Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States of America.
PLoS One. 2012;7(3):e33846. doi: 10.1371/journal.pone.0033846. Epub 2012 Mar 22.
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.
虽然众所周知表皮生长因子受体 (EGFR) 参与肺癌的进展，但 EGFR 是否有助于肺上皮细胞转化尚不清楚。黏蛋白 1（人类中的 MUC1 和动物中的 Muc1）是气道黏液的糖蛋白成分，在肺肿瘤中过度表达；然而，其在早期肺癌发生中的作用和潜在机制仍不清楚。本研究提供了强有力的证据，证明 EGFR 和 MUC1 参与了支气管上皮细胞的转化。MUC1 表达的敲低显著降低了苯并[a]芘二醇环氧化物 (BPDE)诱导的永生化人支气管上皮细胞转化，BPDE 是香烟烟雾 (CS) 致癌物苯并[a]芘 (BaP) 的活性形式。BPDE 暴露强烈激活了由 EGFR、Akt 和 ERK 组成的途径，阻断该途径显著增加了 BPDE 诱导的细胞死亡并抑制了细胞转化。MUC1 表达的抑制导致 EGFR 不稳定，并抑制了 BPDE 诱导的 Akt 和 ERK 的激活以及细胞毒性的增加。这些结果强烈表明 EGFR 在 BPDE 诱导的转化中起重要作用，并证实 MUC1 参与肺癌的发生，至少部分是通过介导致癌剂诱导的 EGFR 介导的细胞存活途径的激活，从而促进细胞转化。
