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PLoS Genet. 2014 Feb 27;10(2):e1004177. doi: 10.1371/journal.pgen.1004177. eCollection 2014 Feb.

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

Author information

1
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
2
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
3
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ; Graduate Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas, United States of America.
4
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ; Cancer Biology Program, Graduate School of Biomedical Sciences, The University of Texas Health, Science Center at Houston, Houston, Texas, United States of America.
5
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
6
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, United States of America.
7
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ; Cancer Biology Program, Graduate School of Biomedical Sciences, The University of Texas Health, Science Center at Houston, Houston, Texas, United States of America.
8
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
9
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America ; Cancer Biology Program, Graduate School of Biomedical Sciences, The University of Texas Health, Science Center at Houston, Houston, Texas, United States of America.

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.

PMID:
24586203
PMCID:
PMC3937226
DOI:
10.1371/journal.pgen.1004177
[Indexed for MEDLINE]
Free PMC Article
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