Journal
EXPERIMENTAL CELL RESEARCH
Volume 360, Issue 2, Pages 243-256Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2017.09.014
Keywords
Hypoxia; Hypoxia inducible factor-1 alpha; Achaete scute-like 2; miRNA-200b; Epithelial-mesenchymal transition; Colorectal cancer
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Funding
- National Natural Science Foundation of China [81500410, 81572903, 81372557]
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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.
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