| First Author | Sato A | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 2 | Pages | e57013 |
| PubMed ID | 23437297 | Mgi Jnum | J:197191 |
| Mgi Id | MGI:5491100 | Doi | 10.1371/journal.pone.0057013 |
| Citation | Sato A, et al. (2013) CCAAT/enhancer-binding protein-alpha suppresses lung tumor development in mice through the p38alpha MAP kinase pathway. PLoS One 8(2):e57013 |
| abstractText | The transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha) is a basic leucine zipper transcription factor and is expressed in alveolar type II cells, alveolar macrophages and Clara cells in the lung. Although decrease or absence of C/EBPalpha expression in human non-small cell lung cancer suggests a possible role of C/EBPalpha as a lung tumor suppressor, there is no direct proof for this hypothesis. In this study, we investigated, for the first time, the role of C/EBPalpha in lung tumors in vivo using transgenic mice with lung epithelial specific conditional deletion of Cebpa (Cebpalpha(Delta/Delta) mice) and a urethane-induced lung tumor model. C/EBPalpha expression in the lung was dispensable, and its deletion was not oncogenic under unstressed conditions. However, at 28 wk after urethane injection, the number and size of tumors and the tumor burden were significantly higher in Cebpalpha(Delta/Delta) mice than in littermate control mice. Urethane-injected Cebpalpha(Delta/Delta) mice showed highly proliferative adenomas and adenocarcinomas in the lung, and survival time after urethane-injection was significantly shorter than that in control mice. In control mice, C/EBPalpha was strongly induced in the tumor tissues at 28 weeks after urethane-injection, but became weakened or absent as tumors progressed after long-term observation for over 1 year. Using intraperitoneal injection of p38 inhibitor (SB203580), we demonstrated that the induction of C/EBPalpha is strongly regulated by the p38 MAP kinase in murine alveolar epithelial cells. A high correlation was demonstrated between the expression of C/EBPalpha and p38alpha MAP kinase in tumor cells, suggesting that C/EBPalpha silencing in tumor cells is caused by down-regulation of p38alpha MAP kinase. In conclusion, the role of C/EBPalpha as a lung tumor suppressor was demonstrated for the first time in the present study, and the extinguished C/EBPalpha expression through p38alpha inactivation leads tumor promotion and progression. |
