Downregulation of p63 upon exposure to bile salts and acid in normal and cancer esophageal cells in culture

Abstract

Roman S, Pétré A, Thépot A, Hautefeuille A, Scoazec J-Y, Mion F, Hainaut P. Downregulation of p63 upon exposure to bile salts and acid in normal and cancer esophageal cells in culture. Am J Physiol Gastrointest Liver Physiol 293: G45-G53, 2007. doi:10.1152/ajpgi.00583.2006. p63 is a member of the p53 protein family that regulates differentiation and morphogenesis in epithelial tissues and is required for the formation of squamous epithelia. Barrett's mucosa is a glandular metaplasia of the squamous epithelium that develops in the lower esophagus in the context of chronic, gastroesophageal reflux and is considered as a precursor for adenocarcinoma. Normal or squamous cancer esophageal cells were exposed to deoxycholic acid (DCA, 50, 100, or 200 M) and chenodeoxycholic and taurochenodeoxycholic acid at pH 5. p63 and cyclooxygenase-2 (COX-2) expressions were studied by Western blot and RT-PCR. DCA exposure at pH 5 led to a spectacular decrease in the levels of all isoforms of the p63 proteins. This decrease was observed within minutes of exposure, with a synergistic effect between DCA and acid. Within the same time frame, levels of p63 mRNA were relatively unaffected, whereas levels of COX-2, a marker of stress responses often induced in Barrett's mucosa, were increased. Similar results were obtained with chenodeoxycholic acid but not its taurine conjugate at pH 5. Proteasome inhibition by lactacystin or MG-132 partially blocked the decrease in p63, suggesting a posttranslational degradation mechanism. These results show that combined exposure to bile salt and acid downregulates a critical regulator of squamous differentiation, providing a mechanism to explain the replacement of squamous epithelium by a glandular metaplasia upon exposure of the lower esophagus to gastric reflux.

The p63 Protein Isoform ΔNp63α Inhibits Epithelial-Mesenchymal Transition in Human Bladder Cancer Cells

“…1B). Among the six p63 isoforms, TAp63␣, TAp63␤, and ⌬Np63␣ are each ϳ75 kDa in size (23). Because ⌬Np63 was the most abundant isoform subgroup (Fig.…”

Recent advances in p53 research: an interdisciplinary perspective

“…44 Second, in esophageal cells, degradation of TP63 isoforms by the proteasome occurs in cells exposed to acid/bile stress, the main condition inducing the formation of intestinal metaplasia and adenocarcinoma in lower esophagus. 45 In breast cancer, five gene-expression profiling subtypes have been identified: normal breast-like, ERBB2 þ , basallike, luminal-B and luminal-A. 46 These subtypes have been reproduced in many other data sets and with different array platforms, and have been found in breast cancers of different stages.…”

A surprise cell of origin for Barrett’s esophagus

“…8 Exposure of esophageal squamous epithelial cells to bile and acid led to the downregulation of p63, a possible explanation why p63 is lost in Barrett's metaplasia. 16 However, the work discussed here argues for the origin of Barrett's from a cell that is inherently p63 -, rather than transdifferentiation of a p63 + cell. What is to be made of the lack of Cdx2 in the p63-null metaplasia?…”