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SIX2 Effects on Wilms Tumor Biology()
Wilms tumor (WT) blastema retains gene expression profiles characteristic of the multipotent nephron progenitor pool, or cap mesenchyme (CM), in the developing kidney. As a result, WT blastema and the CM are believed to represent contextual analogues of one another. Sine oculis homeobox 2 (SIX2) is...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311027/ https://www.ncbi.nlm.nih.gov/pubmed/25500091 http://dx.doi.org/10.1016/j.tranon.2014.09.005 |
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author | Pierce, Janene Murphy, Andrew J. Panzer, Alexis de Caestecker, Christian Ayers, Gregory D. Neblett, David Saito-Diaz, Kenyi de Caestecker, Mark Lovvorn, Harold N. |
author_facet | Pierce, Janene Murphy, Andrew J. Panzer, Alexis de Caestecker, Christian Ayers, Gregory D. Neblett, David Saito-Diaz, Kenyi de Caestecker, Mark Lovvorn, Harold N. |
author_sort | Pierce, Janene |
collection | PubMed |
description | Wilms tumor (WT) blastema retains gene expression profiles characteristic of the multipotent nephron progenitor pool, or cap mesenchyme (CM), in the developing kidney. As a result, WT blastema and the CM are believed to represent contextual analogues of one another. Sine oculis homeobox 2 (SIX2) is a transcription factor expressed specifically in the CM, provides a critical mechanism for CM self-renewal, and remains persistently active in WT blastema, although its purpose in this childhood malignancy remains unclear. We hypothesized that SIX2, analogous to its function in development, confers a survival pathway to blastema, the putative WT stem cell. To test its functional significance in WT biology, wild-type SIX2 was overexpressed in the human WT cell line, WiT49. After validating this model, SIX2 effects on anchorage-independent growth, proliferation, invasiveness, canonical WNT pathway signaling, and gene expression of specific WNT pathway participants were evaluated. Relative to controls, WiT49 cells overexpressing SIX2 showed significantly enhanced anchorage-independent growth and early-passage proliferation representing surrogates of cell survival. Interestingly, overexpression of SIX2 generally repressed TCF/LEF-dependent canonical WNT signaling, which activates and coordinates both differentiation and stem pathways, but significantly heightened canonical WNT signaling through the survivin promoter, a mechanism that exclusively maintains the stem state. In summary, when overexpressed in a human WT cell line, SIX2 enhances cell survival and appears to shift the balance in WNT/β-catenin signaling away from a differentiation path and toward a stem cell survival path. |
format | Online Article Text |
id | pubmed-4311027 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Neoplasia Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-43110272015-02-14 SIX2 Effects on Wilms Tumor Biology() Pierce, Janene Murphy, Andrew J. Panzer, Alexis de Caestecker, Christian Ayers, Gregory D. Neblett, David Saito-Diaz, Kenyi de Caestecker, Mark Lovvorn, Harold N. Transl Oncol Article Wilms tumor (WT) blastema retains gene expression profiles characteristic of the multipotent nephron progenitor pool, or cap mesenchyme (CM), in the developing kidney. As a result, WT blastema and the CM are believed to represent contextual analogues of one another. Sine oculis homeobox 2 (SIX2) is a transcription factor expressed specifically in the CM, provides a critical mechanism for CM self-renewal, and remains persistently active in WT blastema, although its purpose in this childhood malignancy remains unclear. We hypothesized that SIX2, analogous to its function in development, confers a survival pathway to blastema, the putative WT stem cell. To test its functional significance in WT biology, wild-type SIX2 was overexpressed in the human WT cell line, WiT49. After validating this model, SIX2 effects on anchorage-independent growth, proliferation, invasiveness, canonical WNT pathway signaling, and gene expression of specific WNT pathway participants were evaluated. Relative to controls, WiT49 cells overexpressing SIX2 showed significantly enhanced anchorage-independent growth and early-passage proliferation representing surrogates of cell survival. Interestingly, overexpression of SIX2 generally repressed TCF/LEF-dependent canonical WNT signaling, which activates and coordinates both differentiation and stem pathways, but significantly heightened canonical WNT signaling through the survivin promoter, a mechanism that exclusively maintains the stem state. In summary, when overexpressed in a human WT cell line, SIX2 enhances cell survival and appears to shift the balance in WNT/β-catenin signaling away from a differentiation path and toward a stem cell survival path. Neoplasia Press 2014-12-10 /pmc/articles/PMC4311027/ /pubmed/25500091 http://dx.doi.org/10.1016/j.tranon.2014.09.005 Text en © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). |
spellingShingle | Article Pierce, Janene Murphy, Andrew J. Panzer, Alexis de Caestecker, Christian Ayers, Gregory D. Neblett, David Saito-Diaz, Kenyi de Caestecker, Mark Lovvorn, Harold N. SIX2 Effects on Wilms Tumor Biology() |
title | SIX2 Effects on Wilms Tumor Biology() |
title_full | SIX2 Effects on Wilms Tumor Biology() |
title_fullStr | SIX2 Effects on Wilms Tumor Biology() |
title_full_unstemmed | SIX2 Effects on Wilms Tumor Biology() |
title_short | SIX2 Effects on Wilms Tumor Biology() |
title_sort | six2 effects on wilms tumor biology() |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311027/ https://www.ncbi.nlm.nih.gov/pubmed/25500091 http://dx.doi.org/10.1016/j.tranon.2014.09.005 |
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