期刊
MOLECULAR THERAPY-NUCLEIC ACIDS
卷 28, 期 -, 页码 366-386出版社
CELL PRESS
DOI: 10.1016/j.omtn.2022.03.020
关键词
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资金
- Natural Science Foundation of Shanghai, China [22ZR1411900]
- Special Foundation for Supporting Biomedical Technology of Shanghai, China [22S11900300]
- Training Programme for the Talents of Zhongshan Hospital, Fudan University [2021ZSYQ24]
The study identified miR-6077 as a key driver of cisplatin/pemetrexed resistance in lung adenocarcinoma (LUAD). Overexpression of miR-6077 desensitized LUAD cells to cisplatin/pemetrexed by affecting cell cycle and ferroptosis, leading to cell death. This research provides a novel therapeutic strategy for overcoming chemoresistance in clinical practice.
Lung adenocarcinoma (LUAD) is one of the most common malignancies worldwide. Combination chemotherapy with cisplatin (CDDP) plus pemetrexed (PEM) remains the predominant therapeutic regimen; however, chemoresistance greatly limits its curative potential. Here, through CRISPR-Cas9 screening, we identified miR-6077 as a key driver of CDDP/ PEM resistance in LUAD. Functional experiments verified that ectopic overexpression of miR-6077 desensitized LUAD cells to CDDP/PEM in both cell lines and patient-derived xenograft models. Through RNA sequencing in cells and single-cell sequencing of samples from patients with CDDP/PEM treatments, we observed CDDP/PEM-induced upregulation of CDKN1A and KEAP1, which in turn activated cell-cycle arrest and ferroptosis, respectively, thus leading to cell death. Through miRNA pull-down, we identified and validated that miR-6077 targets CDKN1A and KEAP1. Furthermore, we demonstrated that miR-6077 protects LUAD cells from cell ferroptosis, thus resulting in chemoresistance in multiple LUAD cells both in vitro and in vivo. Moreover, we found CDDP/PEM by sponging miR-6077. Collectively, these results imply the critical role of miR-6077 in LUAD's sensitivity to CDDP/PEM, thus providing a novel therapeutic strategy for overcoming chemoresistance in clinical practice.
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