Oncotarget

Research Papers:

Tumor necrosis factor-α and interferon-γ stimulate MUC16 (CA125) expression in breast, endometrial and ovarian cancers through NFκB

Micaela Morgado, Margie N. Sutton, Mary Simmons, Curtis R. Warren, Zhen Lu, Pamela E. Constantinou, Jinsong Liu, Lewis LW. Francis, R. Steven Conlan, Robert C. Bast Jr., Daniel D. Carson _

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Oncotarget. 2016; 7:14871-14884. https://doi.org/10.18632/oncotarget.7652

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Abstract

Micaela Morgado1, Margie N. Sutton2,3, Mary Simmons2, Curtis R. Warren4, Zhen Lu2, Pamela E. Constantinou1, Jinsong Liu5, Lewis LW. Francis7, R. Steven Conlan7, Robert C. Bast, Jr.2, Daniel D. Carson1,6

1Department of BioSciences, Wiess School of Natural Sciences, Rice University, Houston, TX 77251, USA

2Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

3The University of Texas Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA

4Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA

5Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

6Department of Genetics, The University of Texas MD Anderson Cancer Center Houston, TX 77030, USA

7Swansea University Medical School, Singleton Park, Swansea, SA2 8PP, Wales, UK

Correspondence to:

Daniel D. Carson, e-mail: dcarson@rice.edu

Keywords: MUC16, CA125, cytokine, NFκB, cancer

Received: July 23, 2015     Accepted: January 31, 2016     Published: February 24, 2016

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.

Author Information

Micaela Morgado

Margie N. Sutton

Mary Simmons

Curtis R. Warren

Zhen Lu

Pamela E. Constantinou

Jinsong Liu

Lewis LW. Francis

R. Steven Conlan

Robert C. Bast Jr.

Daniel D. Carson
Primary Contact  _


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