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Title page for ETD etd-02092016-113707


Type of Document Dissertation
Author Saxon, Jamie Ausborn
URN etd-02092016-113707
Title Investigation of epithelial canonical and non-canonical NF-κB signaling in lung adenocarcinoma
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
Ann Richmond Committee Chair
Barbara Fingleton Committee Member
Stephen Fesik Committee Member
Timothy Blackwell Committee Member
Keywords
  • macrophages
  • cell cycle
  • inflammation
  • lung cancer
  • mouse models
  • ARDS
  • apoptosis
Date of Defense 2016-01-27
Availability unrestricted
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.
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