microRNA-130b-3p contained in MSC-derived EVs promotes lung cancer progression by regulating the FOXO3/NFE2L2/TXNRD1 axis

Abstract

This study aimed to explore the molecular mechanism by which mesenchymal stem cells (MSCs) mediate lung cancer progression. Extracellular vesicles (EVs) were isolated from transfected or untransfected MSCs, and were co-cultured with lung cancer cells with/without microRNA-130b-3p (miR-130b-3p) inhibitor, mimic, overexpression plasmids of FOXO3/NFE2L2, or shRNAs. CCK-8 assay, colony formation, transwell assay, and flow cytometry were carried out to determine the biological functioning of lung cancer cells. Furthermore, FOXO3, Keap1, NFE2L2, and TXNRD1 expression was determined by qRT-PCR and western blot analysis. A tumor xenograft mouse model was used to determine role of EVs-miR-130b-3p and its target FOXO3 in lung cancer progression in vivo . miR-130b-3p was highly expressed in lung cancer tissues and MSC-derived EVs. Moreover, the MSC-derived EVs transferred miR-130b-3p to lung cancer cells to promote cell proliferation, migration, and invasion while repress cell apoptosis. miR-130b-3p directly targeted FOXO3, and FOXO3 elevated Keap1 expression to downregulate NFE2L2, thus inhibiting TXNRD1. FOXO3 overexpression or silencing of NFE2L2 or TXNRD1 diminished lung cancer cell proliferation, invasion, and migration but enhanced apoptosis. EV-delivered miR-130b-3p or FOXO3 silencing promoted lung cancer progression in vivo . In summary, MSC-derived EVs with upregulated miR-130b-3p suppressed FOXO3 to block the NFE2L2/TXNRD1 pathway, thus playing an oncogenic role in lung cancer progression.

miR-4732-3p in Extracellular Vesicles From Mesenchymal Stromal Cells Is Cardioprotective During Myocardial Ischemia

“…Another concern for the use of MSC-derived EVs in the clinical context is the potential involvement of deleterious processes mediated by specific miRNAs. For example, miR-130b-3p in MSC-derived EVs has been shown to promote lung cancer cell proliferation, migration and invasion ( Guo et al, 2021 ) and exacerbates I/R injury after adoptive transfer in diabetic mice ( Gan et al, 2020 ). With the aim of identifying miRNAs responsible (at least in part) for the beneficial effects attributed to EVs, we analyzed miRNA content in MSC derived EVs and investigated a miRNA with cardioprotective features when transplanted as a single molecule.…”

Cancer Stem Cells and Their Vesicles, Together with Other Stem and Non-Stem Cells, Govern Critical Cancer Processes: Perspectives for Medical Development

“…Analogously, miR-199, via stimulation of the mTOR pathway, increases the chemo-sensitivity of hepatocellular carcinoma cells [ 65 ]. In contrast, miR-208a induces proliferation, migration, and invasion of osteosarcoma cells [ 66 ] and two miRNAs, miR-21-5p and miR-130b-3p, promote the growth and mobility of two types of lung cancer by regulating their FoxO3 axis [ 67 , 68 ].…”

Diagnostic and Therapeutic Potential of Extracellular Vesicles

“…MSC-derived EVs in rat models with traumatic brain injury and ischemic brain injury has been shown to increase angiogenesis and neurogenesis, thus improving functional recovery. 129 , 130 Katsuda et al suggested a new treatment possibility using EVs that carry neprilysin, an amyloid degrading enzyme as a cell-free drug therapy for Alzheimer's disease, 131 , 132 Figure 1 .…”