Abstract LB-521: Expression profile of nuclear receptor superfamily in a lung cancer pathogenesis model
Authors: Jeong Yangsik , Kim Jihye , Sato Mitsuo , Lee Woochang , Lee Woochang , Kurie Jonathan M. , Minna John D. , Mangelsdorf David J. 
Published: August 2012

To explore the role of nuclear receptors in lung cancer pathogenesis, we investigated mRNA expression of the 48 human nuclear receptors (NRs) in a panel of immortalized human bronchial epithelial cells (HBEC) and microdissected lung tissues from a mouse lung cancer model with oncogenic K-rasV12, using TaqMan-based quantitative real-time PCR (QPCR). A subset of NRs was revealed with a distinct (but oncogene-dependent) pattern of expression in normal human bronchial epithelial cells (HBEC3) that were immortalized with CDK4, the catalytic subunit of human telomerase (hTERt), and oncogenic alterations (e.g., p53 knock-out and/or K-rasV12 overexpression). For example, peroxisome proliferator activated receptor gamma (PPARγ) expression was increased by 5 to 10 fold in HBEC3 cells harboring either mutant K-ras alone or dual oncogenic alterations with K-ras and p53−/−. Notably, treatment of PPARγ agonist troglitazone reduced both mRNA and protein level of cyclooxygenase-2 (COX2), which was increased by an order of magnitude in the same HBEC3 cell lines with the oncogenic K-ras. This result confirms the potential implication of PPARγ as an anti-inflammation factor. In attempt to determine the tumorigenic potential of the HBEC3 cells, we injected these cells into immunologically compromised nude mice. A subset of HBEC3 clones with dual oncogenic alterations showed tumor growth in this xenograft mouse model, while control cells formed no tumors. Notably, these aggressive cell clones and tumors showed loss of both PPARγ and COX2 expression of which expression were induced in the parental cells. In addition, we sought to understand the relevance of NRs to pathologic disease progression in transgenic K-rasV12 mice, a well-known genetic model for lung adenocarcinoma. The NR profile of microdissected mouse lung tissues provided two interesting groups of NRs based on expression pattern. In one of these groups, 8 out of a total 50 NRs showed expression differences between tumor and pair-matched normal tissue in a mouse-specific manner, implicating potential use of NR profiling as a strategy for individualized treatment against lung cancer. In the other group, there was a dramatic difference between expression of normal tissue and tumors for 10 of the 50 NRs, which may provide potential diagnostic markers as well as therapeutic targets. Further hierarchical clustering analysis in both male and female mice showed a correlation between receptor expression in normal tissues but a complete disorganization of expression in pair-matched tumors. Accordingly, this type of profiling analysis revealed a group of NRs potentially responsible for the disease progression or as biomarkers for disease progression. Overall, these datasets provide insight into clinical utilization of the NR superfamily for predicting disease progression, therapeutic intervention, and further chemoprevention of cancers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-521. doi:1538-7445.AM2012-LB-521