Data from Caspase 9b Drives Cellular Transformation, Lung Inflammation, and Lung Tumorigenesis

Abstract

<div>Abstract<p>Caspase 9 undergoes alternative splicing to produce two opposing isoforms: proapoptotic Caspase 9a and pro-survival Caspase 9b (C9b). Previously, our laboratory reported that C9b is expressed in majority of non–small cell lung cancer tumors and directly activates the NF-κB pathway. In this study, the role of C9b in activation of the NF-κB pathway <i>in vivo</i>, lung inflammation and immune responses, and lung tumorigenesis were examined. Specifically, a transgenic mouse model expressing human C9b in the lung pneumocytes developed inflammatory lung lesions, which correlated with enhanced activation of the NF-κB pathway and increased influx of immunosuppressive myeloid-derived suppressor cells in contrast to wild-type mice. C9b mice presented with facial dermatitis, a thickened and disorganized dermis, enhanced collagen depth, and increased serum levels of IL6. C9b mice also developed spontaneous lung tumors, and C9b cooperated with oncogenic <i>KRAS</i> in lung tumorigenesis. C9b expression also cooperated with oncogenic <i>KRAS</i> and p53 downregulation to drive the full cell transformation of human bronchial epithelial cells (e.g., tumor formation).</p>Implications:<p>Our findings show that C9b can directly activate NF-κB pathway <i>in vivo</i> to modulate lung inflammation, immune cell influx, and peripheral immune responses, which demonstrates that C9b is key factor in driving cell transformation and lung tumorigenesis.</p></div>