title: MUC1 in macrophage: contributions to cigarette smoke-induced lung cancer.
abstract: Expression of the pro-oncogenic mucin MUC1 is elevated by inflammation in airway epithelial cells, but the contributions of MUC1 to the development of lung cancer are uncertain. In this study, we developed our finding that cigarette smoke increases Muc1 expression in mouse lung macrophages, where we hypothesized MUC1 may contribute to cigarette smoke-induced transformation of bronchial epithelial cells. In human macrophages, cigarette smoke extract (CSE) strongly induced MUC1 expression through a mechanism involving the nuclear receptor PPAR-γ. CSE-induced extracellular signal-regulated kinase (ERK) activation was also required for MUC1 expression, but it had little effect on MUC1 transcription. RNA interference-mediated attenuation of MUC1 suppressed CSE-induced secretion of TNF-α from macrophages, by suppressing the activity of the TNF-α-converting enzyme (TACE), arguing that MUC1 is required for CSE-induced and TACE-mediated TNF-α secretion. Similarly, MUC1 blockade after CSE induction through suppression of PPAR-γ or ERK inhibited TACE activity and TNF-α secretion. Conditioned media from CSE-treated macrophages induced MUC1 expression and potentiated CSE-induced transformation of human bronchial epithelial cells in a TNF-α-dependent manner. Together, our results identify a signaling pathway involving PPAR-γ, ERK, and MUC1 for TNF-α secretion induced by CSE from macrophages. Furthermore, our results show how MUC1 contributes to smoking-induced lung cancers that are driven by inflammatory signals from macrophages.
authors.affiliation: Authors' Affiliations: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico; and Department of Physiology & Lung Center, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Xiuling
authors.initials: X
authors.lastname: Xu
authors.forename: Mabel T
authors.initials: MT
authors.lastname: Padilla
authors.forename: Bilan
authors.initials: B
authors.lastname: Li
authors.forename: Alexandria
authors.initials: A
authors.lastname: Wells
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kato
authors.forename: Carmen
authors.initials: C
authors.lastname: Tellez
authors.forename: Steven A
authors.initials: SA
authors.lastname: Belinsky
authors.forename: Kwang Chul
authors.initials: KC
authors.lastname: Kim
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
mesh_terms: D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018396:Mucin-1 / Q000378:metabolism*; D034622:RNA Interference; D012906:Smoke / Q000009:adverse effects; D012907:Smoking / Q000009:adverse effects; D014026:Nicotiana / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020298:U937 Cells
chemical_list: C060192:MUC1 protein, human; D018396:Mucin-1; D012906:Smoke; D014409:Tumor Necrosis Factor-alpha; C577056:muc1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases