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.

中文翻译：

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溶酶体 Fe2+ 释放是依托泊苷和顺铂诱导的小细胞肺癌细胞干性的原因

铁代谢已被证明可以移交癌症干细胞，这被认为是肿瘤进展、复发和耐药性的根源。本研究旨在探讨铁代谢是否与依托泊苷和顺铂诱导的小细胞肺癌 (SCLC) 细胞干细胞有关。在这里，对肿瘤球形成和干细胞标记表达进行分析，以确定依托泊苷和顺铂是否可以诱导 SCLC 细胞干细胞。构建在线数据集分析以确定铁转运与肺癌患者生存之间的相关性。染色质免疫沉淀结合拯救实验进行以揭示潜在的机制。此外，非致死剂量的依托泊苷和顺铂可以以浓度依赖的方式诱导 SCLC 细胞干细胞，并降低依赖于铁蛋白表达的溶酶体铁浓度，铁蛋白受 HIF-1α/β 正调控。此外，HIF-1α/β 可以直接结合铁蛋白启动子区域。这种 HIF/铁蛋白轴负责依托泊苷和顺铂诱导的溶酶体铁减少和 SCLC 细胞的干细胞。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 细胞干细胞至关重要，该干细胞受 HIF/铁蛋白轴调节。这种 HIF/铁蛋白轴负责依托泊苷和顺铂诱导的溶酶体铁减少和 SCLC 细胞的干细胞。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 细胞干细胞至关重要，该干细胞受 HIF/铁蛋白轴调节。这种 HIF/铁蛋白轴负责依托泊苷和顺铂诱导的溶酶体铁减少和 SCLC 细胞的干细胞。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 细胞干细胞至关重要，该干细胞受 HIF/铁蛋白轴调节。