Exosome-mediated miR-144-3p promotes ferroptosis to inhibit osteosarcoma proliferation, migration, and invasion through regulating ZEB1

Jiang，Mingyang1; Jike，Yiji1; Liu，Kaicheng1; Gan，Fu2; Zhang，Ke1; Xie，Mingjing1; Zhang，Junlei3; Chen，Chuanliang1; Zou，Xiaochong1; Jiang，Xiaohong4; Dai，Yongheng1; Chen，Weikui5; Qiu，Yue1; Bo，Zhandong1

2023-12-01

10.1186/s12943-023-01804-z

Molecular Cancer   Impact Factor & Quartile

1476-4598

Background: Osteosarcoma (OS) is the most prevalent orthopedic malignancy with a dismal prognosis. The high iron absorption rate in OS cells of patients suggests that ferroptosis may be related to the progression of OS, but its potential molecular regulatory role is still unclear. Based on the ability to couple with exosomes for targeted delivery of signals, exosome-derived micro ribonucleic acids (miRNAs) can potentially serve as diagnostic biomarkers for OS. Methods: We identified ferroptosis-related miRNAs and messenger ribonucleic acids(mRNAs) in OS using bioinformatics analysis and performed survival analysis. Then we measured miRNA expression levels through exosome microarray sequencing, and used RT-qPCR and IHC to verify the expression level of miR-144-3p and ZEB1. Stable gene expression cell lines were fabricated for in vitro experiments. Cell viability, migration and invasion were determined by CCK-8 and transwell experiment. Use the corresponding reagent kit to detect GSH/GSSG ratio, Fe level, MDA level and ROS level, and measure the expression levels of GPX4, ACSL4 and xCT through RT-qPCR and WB. We also constructed nude mice model for in vivo experiments. Finally, the stability of the miRNA/mRNA axis was verified through functional rescue experiments. Results: Low expression of miR-144-3p and high expression of ZEB1 in OS cell lines and tissues was observed. Overexpression of miR-144-3p can promote ferroptosis, reduce the survival ability of OS cells, and prevent the progression of OS. In addition, overexpression of miR-144-3p can downregulate the expression of ZEB1 in cell lines and nude mice. Knockdown of miR-144-3p has the opposite effect. The functional rescue experiment validated that miR-144-3p can regulate downstream ZEB1, and participates in the occurrence and development of OS by interfering with redox homeostasis and iron metabolism. Conclusions: MiR-144-3p can induce the occurrence of ferroptosis by negatively regulating the expression of ZEB1, thereby inhibiting the proliferation, migration, and invasion of OS cells. Graphical Abstract: [Figure not available: see fulltext.]

Exosome Ferroptosis miR-144-3p Osteosarcoma ZEB1

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English

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Natural Science Foundation of Guangxi Province[2017JJA140088z];

Biochemistry & Molecular Biology ; Oncology

Biochemistry & Molecular Biology ; Oncology

WOS:001032504700002

BMC

2-s2.0-85165293080

Scopus

1.Department of Bone and Joint Surgery,The First Affiliated Hospital of Guangxi Medical University,Nanning,Guangxi,China
2.Department of Urology Surgery,The Affiliated Hospital of Youjiang Medical University for Nationalities,Baise,China
3.Department of Sports Medicine,Southern University of Science and Technology Hospital,Shenzhen,China
4.Department of Trauma Orthopedic and Hand Surgery,The First Affiliated Hospital of Guangxi Medical University,Nanning,China
5.Department of Radiology,The First Affiliated Hospital of Guangxi Medical University,Nanning,China

Jiang，Mingyang,Jike，Yiji,Liu，Kaicheng,et al. Exosome-mediated miR-144-3p promotes ferroptosis to inhibit osteosarcoma proliferation, migration, and invasion through regulating ZEB1[J]. Molecular Cancer,2023,22(1).

Jiang，Mingyang.,Jike，Yiji.,Liu，Kaicheng.,Gan，Fu.,Zhang，Ke.,...&Bo，Zhandong.(2023).Exosome-mediated miR-144-3p promotes ferroptosis to inhibit osteosarcoma proliferation, migration, and invasion through regulating ZEB1.Molecular Cancer,22(1).

Jiang，Mingyang,et al."Exosome-mediated miR-144-3p promotes ferroptosis to inhibit osteosarcoma proliferation, migration, and invasion through regulating ZEB1".Molecular Cancer 22.1(2023).