Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/120889
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Type: Journal article
Title: Betaglycan alters NFκB-TGFβ2 Cross talk to reduce survival of human granulosa tumor cells
Other Titles: Betaglycan alters NFkappaB-TGFbeta2 Cross talk to reduce survival of human granulosa tumor cells
Author: Bilandzic, M.
Chu, S.
Wang, Y.
Tan, H.L.
Fuller, P.J.
Findlay, J.K.
Stenvers, K.L.
Citation: Molecular Endocrinology, 2013; 27(3):466-479
Publisher: Oxford University Press
Issue Date: 2013
ISSN: 0888-8809
1944-9917
Statement of
Responsibility: 
Maree Bilandzic, Simon Chu, Yao Wang, Han L. Tan, Peter J. Fuller, Jock K. Findlay and Kaye L. Stenvers
Abstract: The molecular pathways controlling granulosa cell tumor (GCT) survival are poorly understood. In many cell types, nuclear factor-κB (NFκB) and TGFβ coordinately regulate cell survival to maintain tissue homeostasis. Because GCT cell lines exhibit constitutively activated NFκB, we hypothesized that NFκB blocks TGFβ-mediated cell death in GCT cells. To test this hypothesis, we used the human GCT cell line KGN, which exhibits loss of betaglycan, a TGFβ co-receptor. After inhibition of NFκB in KGN cells, re-expression of betaglycan resulted in a decrease in cell viability, which was further decreased by TGFβ2. Intriguingly, TGFβ2 increased NFκB reporter activity in control cells, but betaglycan expression suppressed both basal and TGFβ2-stimulated NFκB activity. Chemical inhibition of Mothers against decapentaplegic homolog 2/3 (SMAD2/3) signaling or SMAD2/3 gene silencing revealed that both SMADs contributed to cell survival. Furthermore, inhibiting NFκB activity resulted in a specific reduction in SMAD3 expression. Conversely, overexpression of SMAD3 increased basal NFκB activity and countered betaglycan-mediated suppression of NFκB activity. Finally, ERK1/2 activation emerged as the point of convergence of NFκB, SMAD3, and TGFβ2/betaglycan governance of GCT cell viability. Key findings in KGN cells were reproduced in a second GCT cell line, COV434. Collectively, our data establish that both SMAD2/3 and NFκB signaling pathways support GCT cell viability and suggest the existence of a positive feedback loop between NFκB and SMAD3 signaling in late-stage GCT. Furthermore, our data suggest that loss of betaglycan during tumor progression in GCT alters the functional outcomes generated by NFκB and TGFβ pathway cross talk.
Keywords: Cell Line, Tumor
Rights: © 2013 by The Endocrine Society.
DOI: 10.1210/me.2012-1239
Grant ID: http://purl.org/au-research/grants/nhmrc/338516
http://purl.org/au-research/grants/nhmrc/494802
http://purl.org/au-research/grants/nhmrc/441101
http://purl.org/au-research/grants/nhmrc/1002559
Published version: http://dx.doi.org/10.1210/me.2012-1239
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