Abstract 3456: MUC16/CA125, TNFα and IFNγ are co-expressed in malignant gynecologic neoplasms

MUC16 is a very large, heavily glycosylated cell surface mucin that carries the CA125 epitope, a well-known molecular marker for human epithelial ovarian cancer. MUC16 is primarily found at the apical surface of normal simple epithelia serving various functions including lubrication and protection against pathogenic infections. MUC16 is aberrantly over-expressed in many diseases including cancers of the ovary, uterus, breast, and pancreas. MUC16 also may support disease progression and ectopic cell colonization in cancer and endometriosis via binding to cell surface proteins including mesothelin and Siglec-9. We demonstrate that MUC16 expression is highly stimulated by the proinflammatory cytokines, tumor necrosis factor α (TNFα) and interferon γ (IFNγ), in multiple cell lines of various origins, an effect mediated by NFκB. MUC16 mRNA and protein expression is mildly stimulated by low concentrations of TNFα (2.5ng/ml) or IFNγ (20 IU/ml) alone. Interestingly, combined treatment with both cytokines at these concentrations resulted in a moderate to large stimulation of MUC16 mRNA and protein expression in a variety of cell contexts indicating that this may be a general response. To further confirm our in vitro results, the multi-cancer tissue-microarrays were used to perform immunohistochemistry testing with anti-Ca125, anti-TNFα and anti-IFNγ antibodies, respectively. Our results demonstrated that MUC16 expression is positively correlated with the TNFα and IFNγ expressions in multiple human cancers, however the most significant positive correlations between MUC16 expression with the TNFα and IFNγ expressions were observed in ovarian and breast cancer. Of the 94 tumors stained, 64 (70.3%) were positive for TNFα, IFNγ, and MUC16 expression. Only 8 cases (8.8%) were negative for all three protein markers, while 18 cases (19.8%) were MUC16 negative but positive for the proinflammatory cytokines, and 1 case (1.1%) was MUC16 positive but negative for both TNFα and IFNγ cytokines. These studies provide in vivo documentation of the synergistic effect tumor necrosis factor α and interferon γ have on MUC16 expression across several disease sites demonstrating that MUC16 is a target of proinflammatory cytokines, which may contribute to mucosal defense, and progression of MUC16-expressing tumors. Altogether, our data for first time provides an explanation for elevated CA 125 expression in various cancers. (Supported by Rice Institute of Biosciences and Bioengineering Me