BACKGROUND: Escaping cell death pathways is an important event during carcinogenesis. We previously identified anti-TNFα-induced apoptosis (ATIA, also known as vasorin) as an antiapoptotic factor that suppresses reactive oxygen species (ROS) production. However, the role of vasorin in lung carcinogenesis has not been investigated. METHODS: Vasorin expression was examined in human lung cancer tissues with immunohistochemistry and database analysis. Genetic and pharmacological approaches were used to manipulate protein expression and autophagy activity in human bronchial epithelial cells (HBECs). ROS generation was measured with fluorescent indicator, apoptosis with release of lactate dehydrogenase, and cell transformation was assessed with colony formation in soft agar. RESULTS: Vasorin expression was increased in human lung cancer tissues and cell lines, which was inversely associated with lung cancer patient survival. Cigarette smoke extract (CSE) and benzo[a]pyrene diol epoxide (BPDE)–induced vasorin expression in HBECs. Vasorin knockdown in HBECs significantly suppressed CSE-induced transformation in association with enhanced ROS accumulation and autophagy. Scavenging ROS attenuated autophagy and cytotoxicity in vasorin knockdown cells, suggesting that vasorin potentiates transformation by impeding ROS-mediated CSE cytotoxicity and improving survival of the premalignant cells. Suppression of autophagy effectively inhibited CSE-induced apoptosis, suggesting that autophagy was pro-apoptotic in CSE-treated cells. Importantly, blocking autophagy strongly potentiated CSE-induced transformation. CONCLUSION: These results suggest that vasorin is a potential lung cancer–promoting factor that facilitates cigarette smoke–induced bronchial epithelial cell transformation by suppressing autophagy-mediated apoptosis, which could be exploited for lung cancer prevention.

背景：逃避细胞死亡途径是癌发生过程中的一个重要事件。我们之前发现抗 TNFα 诱导的细胞凋亡（ATIA，也称为血管素）是一种抑制活性氧 (ROS) 产生的抗细胞凋亡因子。然而，血管素在肺癌发生中的作用尚未得到研究。方法：通过免疫组织化学和数据库分析检测人肺癌组织中 Vasorin 的表达。使用遗传和药理学方法来操纵人支气管上皮细胞（HBEC）中的蛋白质表达和自噬活性。用荧光指示剂测量ROS的产生，用乳酸脱氢酶的释放测量细胞凋亡，并用软琼脂中的集落形成评估细胞转化。结果：人类肺癌组织和细胞系中 Vasorin 表达增加，与肺癌患者的生存率呈负相关。香烟烟雾提取物 (CSE) 和苯并[a]芘二醇环氧化物 (BPDE) 诱导 HBEC 中血管素的表达。 HBEC 中 Vasorin 敲低显着抑制了 CSE 诱导的转化，并与 ROS 积累和自噬增强相关。清除 ROS 会减弱 vasorin 敲低细胞的自噬和细胞毒性，这表明 vasorin 通过阻止 ROS 介导的 CSE 细胞毒性并改善癌前细胞的存活来增强转化。抑制自噬可有效抑制 CSE 诱导的细胞凋亡，表明自噬在 CSE 处理的细胞中是促凋亡的。重要的是，阻断自噬会强烈增强 CSE 诱导的转化。 结论：这些结果表明，血管素是一种潜在的肺癌促进因子，通过抑制自噬介导的细胞凋亡来促进香烟烟雾诱导的支气管上皮细胞转化，可用于肺癌的预防。