SIX2 Effects on Wilms Tumor Biology
| Autor: | Janene Pierce, Andrew J. Murphy, Alexis Panzer, Christian de Caestecker, Gregory D. Ayers, David Neblett, Kenyi Saito-Diaz, Mark de Caestecker, Harold N. Lovvorn, III |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: | |
| Zdroj: | Translational Oncology, Vol 7, Iss 6, Pp 800-811 (2014) |
| Druh dokumentu: | article |
| ISSN: | 1936-5233 1944-7124 |
| DOI: | 10.1016/j.tranon.2014.09.005 |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
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