miR-6077 promotes cisplatin/pemetrexed resistance in lung adenocarcinoma via CDKN1A/cell cycle arrest and KEAP1/ferroptosis pathways

被引：80

作者：

Bi, Guoshu ^{[1
,2
]}

Liang, Jiaqi ^{[1
,2
]}

Zhao, Mengnan ^{[1
,2
]}

Zhang, Huan ^{[1
,2
]}

Jin, Xing ^{[1
,2
]}

Lu, Tao ^{[1
,2
]}

Zheng, Yuansheng ^{[1
,2
]}

Bian, Yunyi ^{[1
,2
]}

Chen, Zhencong ^{[1
,2
]}

Huang, Yiwei ^{[1
,2
]}

Besskaya, Valeria ^{[1
,2
]}

Zhan, Cheng ^{[1
,2
]}

Wang, Qun ^{[1
,2
]}

Tan, Lijie ^{[1
,2
]}

机构：

[1] Fudan Univ, Zhongshan Hosp, Dept Thorac Surg, 180 Fenglin Rd, Shanghai 200032, Peoples R China

[2] Fudan Univ, Zhongshan Hosp, Canc Ctr, Shanghai 200032, Peoples R China

来源：

MOLECULAR THERAPY NUCLEIC ACIDS | 2022年 / 28卷

基金：

上海市自然科学基金;

关键词：

OXIDATIVE STRESS; CELL-CYCLE; CISPLATIN RESISTANCE; CANCER CELLS; P21; CRISPR-CAS9; ACTIVATION; THERAPY; DAMAGE; TRIAL;

D O I：

10.1016/j.omtn.2022.03.020

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：366 / 386

页数：21

共 78 条

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