Crosstalk between NF-kappa B/p65 and beta-catenin/TCF4/p300 signalling pathway through alterations in GSK-3 beta expression during trans-differntiation of endometrial carcinoma cells

beta-Catenin/TCF4/p300 signalling loops play an important role in trans-differentiation towards the morular phenotype of endometrial carcinomas. Crosstalk between NF-kappa B and beta-catenin pathways has been proposed and we focused here on associations between these two pathways during trans-differentiation. In normal endometrium, nuclear phosphorylated p65 (pp65), the active form NF-kappa B subunit, was found to be significantly increased in the secretory phase, correlating positively with vimentin and E-cadherin and inversely with Snail mRNA expression. On transfection of p65, vimentin, E-cadherin, and Snail were transcriptionally altered, indicating possible roles in establishment and maintenance of the secretory phenotype. In endometrial carcinomas with morules, levels of nuclear pp65, Snail mRNA, vimentin, and cytoplasmic TNF-alpha were reduced during trans-differentiation, correlating inversely with nuclear beta-catenin. Nuclear accumulation of GSK-3 beta, along with beta-catenin, was observed in morules. In cell lines, overexpression of p65 inhibited beta-catenin/TCF4-mediated transcription, while transfection of GSK-3 beta resulted in repression of TNF-alpha -induced NF-kappa B activity. Moreover, nuclear GSK-3 beta was increased by overexpression of beta-catenin, as well as induction of G1-cell cycle arrest. These findings provide evidence that a shift from NF-kappa B to beta-catenin signalling pathways through alterations in GSK3 beta expression may be essential for the induction of trans-differentiation of endometrial carcinoma cells, leading to a shut-down of mesenchymal markers. Copyright (c) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.