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.
Highlights
Lung cancer is a major health concern, afflicting approximately 160,000 people each year in the United States [1,2]
To investigate if MUC1 plays a role in bronchial epithelial cell transformation, MUC1 was knocked down by RNA interference in BEAS-2B, an immortalized human bronchial epithelial cell line that is sensitive to carcinogen-induced transformation in vitro [33]
This study provides strong evidence supporting a cancerpromoting role of MUC1 in cigarette smoke (CS)-induced lung carcinogenesis: MUC1 potentiated transformation of human bronchial cells induced by the tobacco carcinogen benzo[a]pyrene diol epoxide (BPDE); BPDE markedly activated epidermal growth factor receptor (EGFR) and its downstream pathways Akt and ERK, and blocking these pathways significantly increased BPDE-induced cytotoxicity and inhibited cell transformation; Suppression of MUC1 expression destabilized EGFR protein and inhibited BPDE-induced activation of EGFR, Akt and ERK, and subsequently increased BPDE-induced cell death
Summary
Lung cancer is a major health concern, afflicting approximately 160,000 people each year in the United States [1,2]. Most lung cancers are associated with mainstream or sidestream cigarette smoke (CS). Carcinogens derived from CS such as benzo(a)pyrene (BaP) induce lung cancer through DNA damage. Cancer development and progression likely depend on the balance between cell survival and apoptosis signals, both of which are activated by carcinogens and environmental factors. We have learned a great deal about the tumor-promoting role of survival signaling, how CS activates these pathways in lung cancer initiation and progression remains poorly understood. Delineating the mechanisms underlying the influences of survival signaling on cell transformation and tumor development could identify novel intervention targets for prevention and therapy for lung cancer
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