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.
Highlights
Lung cancer is the leading cause of cancer-related death in the U.S, with an estimated 224,390 new lung cancer diagnoses in 2016 and a 5-year survival rate of less than 20 percent[1]
Non-canonical NF-κB signaling is defined by nuclear accumulation of p52, which hinges on proteolytic processing of p100 removing an inhibitory C-terminal domain and resulting in p52 activation. p52 is able to enter the nucleus, typically as a heterodimer bound to RelB
Applying a false discovery rate (FDR) of 0.001, we found that p52-associated genes were over-represented in processes related to cell cycle progression (Table 2), suggesting that p52 regulates expression of genes involved in proliferation
Summary
To test the strength of this protein interaction network, a survival analysis was performed based only on expression of the 13 imputed mediator genes. High expression of the imputed genes correlated with shorter survival (log-rank test p = 0.047 by expression summation, p = 0.097 by votes) (Fig. 4F and Supplementary Fig. S3B), supporting the strength of this p52-derived interaction network in predicting patient prognosis. Using normal and lung adenocarcinoma expression data from the BATTLE study[21,22], we performed unsupervised hierarchical clustering and found that this p52-associated gene signature segregated normal and lung adenocarcinoma samples (Fisher’s exact test p = 0.000003) (Fig. 5A). Higher p100/p52 (Nfkb2) expression in lung adenocarcinomas correlated with reduced patient survival (p = 3 × 10−7) (Supplementary Fig. S4B).
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call