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Crosstalk between NF‐κB/p65 and β‐catenin/TCF4/p300 signalling pathways through alterations in GSK‐3β expression during trans ‐differentiation of endometrial carcinoma cells
Author(s) -
Saegusa M,
Hashimura M,
Kuwata T,
Hamano M,
Okayasu I
Publication year - 2007
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2198
Subject(s) - vimentin , biology , catenin , transfection , microbiology and biotechnology , beta catenin , hedgehog signaling pathway , cancer research , signal transduction , chemistry , cell culture , wnt signaling pathway , immunology , immunohistochemistry , genetics
β‐Catenin/TCF4/p300 signalling loops play an important role in trans ‐differentiation towards the morular phenotype of endometrial carcinomas. Crosstalk between NF‐κB and β‐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‐κB 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‐α were reduced during trans ‐differentiation, correlating inversely with nuclear β‐catenin. Nuclear accumulation of GSK‐3β, along with β‐catenin, was observed in morules. In cell lines, overexpression of p65 inhibited β‐catenin/TCF4‐mediated transcription, while transfection of GSK‐3β resulted in repression of TNF‐α‐induced NF‐κB activity. Moreover, nuclear GSK‐3β was increased by overexpression of β‐catenin, as well as induction of G1‐cell cycle arrest. These findings provide evidence that a shift from NF‐κB to β‐catenin signalling pathways through alterations in GSK‐3β expression may be essential for the induction of trans ‐differentiation of endometrial carcinoma cells, leading to a shut‐down of mesenchymal markers. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.