Tumor necrosis factor-? and interferon-? stimulate MUC16 (CA125) expression in breast, endometrial and ovarian cancers through NF?B.

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 TNF? (2.5 ng/ml) or IFN? (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 TNF? and IFN? staining intensities in certain cancers. We show that NF?B is an important mediator of cytokine stimulation of MUC16 since siRNA-mediated knockdown of NF?B/p65 greatly reduced cytokine responsiveness. Finally, we demonstrate that the 250 bp proximal promoter region of MUC16 contains an NF?B binding site that accounts for a large portion of the TNF? 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.

SUBMITTER: Morgado M 

PROVIDER: S-EPMC4924758 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature