Cytokine Stimulation and Rosiglitazone Antagonism of MUC16 Expression in Human Endometrial and Ovarian Epithelial Cell Lines

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 561-585-Ovarian & Uterine Function II
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-585
Micaela Morgado*1, Margie N Sutton2, Zhen Lu3, Robert Bast4 and Mary Simmons5
1Rice, Houston, TX, 2UT MD Anderson Cancer Center, Houston, TX 77024, 3MD Anderson Cancer Center, Houston TX. 77024, 4MD Anderson Cancer Center, 5UT Southwestern Medical School
Transmembrane mucins influence normal uterine functions by providing lubrication, protecting these surfaces from infection and acting as barriers that must be removed to allow embryo attachment. Normally membrane bound mucins are localized at the apical surface of simple epithelia; however, membrane bound mucins are not only aberrantly over-expressed in many diseases including cancers of the uterus, breast, ovary and pancreas, but also lose their polarized distribution. MUC16 is a high molecular weight, heavily glycosylated cell surface mucin which carries the CA125 epitope, an established ovarian cancer marker.  MUC16 binds mesothelin and may contribute to abnormal cell colonization of mesothelial surfaces in endometriosis and cancer.  MUC1 expression is highly stimulated by the proinflammatory cytokines, tumor necrosis factor α (TNFα) and interferon γ (IFNγ), in many cellular contexts.  High levels of these cytokines are detected in female reproductive tract tissues in a cycle-dependent manner. We hypothesized that cytokines also might stimulate MUC16 expression. MUC16 mRNA and protein expression is stimulated in a dose-dependent manner up to 18-fold with either TNFα or IFNγ alone at concentrations up to 25 ng/ml or 200 IU/ml, respectively, in IHEEC cells, a telomerase immortalized human endometrial epithelial cell line derived from normal endometrium.  Low concentrations of either cytokine alone (TNFα, 2.5 ng/ml; IFNγ, 20 IU/ml) only stimulate 2- to 4-fold; however, combined treatment with both cytokines resulted in a large (20- to 60-fold), synergistic stimulation of MUC16 mRNA and protein expression. Cytokine stimulation of MUC16 expression was observed in other uterine epithelial cell lines as well as ovarian cancer cell lines indicating that this may be a general response.  We previously demonstrated that rosiglitazone inhibits MUC1 expression in a variety of contexts. Rosiglitazone also effectively inhibited cytokine-stimulated MUC16 expression, an effect that was fully reversible by GW9662, an antagonist of the peroxisome proliferator-activated receptor gamma (PPARγ), indicating that rosiglitazone inhibition was PPARγ-dependent. We currently are examining how cytokines and rosiglitazone responses are mediated at the level of the MUC16 promoter. Collectively, these studies demonstrate that MUC16 is a target of proinflammatory cytokine actions and may contribute to mucosal defense responses and progression of MUC16-expressing tumors. (Supported by NIH grant HD29963 awarded to DDC)

Disclosure: RB: Consultant, Fujirebio , Consultant, Vermillion . Nothing to Disclose: MM, MNS, ZL, MS

*Please take note of The Endocrine Society's News Embargo Policy at

Sources of Research Support: Supported by NIH grant HD29963 awarded to DDC
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