Department of Thoracic Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China.
Department of Geriatrics, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China.
Environ Toxicol. 2021 Aug;36(8):1654-1663. doi: 10.1002/tox.23161. Epub 2021 May 10.
Iron metabolism has been shown to hand over cancer stem cell, which is regarded as the root of tumor progression, recurrence and chemoresistance. This study aims to explore whether iron metabolism is involved in etoposide- and cisplatin-induced stemness in small cell lung cancer (SCLC) cells. Here, analysis on tumor-sphere formation and stemness marker expression is performed to determine whether etoposide and cisplatin can induce SCLC cell stemness. Online dataset analysis is constructed to determine the correlation between iron transportation and the survival of lung cancer patients. Chromatin immunoprecipitation combined with rescuing experiments are carried out to reveal the underlying mechanisms. Additionally, the non-lethal doses of etoposide and cisplatin can induce SCLC cell stemness in a concentration-dependent manner and reduce the lysosome iron concentration dependent on Ferritin expression, which is positively regulated by HIF-1α/β. Moreover, HIF-1α/β can directly bind to Ferritin promoter region. This HIF/Ferritin axis is responsible for etoposide- and cisplatin-induced iron reduction in lysosomes and stemness of SCLC cells. This work demonstrates that iron in lysosomes is essential for etoposide and cisplatin-induced stemness of SCLC cells, which is regulated by the HIF/Ferritin axis.
铁代谢被发现与癌症干细胞有关，癌症干细胞被认为是肿瘤进展、复发和化疗耐药的根源。本研究旨在探讨铁代谢是否参与依托泊苷和顺铂诱导的小细胞肺癌（SCLC）细胞干性。在此，通过肿瘤球形成和干性标志物表达分析来确定依托泊苷和顺铂是否能诱导 SCLC 细胞干性。构建在线数据集分析来确定铁转运与肺癌患者生存的相关性。通过染色质免疫沉淀结合挽救实验来揭示潜在的机制。此外，非致死剂量的依托泊苷和顺铂可以浓度依赖性地诱导 SCLC 细胞干性，并降低依赖于转铁蛋白表达的溶酶体铁浓度，转铁蛋白表达受 HIF-1α/β正向调节。此外，HIF-1α/β可以直接结合转铁蛋白启动子区域。这个 HIF/转铁蛋白轴负责依托泊苷和顺铂诱导的溶酶体中铁减少以及 SCLC 细胞的干性。这项工作表明，溶酶体中的铁对于依托泊苷和顺铂诱导的 SCLC 细胞干性是必不可少的，这是由 HIF/转铁蛋白轴调节的。
