A novel AP-1/miR-101 regulatory feedback loop and its implication in the migration and invasion of hepatoma cells.
A novel AP-1/miR-101 regulatory feedback loop and its implication in the migration and invasion of hepatoma cells.
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一种新的AP-1/miR-101调节反馈环路及其在肝癌细胞迁移和侵袭中的意义
DOI：
10.1093/nar/gku872
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发表时间：
2014-10-29
影响因子：
14.9
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Liu JJ;Lin XJ;Yang XJ;Zhou L;He S;Zhuang SM;Yang J
microRNA-101（miR-101）在多种癌症中经常下调。迄今为止，miR-101的调控网络仍然不清楚。在本研究中，我们证明了miR-101主要从人miR-101-2和小鼠miR-101 b基因位点转录。随后的分析显示，激活蛋白-1（AP-1）直接结合到前体miR-101-2上游的−17.4至−16.4 k区域，并激活miR-101的表达。另一方面，miR-101可通过与AP-1信号通路中的两个关键因子ERK 2和c-Fos的3′-UTR结合而抑制其表达。此外，重新引入miR-101有效地抑制AP-1活性和pri-miR-101-2转录。因此，这些数据表明了一种新的AP-1/miR-101调节回路，即AP-1促进miR-101的转录，而miR-101的表达降低ERK 2和c-Fos的水平，从而减弱AP-1信号传导。进一步研究发现，AP-1激活剂TPA诱导的MMP 9活性和TPA促进的肝癌细胞迁移和侵袭能力均被miR-101显著减弱，但被miR-101抑制剂增强。我们的研究结果表明，AP-1/miR-101反馈环可以防止ERK 2/AP-1施加的转移信号的过度激活，并突出了miR-101下调在癌症转移中的生物学意义。
MicroRNA-101 (miR-101) is frequently downregulated in various cancers. To date, the regulatory networks of miR-101 remain obscure. In this study, we demonstrated that miR-101 was mainly transcribed from human miR-101-2 and mouse miR-101bgene loci. Subsequent analyses revealed that activator protein-1 (AP-1) directly binded to the −17.4 to −16.4 k region upstream of pre-miR-101-2 and activated the expression of miR-101. On the other hand, miR-101 could inhibit the expression of ERK2 and c-Fos, two key factors of the AP-1 pathway, by binding to their 3′-UTRs. Furthermore, reintroduction of miR-101 efficiently suppressed the AP-1 activity and pri-miR-101-2 transcription. These data thus suggest a novel AP-1/miR-101 regulatory circuitry, that is, AP-1 promotes the transcription of miR-101, whereas the expression of miR-101 reduces the level of ERK2 and c-Fos and thereby attenuates the AP-1 signaling. Further investigation disclosed that the AP-1 activator TPA-induced MMP9 activity and the TPA-promoted migration and invasion of hepatoma cells were significantly attenuated by miR-101 but were enhanced by miR-101 inhibitor. Our results suggest that the AP-1/miR-101 feedback loop may prevent the excessive activation of metastatic signals imposed by ERK2/AP-1 and highlight the biological significance of miR-101 downregulation in cancer metastasis.
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DOI：
10.1084/jem.180.1.53
发表时间：
1994-07-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bartolazzi A;Peach R;Aruffo A;Stamenkovic I
通讯作者：
Stamenkovic I
影响因子：
64.8
作者：
O'Donnell, KA;Wentzel, EA;Mendell, JT
通讯作者：
Mendell, JT
影响因子：
7.3
作者：
Strillacci, Antonio;Valerii, Maria Chiara;Spisni, Enzo
通讯作者：
Spisni, Enzo
影响因子：
16
作者：
Kottakis F;Polytarchou C;Foltopoulou P;Sanidas I;Kampranis SC;Tsichlis PN
通讯作者：
Tsichlis PN
影响因子：
64.8
作者：
PULVERER, BJ;KYRIAKIS, JM;WOODGETT, JR
通讯作者：
WOODGETT, JR