Prostacyclin and EMT Pathway Markers for Monitoring Response to Lung Cancer Chemoprevention

Lung cancer is the leading cause of cancer death worldwide and global burden could be reduced through targeted application of chemoprevention. The development of squamous lung carcinoma has been linked with persistent, high-grade bronchial dysplasia. Bronchial histology improved in former smokers in a chemoprevention trial with the prostacydin analogue iloprost. Prostacydin acts through peroxisome proliferator-activated receptor gamma (PPAR gamma) to reverse epithelial to mesenchymal transition and promote anticancer signaling. We hypothesized that the prostacydin signaling pathway and EMT could provide response markers for prostacydin chemoprevention of lung cancer. Human bronchial epithelial cells were treated with cigarette smoke condensate (CSC) or iloprost for 2 weeks, CSC for 16 weeks, or CSC for 4 weeks followed by 4 weeks of CSC and/or iloprost, and RNA was extracted. Wild-type or prostacydin synthase transgenic mice were exposed to 1 week of cigarette smoke or one injection of urethane, and RNA was extracted from the lungs. We measured potential markers of prostacydin and iloprost efficacy in these models. We identified a panel of markers altered by tobacco carcinogens and inversely affected by prostacydin, including PPAR gamma, 15PGDH, CES1, COX-2, ECADHERIN, SNAIL, VIMENTIN, CRB3, MIR34c, and MIR221. These data introduce a panel of potential markers for monitoring interception of bronchial dysplasia progression during chemoprevention with prostacydin. Chemoprevention is a promising approach to reduce lung cancer mortality in a high-risk population. Identifying markers for targeted use is critical for success in future clinical trials of prostacyclin for lung cancer chemoprevention. (C) 2018 AACR.