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| Status |
Public on Feb 26, 2015 |
| Title |
TWIST1-induced microRNA-424 drives an intermediate epithelial-to-mesenchymal transition that opposes metastasis |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Epithelial-to-mesenchymal transition (EMT) is a dynamic process that relies on cellular plasticity; an EMT/MET axis is critical for metastatic colonization of carcinomas. Unlike epithelial programming, regulation of mesenchymal programming is not well understood in EMT. Here we describe the first microRNA that enhances exclusively mesenchymal programming. We demonstrate that microRNA-424 is up-regulated early during a TWIST1/SNAI1-induced EMT, and that it causes cells to express mesenchymal genes without affecting epithelial genes, resulting in a mixed/intermediate EMT. Further, microRNA-424 increases motility, decreases adhesion and induces a growth arrest, changes associated with a complete EMT. Patient microRNA-424 levels positively associate with TWIST1/2 and EMT-like gene signatures and is increased in primary tumors versus matched normal breast. However, microRNA-424 is down-regulated in metastases versus matched primary tumors. Correspondingly, microRNA-424 decreases tumor initiation and is post-transcriptionally down-regulated in macrometastases in mice. RNA-seq identified microRNA-424 regulates numerous genes associated with EMT and breast cancer stemness including the novel miR-424 target, TGFBR3, which regulates mesenchymal phenotypes without influencing miR-424 effects on tumor-initiating phenotypes; instead, we show that ERK signaling is critical for such tumor-initiating effects of miR-424. These findings suggest microRNA-424 plays distinct roles downstream of EMT-inducing factors, facilitating earlier stages, but repressing later stages, of metastasis.
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| Overall design |
Examination of mRNA levels in MCF12A human breast cell lines that stably over-expressed miR-424 or an empty vector (EV) control. Each group has three replicates.
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| Contributor(s) |
Drasin DJ, Guarnieri AL, Neelakantan D, Kim J, Cabrera JH, Wang CA, Zaberezhnyy V, Gasparini P, Cascione L, Heubner K, Tan AC, Ford HL |
| Citation(s) |
25716682 |
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| Submission date |
Jan 29, 2014 |
| Last update date |
May 15, 2019 |
| Contact name |
Jihye Kim |
| E-mail(s) |
kim.jihey@gmail.com
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| Phone |
7209755448
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| Organization name |
Cleveland Clinic
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| Department |
Quantitative Health Sciences
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| Street address |
9500 Euclid Ave.
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| City |
Cleveland |
| State/province |
Ohio |
| ZIP/Postal code |
44195 |
| Country |
USA |
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| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA236738 |
| SRA |
SRP036035 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE54505_EVvs424_FPKM_Annot.txt.gz |
1.0 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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