title: MUC1 contributes to BPDE-induced human bronchial epithelial cell transformation through facilitating EGFR activation.
abstract: Although it is well known that epidermal growth factor receptor (EGFR) is involved in lung cancer progression, whether EGFR contributes to lung epithelial cell transformation is less clear. Mucin 1 (MUC1 in human and Muc1 in animals), a glycoprotein component of airway mucus, is overexpressed in lung tumors; however, its role and underlying mechanisms in early stage lung carcinogenesis is still elusive. This study provides strong evidence demonstrating that EGFR and MUC1 are involved in bronchial epithelial cell transformation. Knockdown of MUC1 expression significantly reduced transformation of immortalized human bronchial epithelial cells induced by benzo[a]pyrene diol epoxide (BPDE), the active form of the cigarette smoke (CS) carcinogen benzo(a)pyrene (BaP)s. BPDE exposure robustly activated a pathway consisting of EGFR, Akt and ERK, and blocking this pathway significantly increased BPDE-induced cell death and inhibited cell transformation. Suppression of MUC1 expression resulted in EGFR destabilization and inhibition of the BPDE-induced activation of Akt and ERK and increase of cytotoxicity. These results strongly suggest an important role for EGFR in BPDE-induced transformation, and substantiate that MUC1 is involved in lung cancer development, at least partly through mediating carcinogen-induced activation of the EGFR-mediated cell survival pathway that facilitates cell transformation.
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States of America.
authors.forename: Xiuling
authors.initials: X
authors.lastname: Xu
authors.forename: Lang
authors.initials: L
authors.lastname: Bai
authors.forename: Wenshu
authors.initials: W
authors.lastname: Chen
authors.forename: Mabel T
authors.initials: MT
authors.lastname: Padilla
authors.forename: Yushi
authors.initials: Y
authors.lastname: Liu
authors.forename: Kwang Chul
authors.initials: KC
authors.lastname: Kim
authors.forename: Steven A
authors.initials: SA
authors.lastname: Belinsky
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000633:toxicity*; D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002461:Cell Line, Transformed; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D018396:Mucin-1 / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: C060192:MUC1 protein, human; D018396:Mucin-1; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases