| First Author | Kim M | Year | 2022 |
| Journal | Mol Cancer Res | Volume | 20 |
| Issue | 8 | Pages | 1284-1294 |
| PubMed ID | 35412615 | Mgi Jnum | J:329873 |
| Mgi Id | MGI:7346335 | Doi | 10.1158/1541-7786.MCR-21-0905 |
| Citation | Kim M, et al. (2022) Caspase 9b Drives Cellular Transformation, Lung Inflammation, and Lung Tumorigenesis. Mol Cancer Res 20(8):1284-1294 |
| abstractText | 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-kappaB pathway. In this study, the role of C9b in activation of the NF-kappaB pathway in vivo, 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-kappaB 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 KRAS in lung tumorigenesis. C9b expression also cooperated with oncogenic KRAS and p53 downregulation to drive the full cell transformation of human bronchial epithelial cells (e.g., tumor formation). IMPLICATIONS: Our findings show that C9b can directly activate NF-kappaB pathway in vivo 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. |
