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P63 attenuates epithelial to mesenchymal potential in an experimental prostate cell model.

ABSTRACT: The transcription factor p63 is central for epithelial homeostasis and development. In our model of epithelial to mesenchymal transition (EMT) in human prostate cells, p63 was one of the most down-regulated transcription factors during EMT. We therefore investigated the role of p63 in EMT. Over-expression of the predominant epithelial isoform ?Np63? in mesenchymal type cells of the model led to gain of several epithelial characteristics without resulting in a complete mesenchymal to epithelial transition (MET). This was corroborated by a reciprocal effect when p63 was knocked down in epithelial EP156T cells. Global gene expression analyses showed that ?Np63? induced gene modules involved in both cell-to-cell and cell-to-extracellular-matrix junctions in mesenchymal type cells. Genome-wide analysis of p63 binding sites using ChIP-seq analyses confirmed binding of p63 to regulatory areas of genes associated with cell adhesion in prostate epithelial cells. DH1 and ZEB1 are two elemental factors in the control of EMT. Over-expression and knock-down of these factors, respectively, were not sufficient alone or in combination with ?Np63? to reverse completely the mesenchymal phenotype. The partial reversion of epithelial to mesenchymal transition might reflect the ability of ?Np63?, as a key co-ordinator of several epithelial gene expression modules, to reduce epithelial to mesenchymal plasticity (EMP). The utility of ?Np63? expression and the potential of reduced EMP in order to counteract metastasis warrant further investigation.

SUBMITTER: Olsen JR

PROVIDER: S-EPMC3641034 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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p63 attenuates epithelial to mesenchymal potential in an experimental prostate cell model.

Olsen Jan Roger JR Oyan Anne Margrete AM Rostad Kari K Hellem Margrete R MR Liu Jie J Li Lisha L Micklem David R DR Haugen Hallvard H Lorens James B JB Rotter Varda V Ke Xi-Song XS Lin Biaoyang B Kalland Karl-Henning KH

PloS one 20130501 5

The transcription factor p63 is central for epithelial homeostasis and development. In our model of epithelial to mesenchymal transition (EMT) in human prostate cells, p63 was one of the most down-regulated transcription factors during EMT. We therefore investigated the role of p63 in EMT. Over-expression of the predominant epithelial isoform ΔNp63α in mesenchymal type cells of the model led to gain of several epithelial characteristics without resulting in a complete mesenchymal to epithelial t ...[more]

PMID: 23658742

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Project description:BackgroundAcute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are syndromes of acute respiratory failure with extremely high mortality and few effective treatments. Mesenchymal stem cells (MSCs) may reportedly contribute to tissue repair in ALI and ARDS. However, applications of MSCs have been restricted due to safety considerations and limitations in terms of large-scale production and industrial delivery. Alternatively, the MSC secretome has been considered promising for use in therapeutic approaches and has been advanced in pre-clinical and clinical trials. Furthermore, the MSC secretome can be freeze-dried into a stable and ready-to-use supernatant lyophilized powder (SLP) form. Currently, there are no studies on the role of MSC SLP in ALI.MethodsIntratracheal bleomycin was used to induce ALI in mice, and intratracheal MSC SLP was administered as a treatment. Histopathological assessment was performed by hematoxylin and eosin, immunohistochemistry, and immunofluorescence staining. Apoptosis, inflammatory infiltration, immunological cell counts, cytokine levels, and mRNA- and protein-expression levels of relevant targets were measured by performing terminal deoxynucleotidyl transferase dUTP nick-end labeling assays, determining total cell and protein levels in bronchoalveolar lavage fluids, flow cytometry, multiple cytokine-detection techniques, and reverse transcriptase-quantitative polymerase chain reaction and western blot analysis, respectively.ResultsWe found that intratracheal MSC SLP considerably promoted cell survival, inhibited epithelial cell apoptosis, attenuated inflammatory cell recruitment, and reversed immunological imbalances induced by bleomycin. MSC SLP inhibited the interleukin 6-phosphorylated signal transducer and activator of transcription signaling pathway to activate tumor protein 63-jagged 2 signaling in basal cells, suppress T helper 17 cell differentiation, promote p63+ cell proliferation and lung damage repair, and attenuate inflammatory responses.ConclusionsMSC SLP ameliorated ALI by activating p63 and promoting p63+ cell proliferation and the repair of damaged epithelial cells. The findings of this study also shed insight into ALI pathogenesis and imply that MSC SLP shows considerable therapeutic promise for treating ALI and ARDS.

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P63 attenuates epithelial to mesenchymal potential in an experimental prostate cell model.

Publications

p63 attenuates epithelial to mesenchymal potential in an experimental prostate cell model.

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