title: Tumor necrosis factor-α and interferon-γ stimulate MUC16 (CA125) expression in breast, endometrial and ovarian cancers through NFκB.
abstract: Transmembrane mucins (TMs) are restricted to the apical surface of normal epithelia. In cancer, TMs not only are over-expressed, but also lose polarized distribution. MUC16/CA125 is a high molecular weight TM carrying the CA125 epitope, a well-known molecular marker for human cancers. MUC16 mRNA and protein expression was mildly stimulated by low concentrations of TNFα (2.5 ng/ml) or IFNγ (20 IU/ml) when used alone; however, combined treatment with both cytokines resulted in a moderate (3-fold or less) to large (> 10-fold) stimulation of MUC16 mRNA and protein expression in a variety of cancer cell types indicating that this may be a general response. Human cancer tissue microarray analysis indicated that MUC16 expression directly correlates with TNFα and IFNγ staining intensities in certain cancers. We show that NFκB is an important mediator of cytokine stimulation of MUC16 since siRNA-mediated knockdown of NFκB/p65 greatly reduced cytokine responsiveness. Finally, we demonstrate that the 250 bp proximal promoter region of MUC16 contains an NFκB binding site that accounts for a large portion of the TNFα response. Developing methods to manipulate MUC16 expression could provide new approaches to treating cancers whose growth or metastasis is characterized by elevated levels of TMs, including MUC16.
authors.affiliation: Department of BioSciences, Wiess School of Natural Sciences, Rice University, Houston, TX 77251, USA.
authors.forename: Micaela
authors.initials: M
authors.lastname: Morgado
authors.affiliation: Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|The University of Texas Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Margie N
authors.initials: MN
authors.lastname: Sutton
authors.affiliation: Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Simmons
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Warren
authors.affiliation: Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of BioSciences, Wiess School of Natural Sciences, Rice University, Houston, TX 77251, USA.
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Constantinou
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Swansea University Medical School, Singleton Park, Swansea, SA2 8PP, Wales, UK.
authors.forename: Lewis L W
authors.initials: LL
authors.lastname: Francis
authors.affiliation: Swansea University Medical School, Singleton Park, Swansea, SA2 8PP, Wales, UK.
authors.forename: R Steven
authors.initials: RS
authors.lastname: Conlan
authors.affiliation: Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bast
authors.affiliation: Department of BioSciences, Wiess School of Natural Sciences, Rice University, Houston, TX 77251, USA.|Department of Genetics, The University of Texas MD Anderson Cancer Center Houston, TX 77030, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Carson
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D018394:CA-125 Antigen / Q000235:genetics / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011485:Protein Binding; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: CA125; MUC16; NFκB; cancer; cytokine