Expression of p52, a non-canonical NF-kappaB transcription factor, is associated with poor ovarian cancer prognosis
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RESEARCH
Open Access
Expression of p52, a non-canonical NFkappaB transcription factor, is associated with poor ovarian cancer prognosis Demetra H. Hufnagel1, Andrew J. Wilson2,3, Jamie Saxon4, Timothy S. Blackwell3,4, Jaclyn Watkins5, Dineo Khabele6, Marta A. Crispens2,3, Fiona E. Yull2,3,7† and Alicia Beeghly-Fadiel3,8*†
Abstract Background: The canonical and non-canonical nuclear factor-kappaB (NF-κB) signaling pathways have key roles in cancer, but studies have previously evaluated only the association of canonical transcription factors and ovarian cancer survival. Although a number of in vitro and in vivo studies have demonstrated mechanisms by which noncanonical NF-κB signaling potentially contributes to ovarian cancer progression, a prognostic association has yet to be shown in the clinical context. Methods: We assayed p65 and p52 (major components of the canonical and non-canonical NF-κB pathways) by immunohistochemistry in epithelial ovarian tumor samples; nuclear and cytoplasmic staining were semi-quantified by H-scores and dichotomized at median values. Associations of p65 and p52 with progression-free survival (PFS) and overall survival (OS) were quantified by Hazard Ratios (HR) from proportional-hazards regression. Results: Among 196 cases, median p52 and p65 H-scores were higher in high-grade serous cancers. Multivariable regression models indicated that higher p52 was associated with higher hazards of disease progression (cytoplasmic HR: 1.54; nuclear HR: 1.67) and death (cytoplasmic HR: 1.53; nuclear HR: 1.49), while higher nuclear p65 was associated with only a higher hazard of disease progression (HR: 1.40) in unadjusted models. When cytoplasmic and nuclear staining were combined, p52 remained significantly associated with increased hazards of disease progression (HR: 1.91, p = 0.004) and death (HR: 1.70, p = 0.021), even after adjustment for p65 and in analyses among only high-grade serous tumors. Conclusions: This is the first study to demonstrate that p52, a major component of non-canonical NF-κB signaling, may be an independent prognostic factor for epithelial ovarian cancer, particularly high-grade serous ovarian cancer. Approaches to inhibit non-canonical NF-κB signaling should be explored as novel ovarian cancer therapies are needed. Keywords: NF-kappaB, Ovarian cancer, Survival, Prognosis
* Correspondence: [email protected] † Fiona E. Yull and Alicia Beeghly-Fadiel contributed equally to this work. 3 Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA 8 Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37203, USA Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence,
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