Chronic exposure to arsenic increases the risk of developing a variety of human cancers including lung carcinomas. However, the exact molecular mechanism underlying arsenic carcinogenicity remains largely unknown. Autophagy is a conserved catabolic process for maintaining cellular protein homeostasis whose defects might result in accumulation of dysfunctional organelles and damaged proteins thus promoting tumorigenesis. In the present study, we found that chronic exposure of human bronchial epithelial BEAS-2B cells to sub-lethal dose of sodium arsenite led to autophagy activation and induced an epithelial-to-mesenchymal transition (EMT) to enhance cell migratory and invasive capability. The malignant transformation was mediated via activation of MEK/ERK1/2 signaling. Importantly, inhibition of autophagy in these arsenic-exposed cells by pharmacological intervention or genetic deletion further promoted the EMT and increased the generation of inflammasomes. Both autophagy inhibitor and genetic deletion of autophagy core gene Beclin-1 produced similar effects. These results may suggest the important role of autophagy in sodium arsenite-induced lung tumorigenesis which may serve as a potential target in prevention and treatment of arsenic-imposed lung cancer.

中文翻译：

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自噬通过MEK/ERK1/2通路介导慢性砷暴露诱导的支气管细胞恶性转化

长期接触砷会增加患多种人类癌症（包括肺癌）的风险。然而，砷致癌的确切分子机制在很大程度上仍然未知。自噬是维持细胞蛋白质稳态的保守分解代谢过程，其缺陷可能导致功能失调的细胞器和受损蛋白质的积累，从而促进肿瘤发生。在本研究中，我们发现人支气管上皮 BEAS-2B 细胞长期暴露于亚致死剂量的亚砷酸钠会导致自噬激活并诱导上皮间质转化 (EMT) 以增强细胞迁移和侵袭能力。恶性转化是通过激活 MEK/ERK1/2 信号传导介导的。重要的，通过药物干预或基因缺失抑制这些暴露于砷的细胞中的自噬进一步促进了 EMT 并增加了炎性体的产生。自噬抑制剂和自噬核心基因 Beclin-1 的基因缺失都产生了相似的效果。这些结果可能表明自噬在亚砷酸钠诱导的肺肿瘤发生中的重要作用，可作为预防和治疗砷中毒肺癌的潜在靶点。