Prolyl isomerase Pin1 is frequently up-regulated in a variety of human malignancies, modulating signalling in several oncogenic pathways, including those involving NF-κB and β-catenin. Our previous study provided evidence that alterations in these signal pathways are essential events during trans-differentiation of endometrial carcinoma (Em Ca) cells. Here we focused on the functional roles of Pin1. In normal endometrium, Pin1 expression showed a stepwise decrease from proliferative to secretory phases during the menstrual cycle, correlating positively with cell proliferation and expression of several cell cycle-related molecules including E2F1 and pRb. Transfection of E2F1 caused transactivation of Pin1, indicating control by E2F1/Rb pathways. In Em Cas with morules, Pin1 expression was found to be significantly increased in glandular but not in morular components, correlating inversely with nuclear accumulation of β-catenin. Overexpression also caused an increase in the stability of nuclear p65, leading to enhancement of NF-κB-mediated transactivation of the cyclin D1 gene, in contrast to minimal inhibition of β-catenin/TCF4 transcription activity. These findings indicate that Pin1 may play an important role in preserving cell proliferative activity in glandular carcinoma components through enhancement of NF-κB signalling, but its down-regulation may be a key signal for induction of trans-differentiation of Em Ca cells, contributing to a shift from NF-κB to β-catenin/TCF signalling pathways.
Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.