首页> 外文期刊>Stem Cells >MiR-7, inhibited indirectly by LincRNA HOTAIR, directly inhibits SETDB1 and reverses the EMT of breast cancer stem cells by downregulating the STAT3 pathway
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MiR-7, inhibited indirectly by LincRNA HOTAIR, directly inhibits SETDB1 and reverses the EMT of breast cancer stem cells by downregulating the STAT3 pathway

机译:通过LincRNA HOTAIR间接抑制的MiR-7通过下调STAT3途径直接抑制SETDB1并逆转乳腺癌干细胞的EMT

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摘要

Epithelial-mesenchymal transition (EMT) contributes to tumor invasion and metastasis in many cancers and correlates highly with the acquisition of cancer stem cell (CSC) characteristics. EMT also correlates with changes in specific microRNAs (miRNAs) that have already been integrated into tumorigenic programs as either oncogenes or tumor suppressor genes. Here, we show that miR-7, which was downregulated in breast CSCs (BCSCs) isolated from the human MCF-7 and MDA-MB-231 cell lines, inhibited cell invasion and metastasis, decreased the BCSC population and partially reversed EMT in MDA-MB-231 cells by directly targeting the oncogene, SETDB1. The conspicuous epigenetic transition induced by miR-7 overexpression was found not only in MDA-MB-231 cells but also in BCSC xenograft tumors. MiR-7 inhibited the metastasis of BCSCs in lungs, kidneys, and adrenal glands of NOD/SCID mice. ChIP-polymerase chain reaction result suggested that the SETDB1 induced STAT3 expression by binding to the promoter of STAT3. MiR-7-mediated downregulation of SETDB1 resulted in the suppression of STAT3, which led to the downregulation of c-myc, twist, and mir-9. In addition, the downregulation of miR-7 in BCSCs may be indirectly attributed to lincRNA HOTAIR by modulating the expression of HoxD10 that promotes the expression of miR-7. These findings demonstrate that miR-7 was a tumor suppressor and that the overexpression of miR-7 might serve as a good strategy for treating highly invasive breast cancer.
机译:上皮间质转化(EMT)有助于许多癌症的肿瘤侵袭和转移,并与癌症干细胞(CSC)特征的获得高度相关。 EMT还与已经作为致癌基因或抑癌基因整合到致瘤程序中的特定microRNA(miRNA)的变化相关。在这里,我们显示miR-7(在从人MCF-7和MDA-MB-231细胞系分离的乳腺CSC(BCSC)中被下调,抑制了细胞的侵袭和转移,减少了BCSC群体并部分逆转了MDA中的EMT) -MB-231细胞可直接靶向癌基因SETDB1。由miR-7过度表达引起的明显表观遗传转变不仅在MDA-MB-231细胞中发现,而且在BCSC异种移植肿瘤中也发现。 MiR-7抑制了NOD / SCID小鼠肺,肾和肾上腺中BCSC的转移。 ChIP-聚合酶链反应结果表明,SETDB1通过与STAT3的启动子结合而诱导STAT3的表达。 MiR-7介导的SETDB1下调导致STAT3的抑制,从而导致c-myc,twist和mir-9的下调。此外,通过调节促进miR-7表达的HoxD10的表达,BCSC中miR-7的下调可能间接归因于lincRNA HOTAIR。这些发现表明,miR-7是一种肿瘤抑制因子,miR-7的过度表达可能是治疗高浸润性乳腺癌的良好策略。

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