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miR-100 induces epithelial-mesenchymal transition but suppresses tumorigenesis, migration and invasion

Authors :
Han Liang
Julie Teruya-Feldstein
Zhenbo Han
M. James You
Jinsong Zhang
Yutong Sun
Dahu Chen
Peijing Zhang
Sumeet Gupta
Li Ma
Yuan Yuan
Min Wang
Mien Chie Hung
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.

Details

Language :
English
ISSN :
15537404 and 15537390
Volume :
10
Issue :
2
Database :
OpenAIRE
Journal :
PLoS Genetics
Accession number :
edsair.doi.dedup.....fe62b709b2269e361888f67ee11dbed5