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

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

doi:10.1038/srep02687

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

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

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105 Scopus citations

Abstract

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 duringEMTin conjunction with changes inDNAmethylation 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.

Original language	English (US)
Article number	2687
Journal	Scientific reports
Volume	3
DOIs	https://doi.org/10.1038/srep02687
State	Published - Sep 18 2013

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10.1038/srep02687

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Taube, J. H., Malouf, G. G., Lu, E., Sphyris, N., Vijay, V., Ramachandran, P. P., Ueno, K. R., Gaur, S., Nicoloso, M. S., Rossi, S., Herschkowitz, J. I., Rosen, J. M., Issa, J. P. J., Calin, G. A., Chang, J. T., & Mani, S. A. (2013). Epigenetic silencing of microRNA-203 is required for EMT and cancer stem cell properties. Scientific reports, 3, Article 2687. https://doi.org/10.1038/srep02687

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title = "Epigenetic silencing of microRNA-203 is required for EMT and cancer stem cell properties",

abstract = "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 duringEMTin conjunction with changes inDNAmethylation 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.",

author = "Taube, {Joseph H.} and Malouf, {Gabriel G.} and Emily Lu and Nathalie Sphyris and Vidya Vijay and Ramachandran, {Priyanka P.} and Ueno, {Katumasa R.} and Sanchaika Gaur and Nicoloso, {Milena S.} and Simona Rossi and Herschkowitz, {Jason I.} and Rosen, {Jeffrey M.} and Issa, {Jean Pierre J.} and Calin, {George A.} and Chang, {Jeffrey T.} and Mani, {Sendurai A.}",

note = "Funding Information: We acknowledge the entire Mani Lab for invaluable discussion and advice. Also, we appreciate the assistance of Dr. Rudy Guerra of Rice University for additional statistical analysis. This work was supported by DOD Postdoctoral Fellowship BC101115 (JHT). JTC is supported by NIH R00LM009837 and grant R1006 from the Cancer Prevention and Research Institute of Texas. Flow cytometry, and animal imaging were in part funded by the Cancer Center Support Grant from the National Cancer Institute (CA16672). This work was supported in part by an MD Anderson Research Trust Fellow Award, funded by the George and Barbara Bush Endowment for Innovative Cancer Research (SAM). GM was also funded by the following non-for-profit organizations: Fondation Nadine Midy, Foundation Nelia et Amadeo Barletta (F.N.A.B.) and the Association pour l{\textquoteright}Aide {\`a}{\textquoteright}la Recherche et l{\textquoteright}Enseignement en Canc{\'e}rologie (A.A.R.E.C.).",

year = "2013",

month = sep,

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doi = "10.1038/srep02687",

language = "English (US)",

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journal = "Scientific reports",

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T1 - Epigenetic silencing of microRNA-203 is required for EMT and cancer stem cell properties

AU - Taube, Joseph H.

AU - Malouf, Gabriel G.

AU - Lu, Emily

AU - Sphyris, Nathalie

AU - Vijay, Vidya

AU - Ramachandran, Priyanka P.

AU - Ueno, Katumasa R.

AU - Gaur, Sanchaika

AU - Nicoloso, Milena S.

AU - Rossi, Simona

AU - Herschkowitz, Jason I.

AU - Rosen, Jeffrey M.

AU - Issa, Jean Pierre J.

AU - Calin, George A.

AU - Chang, Jeffrey T.

AU - Mani, Sendurai A.

N1 - Funding Information: We acknowledge the entire Mani Lab for invaluable discussion and advice. Also, we appreciate the assistance of Dr. Rudy Guerra of Rice University for additional statistical analysis. This work was supported by DOD Postdoctoral Fellowship BC101115 (JHT). JTC is supported by NIH R00LM009837 and grant R1006 from the Cancer Prevention and Research Institute of Texas. Flow cytometry, and animal imaging were in part funded by the Cancer Center Support Grant from the National Cancer Institute (CA16672). This work was supported in part by an MD Anderson Research Trust Fellow Award, funded by the George and Barbara Bush Endowment for Innovative Cancer Research (SAM). GM was also funded by the following non-for-profit organizations: Fondation Nadine Midy, Foundation Nelia et Amadeo Barletta (F.N.A.B.) and the Association pour l’Aide à’la Recherche et l’Enseignement en Cancérologie (A.A.R.E.C.).

PY - 2013/9/18

Y1 - 2013/9/18

N2 - 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 duringEMTin conjunction with changes inDNAmethylation 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.

AB - 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 duringEMTin conjunction with changes inDNAmethylation 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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Epigenetic silencing of microRNA-203 is required for EMT and cancer stem cell properties

Abstract

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