Investigation of epithelial canonical and non-canonical NF-κB signaling in lung adenocarcinoma
Saxon, Jamie Ausborn
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2016-02-19
Abstract
Nuclear factor κ-light chain enhancer of activated B cells (NF-κB) is a transcription factor that can be activated through canonical or non-canonical signaling pathways, and activation of both pathways has been observed in lung adenocarcinoma tumors. However, the mechanistic links between canonical and non-canonical NF-κB signaling and lung tumorigenesis have not been fully elucidated. Using transgenic mouse models, we demonstrate that canonical NF-κB signaling promotes epidermal growth factor receptor (EGFR)-mediated tumor formation through paracrine signaling to the inflammatory microenvironment, with depletion studies identifying macrophages as a critical cell type promoting EGFR-driven lung tumorigenesis. To study non-canonical NF-κB signaling, we developed a novel transgenic mouse model with inducible over-expression of the non-canonical NF-κB component p52 in the airway epithelium. After injection with the lung carcinogen urethane, p52 over-expression led to increased tumor number, larger tumors, and more malignant tumors, providing the first evidence that non-canonical NF-κB signaling plays a functional role in lung tumorigenesis. Gene expression microarray analysis of lungs from transgenic mice combined with in vitro studies revealed that p52 functions in a cell autonomous manner, promoting proliferation of lung epithelial cells through regulation of cell cycle-associated genes. Since others have shown that non-canonical NF-κB signaling is activated by inflammatory stimuli and regulates cytokine genes, we examined the effect of in vivo p52 over-expression in the context of the inflammatory stimulus lipopolysaccharide (LPS). In conjunction with LPS stimulation, p52 over-expression enhanced lung injury and epithelial cell apoptosis, suggesting p52 can promote proliferation or apoptosis depending on the context. Collectively, these studies indicate that both canonical and non-canonical NF-κB signaling promote lung cancer through different but complementary mechanisms, advancing our understanding of the complexity of these signaling pathways and providing important insights into targeting them therapeutically.