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.
Highlights
Mucins are high molecular weight glycoproteins that are normally found on apical surfaces of epithelial organs such as trachea, stomach, and reproductive organs [1], where they serve various functions including protection against pathogenic infections, hydration and cellular signaling [2]
In the current study we demonstrated that the proinflammatory cytokines TNFα and IFNγ stimulate MUC16 expression in a variety of cellular contexts
We showed that elevated MUC16 expression is associated with elevated cytokine levels in several cancers of female reproductive tissues
Summary
Mucins are high molecular weight glycoproteins that are normally found on apical surfaces of epithelial organs such as trachea, stomach, and reproductive organs [1], where they serve various functions including protection against pathogenic infections, hydration and cellular signaling [2]. MUC16 ( known as the serum tumor marker, CA 125) is the largest transmembrane mucin being 2–5 MDa including O-linked and N-linked glycosylation. Intact MUC16 is the largest membrane glycoprotein known, towering over even other large cell surface mucins like MUC1 and MUC4. As such, it likely represents the initial point of contact with other cells and matrices. MUC16 has been used as a tumor marker for over thirty years due to its overexpression in ovarian and other cancers, yet little is known about its regulation. The importance of MUC16 in the diagnosis, progression and therapy of ovarian cancer, and its overexpression in other cancers, demands a need for research on the regulation of this mucin
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