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miR-100 induces epithelial-mesenchymal transition but suppresses tumorigenesis, migration and invasion
- Source :
- PLoS Genetics, Vol 10, Iss 2, p e1004177 (2014), PLoS Genetics
- Publication Year :
- 2014
- Publisher :
- Public Library of Science (PLoS), 2014.
-
Abstract
- Whether epithelial-mesenchymal transition (EMT) is always linked to increased tumorigenicity is controversial. Through microRNA (miRNA) expression profiling of mammary epithelial cells overexpressing Twist, Snail or ZEB1, we identified miR-100 as a novel EMT inducer. Surprisingly, miR-100 inhibits the tumorigenicity, motility and invasiveness of mammary tumor cells, and is commonly downregulated in human breast cancer due to hypermethylation of its host gene MIR100HG. The EMT-inducing and tumor-suppressing effects of miR-100 are mediated by distinct targets. While miR-100 downregulates E-cadherin by targeting SMARCA5, a regulator of CDH1 promoter methylation, this miRNA suppresses tumorigenesis, cell movement and invasion in vitro and in vivo through direct targeting of HOXA1, a gene that is both oncogenic and pro-invasive, leading to repression of multiple HOXA1 downstream targets involved in oncogenesis and invasiveness. These findings provide a proof-of-principle that EMT and tumorigenicity are not always associated and that certain EMT inducers can inhibit tumorigenesis, migration and invasion.<br />Author Summary Induction of epithelial-mesenchymal transition (EMT) in epithelial tumor cells has been shown to enhance migration, invasion and cancer ‘stemness’. Here we demonstrate that a miRNA downregulated in human breast tumors, miR-100, can simultaneously induce EMT and inhibit tumorigenesis, migration and invasion through direct targeting of distinct genes. This is the first report of an EMT inducer that suppresses cell movement and tumor invasion, which indicates that EMT is not always associated with increased tumorigenesis, migration and invasion, and that all EMT inducers are not equal: while some of them can promote tumorigenicity, motility and invasiveness, others inhibit these properties owing to their ability to concurrently target both EMT-repressing genes and oncogenic/pro-invasive genes. These findings provide new insights into the complex roles of EMT inducers.
- Subjects :
- Cancer Research
Epithelial-Mesenchymal Transition
lcsh:QH426-470
Carcinogenesis
Breast Neoplasms
medicine.disease_cause
Cdh1 Proteins
CDH1
Mice
03 medical and health sciences
0302 clinical medicine
Cell Movement
Cell Line, Tumor
microRNA
Genetics
medicine
Animals
Humans
Neoplasm Invasiveness
Epithelial–mesenchymal transition
Biology
Molecular Biology
Genetics (clinical)
Ecology, Evolution, Behavior and Systematics
030304 developmental biology
Homeodomain Proteins
Regulation of gene expression
0303 health sciences
Mammary tumor
biology
Gene Expression Profiling
Epithelial Cells
Cadherins
Molecular biology
Gene Expression Regulation, Neoplastic
Gene expression profiling
MicroRNAs
lcsh:Genetics
030220 oncology & carcinogenesis
DNA methylation
biology.protein
Cancer research
Medicine
Female
Research Article
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 15537404 and 15537390
- Volume :
- 10
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- PLoS Genetics
- Accession number :
- edsair.doi.dedup.....fe62b709b2269e361888f67ee11dbed5