香烟烟雾是烟草燃烧产生的复杂混合物，含有多种致癌物质，并能引发 DNA 损伤。 c-MET（一种受体酪氨酸激酶）的过度激活可能会导致癌症和细胞 DNA 损伤，但其潜在机制尚不清楚。在这项工作中，我们研究了香烟烟雾提取物（CSE）诱导人支气管上皮细胞（BEAS-2B）恶性转化和DNA损伤的机制。结果表明，CSE 治疗导致与 c-MET 信号通路相关基因的 mRNA 表达上调、DNA 损伤传感器蛋白 γ-H2AX 的表达增加以及 BEAS-2B 细胞中不受控制的增殖。参与DNA损伤修复的ATR、ATR和CHK2，以及c-MET的磷酸化和一组参与DNA损伤反应的激酶（ATM、ATR、CHK1、CHK2）均被CSE激活。此外，CSE 激活促进与 DNA 损伤修复相关的 ATR、CHK1 蛋白的磷酸化修饰。添加 PHA665752（c-MET 的特异性抑制剂）或用 c-MET 进行敲低均可减轻 DNA 损伤，而 c-MET 的过度表达则加剧 DNA 损伤。因此，c-MET 磷酸化可能参与 CSE 诱导的 DNA 损伤，为预防和治疗吸烟引起的肺部疾病提供潜在的干预靶点。版权所有 © 2024。由 Elsevier Inc. 出版。

Cigarette smoke, a complex mixture produced by tobacco combustion, contains a variety of carcinogens and can trigger DNA damage. Overactivation of c-MET, a receptor tyrosine kinase, may cause cancer and cellular DNA damage, but the underlying mechanisms are unknown. In this work, we investigated the mechanisms of cigarette smoke extract (CSE) induced malignant transformation and DNA damage in human bronchial epithelial cells (BEAS-2B). The results demonstrated that CSE treatment led to up-regulated mRNA expression of genes associated with the c-MET signaling pathway, increased expression of the DNA damage sensor protein γ-H2AX, and uncontrolled proliferation in BEAS-2B cells. ATR, ATR, and CHK2, which are involved in DNA damage repair, as well as the phosphorylation of c-MET and a group of kinases (ATM, ATR, CHK1, CHK2) involved in the DNA damage response were all activated by CSE. In addition, CSE activation promotes the phosphorylation modification of ATR, CHK1 proteins associated with DNA damage repair. The addition of PHA665752, a specific inhibitor of c-MET, or knock-down with c-MET both attenuated DNA damage, while overexpression of c-MET exacerbated DNA damage. Thus, c-MET phosphorylation may be involved in CSE-induced DNA damage, providing a potential target for intervention in the prevention and treatment of smoking-induced lung diseases.Copyright © 2024. Published by Elsevier Inc.