MiR-221 promotes stemness of breast cancer cells by targeting DNMT3b.
MiR-221 promotes stemness of breast cancer cells by targeting DNMT3b.
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DOI：
10.18632/oncotarget.5979
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发表时间：
2016-01-05
期刊：
影响因子：
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通讯作者：
Condorelli G
中科院分区：
文献类型：
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作者：
Roscigno G;Quintavalle C;Donnarumma E;Puoti I;Diaz-Lagares A;Iaboni M;Fiore D;Russo V;Todaro M;Romano G;Thomas R;Cortino G;Gaggianesi M;Esteller M;Croce CM;Condorelli G
肿瘤干细胞（cancer stem cells，CSCs）是异质性肿瘤细胞群中的一小部分，具有自我更新和多向分化潜能，并具有很强的维持肿瘤发生的能力。CSC表型的分子途径尚未得到很好的表征。microRNAs（miRs）是一类在生物学过程中发挥重要作用的非编码小分子RNA。早期的研究已经将miR与控制正常和癌症干细胞的自我更新和分化联系起来。我们的目的是研究miR在人乳腺癌干细胞（BCSC）中的功能作用，也称为乳腺球。我们发现miR-221在BCSC中的表达与其分化的对应物相比上调。类似地，与分化的细胞相比，来自T47 D细胞的乳腺球具有增加的miR-221水平。在T47 D细胞中转染miR-221增加了乳腺球的数量和干细胞标志物的表达。在miR-221的靶点中，我们鉴定了DNMT 3b。此外，在BCSC中，我们发现DNMT 3b抑制了各种干性基因的表达，如Nanog和Oct 3/4，作用于其启动子的甲基化，部分逆转了miR-221对干性的影响。我们假设miR-221通过调节干性，至少部分通过控制DNMT 3b表达，促进乳腺癌的致瘤性。
Cancer stem cells (CSCs) are a small part of the heterogeneous tumor cell population possessing self-renewal and multilineage differentiation potential as well as a great ability to sustain tumorigenesis. The molecular pathways underlying CSC phenotype are not yet well characterized. MicroRNAs (miRs) are small noncoding RNAs that play a powerful role in biological processes. Early studies have linked miRs to the control of self-renewal and differentiation in normal and cancer stem cells. We aimed to study the functional role of miRs in human breast cancer stem cells (BCSCs), also named mammospheres. We found that miR-221 was upregulated in BCSCs compared to their differentiated counterpart. Similarly, mammospheres from T47D cells had an increased level of miR-221 compared to differentiated cells. Transfection of miR-221 in T47D cells increased the number of mammospheres and the expression of stem cell markers. Among miR-221's targets, we identified DNMT3b. Furthermore, in BCSCs we found that DNMT3b repressed the expression of various stemness genes, such as Nanog and Oct 3/4, acting on the methylation of their promoters, partially reverting the effect of miR-221 on stemness. We hypothesize that miR-221 contributes to breast cancer tumorigenicity by regulating stemness, at least in part through the control of DNMT3b expression.