Abstract 385: Potentiating MUC1 expression in human bronchial epithelial cells by cigarette smoke carcinogens through induction of TNF-α secretion from macrophages

Abstract

Abstract Although an important role of inflammation in the development of lung cancer has been recognized, how inflammation promotes lung epithelial cell transformation and lung cancer development has not been well elucidated. Cigarette smoke (CS), the major cause of lung cancers, potently elicits chronic pulmonary inflammation. Our recent studies have found that CS significantly induces Muc1 (MUC1 for human and Muc1 for nonhuman species) expression in mouse bronchial epithelial cells and macrophages, and MUC1 facilitates Benzo(a)pyrene diolepoxide (BPDE)-induced human lung epithelial cell transformation. In this study, we investigated the role of inflammatory cells in regulating CS carcinogen-induced MUC1 expression in bronchial epithelial cells. BPDE and N-Nitroso-N-methylurea (MNU), an active CS carcinogen and a mimic, strongly induced tumor necrosis factor-alpha (TNF-α) secretion from human macrophages. The TNF-α induction was effectively blocked when ERK, JNK, and NF-κB were blocked, suggesting these pathways are involved in the induction of TNF-α from macrophages by BPDE and MNU. Interestingly, knockdown of MUC1 in macrophages suppressed BPDE- or MNU-induced TNF-α secretion, suggesting MUC1 plays a role in modulating carcinogen-induced and macrophage-mediated inflammatory responses. Conditioned media from BPDE- or MNU-treated macrophages potently induced MUC1 expression in human bronchial epithelial cells (HBECs), which was inhibited by a TNF-α neutralizing antibody, suggesting that TNF-α derived from macrophages contributes to CS carcinogen-induced MUC1 expression in HBECs. Thus, our results establish a dual role of MUC1 in CS-induced and inflammation-associated lung cancer development: to facilitate TNF-α secretion from macrophages and to potentiate transformation of HBECs. Note: This work is supported by NIH/NIEHS grant 1R01ES017328. 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 385. doi:1538-7445.AM2012-385