Abstract 2960: Identification of Runx3 as a gatekeeper of lung adenocarcinoma

Abstract

Abstract It is thought that SP-C/CC10 double positive cells, which normally contribute to the renewal of lung epithelial cells, are the origin adenocarcinoma (ADC) of the lung. The present study shows that postnatal disruption of Runx3 in the mouse lung results in dedifferentiation of bronchiolar epithelial cells into SP-C/CC10 double positive cells. The double positive cells differentiate into SP-C single positive cells and adenoma (median survival, longer than 1 year). When Adenovirus-Cre was infected, LSL-K-RasG12D mice induced ADC in prolonged latency (median survival, 220 days) and Runx3f/f/LSL-K-RasG12D mice rapidly induced ADC (median survival, 79 days), indicating a strong tumor suppressor activity of Runx3. When Cre was activated in a limited number of cells through a leaky activation of Cretm/ERT in the absence of tamoxifen, K-RasLSL-G12D/+/Cretm/ERT mice did not induce lung ADC. In contrast, simultaneous inactivation of Runx3 and activation of K-Ras (Runx3f/f/K-RasLSL-G12D/+/Cretm/ERT) induced lung ADC with striking morphological similarities to human lung ADC in all mice (median survival, 48 days after birth). We also found that Runx3 forms a complex with BRD2 (a relative of TAF250) in a K-Ras activity-dependent manner and the complex transiently induces p14ARF and p21. When K-Ras was constitutively activated, the Runx3-BRD2 complex was maintained for long time and the expressions of p14ARF and p21 was continued. Disruption of the Runx3-BRD2 complex abolished expression of these two genes. These results suggest that cells recognize oncogenic K-Ras through a monitoring system composed of Runx3-BRD2 complex and Runx3-inactivation leads to abrogation of the monitoring system as well as dedifferentiation of lung epithelial cells. Citation Format: You-Soub Lee, Ju-Won Jang, Xin-Zi Chi, Yoshiaki Ito, Suk-Chul Bae. Identification of Runx3 as a gatekeeper of lung adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2960. doi:10.1158/1538-7445.AM2014-2960