesser grades. Further, we isolated ALDH1+ CSCs from ZR75–1 and MDA-MB-231 (MM-231) breast cancer cell lines to test the role of miR-208a in breast CSCs (BrCSCs). Our studies showed that overexpression of miR-208a in these cells strongly promoted the proportion of ALDH1+ BrCSCs and continuously stimulated the self-renewal ability of BrCSCs. By using siRNAs of SOX2 and/or β-catenin, we found that miR-208a increased LIN28 through stimulation of both SOX2 and β-catenin. The knockdown of either SOX2 or β-catenin only partially attenuated the functions of miR-208a. Let-7a expression was strongly inhibited in miR-208a overexpressed cancer cells, which was achieved by miR-208a induction of LIN28, and the restoration of let-7a significantly inhibited the miR-208a induction of the number of ALDH1+ cells, inhibiting the propagations of BrCSCs. In let-7a overexpressed ZR75–1 and MM-231 cells, DICER1 activity was significantly inhibited with decreased miR-208a. Let-7a failed to decrease miR-208a expression in ZR75–1 and MM-231 cells with DICER1 knockdown. Our research revealed the mechanisms through which miR-208a functioned in breast cancer and BrCSCs, and identified the miR-208a-SOX2/β-catenin-LIN28-let-7a-DICER1 regulatory feedback loop in regulations of stem cells renewal.