muc1 contributes to bpde-induced human bronchial epithelial cell transformation through facilitating egfr activationmuc1有助于bpde-induced人类支气管上皮细胞转换通过促进表皮生长因子受体激活.pdfVIP

MUC1 Contributes to BPDE-Induced Human Bronchial Epithelial Cell Transformation through Facilitating EGFR Activation 1. 1. 1 1 1 2 Xiuling Xu , Lang Bai , Wenshu Chen , Mabel T. Padilla , Yushi Liu , Kwang Chul Kim , 1 1 Steven A. Belinsky , Yong Lin * 1 Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States of America, 2 Department of Physiology and Lung Center, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America 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