Epigenetic silencing of microRNA-203 is required for EMT and cancer stem cell properties

被引：0
作者：
Joseph H. Taube
Gabriel G. Malouf
Emily Lu
Nathalie Sphyris
Vidya Vijay
Priyanka P. Ramachandran
Katumasa R. Ueno
Sanchaika Gaur
Milena S. Nicoloso
Simona Rossi
Jason I. Herschkowitz
Jeffrey M. Rosen
Jean-Pierre J. Issa
George A. Calin
Jeffrey T. Chang
Sendurai A. Mani
机构：
[1] The University of Texas MD Anderson Cancer Center,Department of Translational Molecular Pathology
[2] Metastasis Research Center,Department of Leukemia
[3] The University of Texas MD Anderson Cancer Center,Department of Medical Oncology
[4] The University of Texas MD Anderson Cancer Center,Department of Experimental Therapeutics
[5] Hôpital de la Beaujon,Department of Molecular and Cellular Biology
[6] U 728 Inserm,Department of Integrative Biology and Pharmacology
[7] University Paris VII,Center for Stem Cells & Developmental Biology
[8] Center for Clinical and Translational Sciences,undefined
[9] The University of Texas Health Science Center at Houston,undefined
[10] The University of Texas MD Anderson Cancer Center,undefined
[11] Baylor College of Medicine,undefined
[12] Fels Institute for Cancer Research and Molecular Biology,undefined
[13] Temple University,undefined
[14] The University of Texas Health Science Center at Houston,undefined
[15] The University of Texas MD Anderson Cancer Center,undefined
来源：
Scientific Reports | / 3卷
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摘要：
The epithelial-mesenchymal transition (EMT) imparts metastatic competence on otherwise non-metastatic cancer cells through decreased inter-cellular adhesions, increased migratory capacity, stem cell properties and anoikis and chemotherapy resistance. In this study, we profiled changes in microRNA expression during EMT in conjunction with changes in DNA methylation at microRNA promoters to discover essential mediators of EMT-imparted stemness properties. MicroRNA-203 (miR-203) expression is repressed following EMT induced by multiple different stimuli and in established claudin-low cell lines as well as the CD44hi/CD24lo stem cell-enriched fraction. Expression of miR-203 in mesenchymal cells compromises migratory and invasive capacity in vitro and tumor initiation and metastasis in vivo. Unexpectedly, miR-203 expression affects the sphere-forming capacity of neighboring cells by indirectly enhancing expression of DKK1, a secreted inhibitor of Wnt signaling and stemness resulting in suppression of β-catenin protein levels. Our data suggest that restoring miR-203 expression levels may inhibit metastasis and combat deregulated Wnt signaling.
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