Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Anticancer Drugs. 2024 Jun 1;35(5):397-411. doi: 10.1097/CAD.0000000000001588. Epub 2024 Mar 11.
This study aimed to investigate the role and molecular mechanism of heme oxygenase-1 (HMOX1) in chemotherapy resistance in small-cell lung cancer (SCLC). Employed bioinformatics, qPCR, and Western Blot to assess HMOX1 levels in SCLC versus normal tissues and its prognostic relevance. CCK-8, flow cytometry, and thiobarbituric acid assays determined HMOX1's impact on SCLC chemosensitivity, ferroptosis markers, lipid peroxidation, and mic14's role in chemoresistance. In the GSE40275 and GSE60052 cohorts, HMOX1 expression was downregulated in SCLC tissues compared to normal tissues. Higher HMOX1 expression was associated with improved prognosis in the Sun Yat-sen University Cancer Hospital cohort and GSE60052 cohort. The RNA and protein levels of HMOX1 were reduced in drug-resistant SCLC cell lines compared to chemosensitive cell lines. Upregulation of HMOX1 increased chemosensitivity and reduced drug resistance in SCLC, while downregulation of HMOX1 decreased chemosensitivity and increased drug resistance. Upregulation of HMOX1 elevated the expression of ferroptosis-related proteins ACSL4, CD71, Transferrin, Ferritin Heavy Chain, and Ferritin Light Chain, while decreasing the expression of GPX4 and xCT. Conversely, downregulation of HMOX1 decreased the expression of ACSL4, CD71, Transferrin, Ferritin Heavy Chain, and Ferritin Light Chain, while increasing the expression of GPX4 and xCT. Upregulation of HMOX1 promoted cellular lipid peroxidation, whereas downregulation of HMOX1 inhibited cellular lipid peroxidation. Upregulation of HMOX1 reduced the RNA level of mic14, while downregulation of HMOX1 increased the RNA level of mic14. mic14 exhibited inhibitory effects on cellular lipid peroxidation in SCLC cells and contributed to reduced chemosensitivity and increased drug resistance in chemoresistant SCLC cell lines. HMOX1 plays a role in ferroptosis by regulating mic14 expression, thereby reversing chemoresistance in SCLC.
本研究旨在探讨血红素加氧酶-1（HMOX1）在小细胞肺癌（SCLC）化疗耐药中的作用及其分子机制。采用生物信息学、qPCR 和 Western Blot 方法评估 HMOX1 在 SCLC 与正常组织中的水平及其与预后的相关性。CCK-8、流式细胞术和硫代巴比妥酸测定法评估了 HMOX1 对 SCLC 化疗敏感性、铁死亡标志物、脂质过氧化和 mic14 在化疗耐药中的作用。在 GSE40275 和 GSE60052 队列中，与正常组织相比，SCLC 组织中 HMOX1 的表达下调。在中山大学肿瘤医院队列和 GSE60052 队列中，HMOX1 表达水平较高与预后改善相关。与化疗敏感细胞系相比，耐药 SCLC 细胞系中 HMOX1 的 RNA 和蛋白水平降低。上调 HMOX1 可增加 SCLC 的化疗敏感性并降低耐药性，而下调 HMOX1 则降低化疗敏感性并增加耐药性。上调 HMOX1 可提高铁死亡相关蛋白 ACSL4、CD71、转铁蛋白、铁蛋白重链和铁蛋白轻链的表达，同时降低 GPX4 和 xCT 的表达。相反，下调 HMOX1 可降低 ACSL4、CD71、转铁蛋白、铁蛋白重链和铁蛋白轻链的表达，同时增加 GPX4 和 xCT 的表达。上调 HMOX1 可促进细胞内脂质过氧化，而下调 HMOX1 则抑制细胞内脂质过氧化。上调 HMOX1 可降低 mic14 的 RNA 水平，而下调 HMOX1 则增加 mic14 的 RNA 水平。mic14 在 SCLC 细胞中表现出抑制细胞内脂质过氧化的作用，并导致化疗耐药 SCLC 细胞系中化疗敏感性降低和耐药性增加。HMOX1 通过调节 mic14 表达在铁死亡中发挥作用，从而逆转 SCLC 的化疗耐药性。
