Activation of peroxisome proliferator-activated receptor-gamma reverses squamous metaplasia and induces transitional differentiation in normal human urothelial cells

C.L. Varley; J. Stahlschmidt; B. Smith; M. Stower; J. Southgate

doi:10.1016/S0002-9440(10)63737-6

Activation of peroxisome proliferator-activated receptor-gamma reverses squamous metaplasia and induces transitional differentiation in normal human urothelial cells

C.L. Varley, J. Stahlschmidt, B. Smith, M. Stower, J. Southgate

Research output: Contribution to journal › Article › peer-review

Abstract

We observed that in urothelium, both cornifying and noncornifying forms of squamous metaplasia are accompanied by changes in the localization of the nuclear hormone receptors, peroxisome proliferator activated receptor ¿ (PPAR-¿) and retinoid X receptor (RXR-a). To obtain objective evidence for a role for PPAR--mediated signaling in urothelial differentiation, we examined expression of the cytokeratin isotypes CK13, CK20, and CK14 as indicators of transitional, terminal transitional, and squamous differentiation, respectively, in cultures of normal human urothelial cells. In control culture conditions, normal human urothelial cells showed evidence of squamous differentiation (CK14+, CK13–, CK20–). Treatment with the high-affinity PPAR-¿ agonist, troglitazone (TZ), resulted in gain of CK13 and loss of CK14 protein expression. The effect of TZ was significantly augmented when the autocrine-stimulated epidermal growth factor receptor pathway was inhibited and this resulted in induction of CK20 expression. The RXR-specific inhibitors PA452, HX531, and HX603 inhibited the TZ-induced CK13 expression, supporting a role for RXR in the induction of CK13 expression. Thus, signaling through PPAR-¿ can mediate transitional differentiation of urothelial cells and this is modulated by growth regulatory programs.

Original language	English
Pages (from-to)	1789-1798
Number of pages	9
Journal	American Journal of Pathology
Volume	164
Issue number	5
DOIs	https://doi.org/10.1016/S0002-9440(10)63737-6
Publication status	Published - May 2004

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10.1016/S0002-9440(10)63737-6

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@article{6e27bbbb02434630a6e01ecff49818bc,

title = "Activation of peroxisome proliferator-activated receptor-gamma reverses squamous metaplasia and induces transitional differentiation in normal human urothelial cells",

abstract = "We observed that in urothelium, both cornifying and noncornifying forms of squamous metaplasia are accompanied by changes in the localization of the nuclear hormone receptors, peroxisome proliferator activated receptor ¿ (PPAR-¿) and retinoid X receptor (RXR-a). To obtain objective evidence for a role for PPAR--mediated signaling in urothelial differentiation, we examined expression of the cytokeratin isotypes CK13, CK20, and CK14 as indicators of transitional, terminal transitional, and squamous differentiation, respectively, in cultures of normal human urothelial cells. In control culture conditions, normal human urothelial cells showed evidence of squamous differentiation (CK14+, CK13–, CK20–). Treatment with the high-affinity PPAR-¿ agonist, troglitazone (TZ), resulted in gain of CK13 and loss of CK14 protein expression. The effect of TZ was significantly augmented when the autocrine-stimulated epidermal growth factor receptor pathway was inhibited and this resulted in induction of CK20 expression. The RXR-specific inhibitors PA452, HX531, and HX603 inhibited the TZ-induced CK13 expression, supporting a role for RXR in the induction of CK13 expression. Thus, signaling through PPAR-¿ can mediate transitional differentiation of urothelial cells and this is modulated by growth regulatory programs.",

author = "C.L. Varley and J. Stahlschmidt and B. Smith and M. Stower and J. Southgate",

year = "2004",

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doi = "10.1016/S0002-9440(10)63737-6",

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T1 - Activation of peroxisome proliferator-activated receptor-gamma reverses squamous metaplasia and induces transitional differentiation in normal human urothelial cells

AU - Varley, C.L.

AU - Stahlschmidt, J.

AU - Smith, B.

AU - Stower, M.

AU - Southgate, J.

PY - 2004/5

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N2 - We observed that in urothelium, both cornifying and noncornifying forms of squamous metaplasia are accompanied by changes in the localization of the nuclear hormone receptors, peroxisome proliferator activated receptor ¿ (PPAR-¿) and retinoid X receptor (RXR-a). To obtain objective evidence for a role for PPAR--mediated signaling in urothelial differentiation, we examined expression of the cytokeratin isotypes CK13, CK20, and CK14 as indicators of transitional, terminal transitional, and squamous differentiation, respectively, in cultures of normal human urothelial cells. In control culture conditions, normal human urothelial cells showed evidence of squamous differentiation (CK14+, CK13–, CK20–). Treatment with the high-affinity PPAR-¿ agonist, troglitazone (TZ), resulted in gain of CK13 and loss of CK14 protein expression. The effect of TZ was significantly augmented when the autocrine-stimulated epidermal growth factor receptor pathway was inhibited and this resulted in induction of CK20 expression. The RXR-specific inhibitors PA452, HX531, and HX603 inhibited the TZ-induced CK13 expression, supporting a role for RXR in the induction of CK13 expression. Thus, signaling through PPAR-¿ can mediate transitional differentiation of urothelial cells and this is modulated by growth regulatory programs.

AB - We observed that in urothelium, both cornifying and noncornifying forms of squamous metaplasia are accompanied by changes in the localization of the nuclear hormone receptors, peroxisome proliferator activated receptor ¿ (PPAR-¿) and retinoid X receptor (RXR-a). To obtain objective evidence for a role for PPAR--mediated signaling in urothelial differentiation, we examined expression of the cytokeratin isotypes CK13, CK20, and CK14 as indicators of transitional, terminal transitional, and squamous differentiation, respectively, in cultures of normal human urothelial cells. In control culture conditions, normal human urothelial cells showed evidence of squamous differentiation (CK14+, CK13–, CK20–). Treatment with the high-affinity PPAR-¿ agonist, troglitazone (TZ), resulted in gain of CK13 and loss of CK14 protein expression. The effect of TZ was significantly augmented when the autocrine-stimulated epidermal growth factor receptor pathway was inhibited and this resulted in induction of CK20 expression. The RXR-specific inhibitors PA452, HX531, and HX603 inhibited the TZ-induced CK13 expression, supporting a role for RXR in the induction of CK13 expression. Thus, signaling through PPAR-¿ can mediate transitional differentiation of urothelial cells and this is modulated by growth regulatory programs.

U2 - 10.1016/S0002-9440(10)63737-6

DO - 10.1016/S0002-9440(10)63737-6

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