Wnt-signalling pathway in ovarian epithelial tumours: increased expression of β-catenin and GSK3β

Abstract

Beta-catenin is involved in both cell -cell adhesion and in transcriptional regulation by the Wingless/Wnt signalling pathway. Alterations of components of this pathway have been suggested to play a central role in tumorigenesis. The present study investigated, by immunohistochemistry and immunoblotting, the protein expression and localisation of b-catenin, adenomatous polyposis coli (APC), glycogen synthase kinase 3b (GSK3b) and lymphocyte enhancer factor-1 (Lef-1) in normal human ovaries and in epithelial ovarian tumours in vivo and in vitro. Immortalised human ovarian surface epithelium and ovarian cancer cell cells (OVCAR-3) expressed b-catenin, APC, GSK3b and Lef-1. Nuclear staining of b-catenin and Lef-1 were demonstrated only in OVCAR-3 cells. There were significant increases of b-catenin and GSK3b, while APC was reduced in ovarian cancer compared to the normal ovary. Beta-catenin and Lef-1 were coimmunoprecipitated in ovarian tumours, but not in the normal ovary. Nuclear localisation of b-catenin or Lef-1 could not be demonstrated in the normal ovary or in the ovarian tumours. The absence of nuclear localisation of b-catenin could be due to an increased binding to the cadherin -a-catenin cell adhesion complex. In fact, we have earlier reported an increased expression of E-cadherin in ovarian adenocarcinomas. In summary, this study demonstrates an increase in the expression of components of the Wingless/Wnt pathway in malignant ovarian tumours. The increase suggests a role for this signalling pathway in cell transformation and in tumour progression. However, it remains to be demonstrated whether it is an increased participation of b-catenin in transcriptional regulation, or in the stabilisation of cellular integrity, or both, that is the crucial event in ovarian tumorigenesis.

Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

“…Nevertheless, nuclear ␤-catenin has been observed in serous ovarian cancers, and coimmunoprecipitation of Lef-1 and ␤-catenin from serous tumors has been reported (53,(55)(56)(57). It should be noted that Wnt signaling is not constitutively activated in the majority of individual cells in cases positive for nuclear ␤-catenin; however, current approaches do not enable detection of transient activation of Wnt signaling, such as may occur following initial engagement of tumor cell integrins with submesothelial collagens.…”

The Pivotal Roles of GSK3β in Glioma Biology

“…This suggests that GSK3 inhibitors could exert a therapeutically negative, pro-survival effect on tumor cells. In addition, some studies found that GSK3 is part of a tumor suppressor complex consisting of axin and APC that phosphorylates the oncoprotein -catenin and that, when GSK3 is inactivated, could possibly lead to tumor promotion (Hinoi et al, 2000;Rask et al, 2003). Available evidence indicates that GSK3 may function as a "tumor suppressor" for certain types of tumors such as skin and mammary tumors (Farago et al, 2005;Ma et al, 2007).…”

Glycogen synthase kinase-3β positively regulates the proliferation of human ovarian cancer cells

“…Interestingly, although the level of GSK-3β was almost identical in the two cell lines, the level of pGSK-3β Ser9 in SKOV3 was lower than that in ES-2, indicating that SKOV3 may have more active form of GSK-3β, we thus used SKOV3 as a model for further studies. GSK-3β has been frequently detected in high levels in ovarian cancer tissues than in normal ovary [15], which suggests that GSK-…”