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Sci Rep. 2018 Apr 17;8(1):6078. doi: 10.1038/s41598-018-24488-8.

p52 expression enhances lung cancer progression.

Author information

1
Department of Cancer Biology, Vanderbilt University, Nashville, TN, 37232, USA.
2
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA.
3
Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
4
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN, 37232, USA.
5
Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), University Hospital, Ludwig-Maximilian University (LMU) and Helmholtz Center Munich, Member of the German Center for Lung Research (DZL), Max-Lebsche-Platz 31, 81377, Munich, Bavaria, Germany.
6
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, 1 Asklepiou Str., 26504, Rio, Achaia, Greece.
7
Department of Veterans Affairs Medical Center, Nashville, TN, 37232, USA.
8
Department of Cancer Biology, Vanderbilt University, Nashville, TN, 37232, USA. timothy.blackwell@vanderbilt.edu.
9
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN, 37232, USA. timothy.blackwell@vanderbilt.edu.
10
Department of Veterans Affairs Medical Center, Nashville, TN, 37232, USA. timothy.blackwell@vanderbilt.edu.
11
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA. timothy.blackwell@vanderbilt.edu.

Abstract

While many studies have demonstrated that canonical NF-κB signaling is a central pathway in lung tumorigenesis, the role of non-canonical NF-κB signaling in lung cancer remains undefined. We observed frequent nuclear accumulation of the non-canonical NF-κB component p100/p52 in human lung adenocarcinoma. To investigate the impact of non-canonical NF-κB signaling on lung carcinogenesis, we employed transgenic mice with doxycycline-inducible expression of p52 in airway epithelial cells. p52 over-expression led to increased tumor number and progression after injection of the carcinogen urethane. Gene expression analysis of lungs from transgenic mice combined with in vitro studies suggested that p52 promotes proliferation of lung epithelial cells through regulation of cell cycle-associated genes. Using gene expression and patient information from The Cancer Genome Atlas (TCGA) database, we found that expression of p52-associated genes was increased in lung adenocarcinomas and correlated with reduced survival, even in early stage disease. Analysis of p52-associated gene expression in additional human lung adenocarcinoma datasets corroborated these findings. Together, these studies implicate the non-canonical NF-κB component p52 in lung carcinogenesis and suggest modulation of p52 activity and/or downstream mediators as new therapeutic targets.

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