MUC16/CA125 Regulation by the Proinflammatory Cytokines TNF α and IFNγ and the PPARγ Agonist Rosiglitazone in Breast and Ovarian Cancers

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dc.contributor.advisorBartel, Bonnieen_US
dc.contributor.advisorCarson, Daniel Den_US
dc.creatorMorgado, Micaelaen_US
dc.date.accessioned2017-08-07T17:37:16Zen_US
dc.date.available2017-08-07T17:37:16Zen_US
dc.date.created2016-05en_US
dc.date.issued2016-04-22en_US
dc.date.submittedMay 2016en_US
dc.date.updated2017-08-07T17:37:16Zen_US
dc.description.abstractMUC16 is a high molecular weight transmembrane mucin (TM) carrying the CA125 epitope, a well-known molecular marker for human cancers. TMs are restricted to the apical surface of normal epithelia. TMs not only are over-expressed, but also lose polarized distribution in cancers. Similar to other TMs, MUC16 is overexpressed in a variety of epithelial cancers. In this work the regulation of MUC16 by the proinflammatory cytokines, TNFα and IFNγ, in addition to the PPARγ agonist rosiglitazone, a drug used in the treatment of type 2 diabetes, was explored. MUC16 mRNA and protein expression was mildly stimulated by low concentrations of TNFα or IFNγ 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. NFκB is an important mediator of cytokine stimulation of MUC16 since siRNA-mediated knockdown of NFκB/p65 greatly reduced cytokine responsiveness. The 250 bp proximal promoter region of MUC16 contains an NFκB binding site that accounts for a large portion of the TNFα response. Rosiglitazone exerts a dual role in the regulation of MUC16 since at low pharmacologically relevant concentrations it further stimulates MUC16 in combination with cytokines, but at high concentrations inhibits cytokine stimulated MUC16. This regulation also is PPARγ dependent. In this work methods were developed to manipulate MUC16 expression that can provide new approaches to treating cancers whose growth or metastasis is characterized by elevated levels of TMs, including MUC16.en_US
dc.format.mimetypeapplication/pdfen_US
dc.identifier.citationMorgado, Micaela. "MUC16/CA125 Regulation by the Proinflammatory Cytokines TNF α and IFNγ and the PPARγ Agonist Rosiglitazone in Breast and Ovarian Cancers." (2016) Diss., Rice University. <a href="https://hdl.handle.net/1911/96604">https://hdl.handle.net/1911/96604</a>.en_US
dc.identifier.urihttps://hdl.handle.net/1911/96604en_US
dc.language.isoengen_US
dc.rightsCopyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.en_US
dc.subjectMUC16en_US
dc.subjectCA125en_US
dc.subjectTNFαen_US
dc.subjectIFNγen_US
dc.subjectNFκBen_US
dc.subjectPPARγen_US
dc.subjectrosiglitazoneen_US
dc.titleMUC16/CA125 Regulation by the Proinflammatory Cytokines TNF α and IFNγ and the PPARγ Agonist Rosiglitazone in Breast and Ovarian Cancersen_US
dc.typeThesisen_US
dc.type.materialTexten_US
thesis.degree.departmentBiochemistry and Cell Biologyen_US
thesis.degree.disciplineNatural Sciencesen_US
thesis.degree.grantorRice Universityen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophyen_US
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