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NEAT1_1 confers gefitinib resistance in lung adenocarcinoma through promoting AKR1C1-mediated ferroptosis defence

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收录情况： ◇ SCIE

作者：
Zhen Shuman[1,2,3] * ; Jia Yunlong[1,2] * ; Zhao Yan[1,2,4] * ; Wang Jiali[1,2] ; Zheng Boyang[1] ; Liu Tianxu[1,2] ; Duan Yuqing[1,2] ; Lv Wei[1,2] ; Wang Jiaqi[1] ; Xu Fan[1,5] ; Liu Yueping[6] ; Zhang Yi[7] ; Liu Lihua[1,2,8] ;
机构： [1]Department of Tumor Immunotherapy, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050035, China. [2]China International Cooperation Laboratory of Stem Cell Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang, 050017, China. [3]Department of Radiotherapy, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050017, China. [4]Department of Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050017, China. [5]Department of Oncology, Affiliated Hospital of Chengde Medical College, Chengde, 067000, China. [6]Department of Pathology, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050017, China. [7]Biotherapy Center, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China. [8]Cancer Research Institute of Hebei Province, Shijiazhuang 050017, China.
出处：
DOI： 10.1038/s41420-024-01892-w

摘要：
Gefitinib is one of the most extensively utilized epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) for treating advanced lung adenocarcinoma (LUAD) patients harboring EGFR mutation. However, the emergence of drug resistance significantly compromised the clinical efficacy of EGFR-TKIs. Gaining further insights into the molecular mechanisms underlying gefitinib resistance holds promise for developing novel strategies to overcome the resistance and improve the prognosis in LUAD patients. Here, we identified that the inhibitory efficacy of gefitinib on EGFR-mutated LUAD cells was partially dependent on the induction of ferroptosis, and ferroptosis protection resulted in gefitinib resistance. Among the ferroptosis suppressors, aldo-keto reductase family 1 member C1 (AKR1C1) exhibited significant upregulation in gefitinib-resistant strains of LUAD cells and predicted poor progression-free survival (PFS) and overall survival (OS) of LUAD patients who received first-generation EGFR-TKI treatment. Knockdown of AKR1C1 partially reversed drug resistance by re-sensitizing the LUAD cells to gefitinib-mediated ferroptosis. The decreased expression of miR-338-3p contributed to the aberrant upregulation of AKR1C1 in gefitinib-resistant LUAD cells. Furthermore, upregulated long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1_1 (NEAT1_1) sponged miR-338-3p to neutralize its suppression on AKR1C1. Dual-luciferase reporter assay and miRNA rescue experiment confirmed the NEAT1_1/miR-338-3p/AKR1C1 axis in EGFR-mutated LUAD cells. Gain- and loss-of-function assays demonstrated that the NEAT1_1/miR-338-3p/AKR1C1 axis promoted gefitinib resistance, proliferation, migration, and invasion in LUAD cells. This study reveals the effects of NEAT1_1/miR-338-3p/AKR1C1 axis-mediated ferroptosis defence in gefitinib resistance in LUAD. Thus, targeting NEAT1_1/miR-338-3p/AKR1C1 axis might be a novel strategy for overcoming gefitinib resistance in LUAD harboring EGFR mutation.© 2024. The Author(s).

基金：
This study was supported by the National Natural Science Foundation of China (82203079 and 81871894); the Precision Medicine United Fund Key Program of Hebei Natural Science Foundation (H2021206070); the Hebei Natural Science Fund for Young Scholars (H2020206236); the Clinical Research and Innovation Team Support Program of Hebei Medical University (2022LCTD-A11); the Research and Innovation Team Support Program of Fourth Hospital of Hebei Medical University (2023C11).
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外文
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出版当年[2025]版：
大类 | 2 区 生物学
小类 | 2 区 细胞生物学
最新[2025]版：
大类 | 2 区 生物学
小类 | 2 区 细胞生物学
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出版当年[2024]版：
Q1 CELL BIOLOGY
最新[2024]版：
Q1 CELL BIOLOGY

影响因子： 最新[2024版] 最新五年平均 出版当年[2024版] 出版当年五年平均 出版前一年[2023版]

第一作者：
第一作者机构： [1]Department of Tumor Immunotherapy, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050035, China. [2]China International Cooperation Laboratory of Stem Cell Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang, 050017, China. [3]Department of Radiotherapy, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050017, China.
共同第一作者：
通讯作者：
通讯机构： [1]Department of Tumor Immunotherapy, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050035, China. [2]China International Cooperation Laboratory of Stem Cell Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang, 050017, China. [8]Cancer Research Institute of Hebei Province, Shijiazhuang 050017, China.
推荐引用方式(GB/T 7714)：
Zhen Shuman,Jia Yunlong,Zhao Yan,et al.NEAT1_1 confers gefitinib resistance in lung adenocarcinoma through promoting AKR1C1-mediated ferroptosis defence[J].CELL DEATH DISCOVERY.2024,10(1):131.doi:10.1038/s41420-024-01892-w.
APA：
Zhen Shuman,Jia Yunlong,Zhao Yan,Wang Jiali,Zheng Boyang...&Liu Lihua.(2024).NEAT1_1 confers gefitinib resistance in lung adenocarcinoma through promoting AKR1C1-mediated ferroptosis defence.CELL DEATH DISCOVERY,10,(1)
MLA：
Zhen Shuman,et al."NEAT1_1 confers gefitinib resistance in lung adenocarcinoma through promoting AKR1C1-mediated ferroptosis defence".CELL DEATH DISCOVERY 10..1(2024):131

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