HIF-1α/Ascl2/miR-200b regulatory feedback circuit modulated the epithelial-mesenchymal transition (EMT) in colorectal cancer cells
HIF-1α/Ascl2/miR-200b regulatory feedback circuit modulated the epithelial-mesenchymal transition (EMT) in colorectal cancer cells
复制标题
HIF-1α/Ascl2/miR-200b调节反馈电路调节结直肠癌细胞的上皮间质转化（EMT）
DOI：
10.1016/j.yexcr.2017.09.014
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发表时间：
2017-11-15
影响因子：
3.7
通讯作者：
Wang, Rongquan
中科院分区：
文献类型：
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作者：
Shang, Yangyang;Chen, Haoyuan;Wang, Rongquan
我们已经报道了Achaete scute-like 2（Ascl 2）在转录上抑制miR-200家族成员并影响结直肠癌（CRC）细胞中的上皮-间充质转化（EMT）-间充质-上皮转化（MET）可塑性。然而，关于Ascl 2/miR-200轴的调控知之甚少。在此，我们发现，在CRC样本中，缺氧诱导因子-1 α（HIF-1 α）mRNA水平与Ascl 2 mRNA水平呈正相关，与miR-200 b呈负相关。从机制上讲，我们表明Ascl 2是HIF-1 α的下游靶点，在缺氧或HIF-1 α过度表达诱导的EMT表型中起关键作用。低氧或HIF-1 α过表达通过与近端Ascl 2启动子处的低氧应答元件（HRE）结合以直接转录机制激活CRC细胞中的Ascl 2表达。HIF-1 α诱导的Ascl 2表达抑制了miR-200 b的表达，从而诱导EMT的发生。此外，我们发现HIF-1 α是miR-200 b的直接靶点。miR-200 b与CRC细胞中HIF-1 α的3 '-UTR结合。HIF-1 alpha/Ascl 2/miR-200 b调控反馈回路调节CRC细胞的EMT-MET可塑性。我们的研究结果证实了一种新的HIF-1 alpha/Ascl 2/miR-200 b调节反馈回路在调节CRC细胞的EMT-MET可塑性中，这可能是一个可能的治疗靶点。
We have reported that Achaete scute-like 2 (Ascl2) transcriptionally repressed miR-200 family members and affected the epithelial-mesenchymal transition (EMT)-mesenchymal-epithelial transition (MET) plasticity in colorectal cancer (CRC) cells. However, little is known about the regulation of the Ascl2/miR-200 axis. Here, we found that hypoxia inducible factor-1 alpha (HIF-1 alpha) mRNA levels were positively correlated with Ascl2 mRNA levels and inversely correlated with miR-200b in CRC samples. Mechanistically, we showed that Ascl2 was a downstream target of HIF-1 alpha and had a critical role in the EMT phenotype induced by hypoxia or HIF-1 alpha over expression. Hypoxia or HIF-1 alpha over-expression activated Ascl2 expression in CRC cells in a direct transcriptional mechanism via binding with the hypoxia-response element (HRE) at the proximal Ascl2 promoter. HIF-1 alpha induced Ascl2 expression repressed miR-200b expression to induce EMT occurrence. Furthermore, we found HIF-1 alpha was a direct target of miR-200b. MiR-200b bound with the 3'-UTR of HIF-1 alpha in CRC cells. HIF-1 alpha/Ascl2/miR-200b regulatory feedback circuit modulated the EMT-MET plasticity of CRC cells. Our results confirmed a novel HIF-1 alpha/Ascl2/miR-200b regulatory feedback circuit in modulating EMT-MET plasticity of CRC cells, which could serve as a possible therapeutic target.