MicroRNA-7, a homeobox D10 target, inhibits p21-activated kinase 1 and regulates its functions.
MicroRNA-7, a homeobox D10 target, inhibits p21-activated kinase 1 and regulates its functions.
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DOI：
10.1158/0008-5472.can-08-2103
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发表时间：
2008-10-15
期刊：
影响因子：
11.2
通讯作者：
Kumar R
中科院分区：
文献类型：
--
作者：
Reddy SD;Ohshiro K;Rayala SK;Kumar R
微小RNA（microRNAs，miRs）是一类非编码RNA，能以序列特异性的方式抑制靶基因的表达，在肿瘤发生过程中发挥重要作用。在这里，我们发现miR-7通过靶向Pak 1 mRNA的3′-UTR抑制p21激活激酶1（Pak 1）的表达，Pak 1是一种在多种人类癌症（包括乳腺癌和神经胶质瘤）中广泛上调的信号激酶。我们注意到人类癌细胞中内源性miR-7和Pak 1表达水平之间存在负相关性。我们发现内源性miR-7表达受同源域转录因子HoxD 10的正调控，HoxD 10的缺失导致侵袭性增加。HoxD 10直接与miR-7染色质相互作用。因此，在乳腺癌从低侵袭性表型进展到高侵袭性表型的细胞模型中，Pak 1蛋白的水平逐渐上调，而miR-7及其上游激活剂HoxD 10的水平逐渐下调。此外，HoxD 10在高侵袭性乳腺癌细胞中的表达导致miR-7表达增加，但Pak 1 3′ UTR-荧光素酶活性降低以及Pak 1蛋白减少。最后，我们发现miR-7的引入抑制了高侵袭性乳腺癌细胞的运动性、侵袭性、锚定非依赖性生长和致瘤潜力。总的来说，这些发现首次证实了Pak 1是miR-7的靶点，并且HoxD 10在修饰miR-7的表达中起调节作用，从而在人类癌细胞中修饰miR 7-Pak 1通路的功能。
MicroRNAs (miRs) are non-coding RNAs that inhibit expression of their targets in a sequence-specific manner and play crucial roles during oncogenesis. Here we show that miR-7 inhibits p21-activated kinase 1 (Pak1) expression, a widely upregulated signaling kinase in multiple human cancers including breast and gliomas, by targeting the 3′-UTR of Pak1 mRNA. We noticed an inverse correlation between the levels of endogenous miR-7 and Pak1 expression in human cancer cells. We discovered that endogenous miR-7 expression is positively regulated by a homeodomain transcription factor HoxD10, loss of which leads to an increased invasiveness. The HoxD10 directly interacts with the miR-7 chromatin. Accordingly, the levels of Pak1 protein are progressively upregulated while that of miR-7 and its upstream activator HoxD10 are progressively downregulated in a cellular model of breast cancer progression from low to highly invasive phenotypes. Furthermore, HoxD10 expression in highly invasive breast cancer cells resulted in an increased expression of miR-7 but a reduced Pak1 3′UTR-luciferase activity as well as reduced Pak1 protein. Finally, we show that miR-7 introduction inhibits the motility, invasiveness, anchorage-independent growth and tumorigenic potential of highly invasive breast cancer cells. Collectively, these findings establish for the first time that Pak1 is a target of miR-7 and that HoxD10 play a regulatory role in modifying the expression of miR-7, and consequently, functions of miR7 - Pak1 pathway in human cancer cells.