Fibroblast‑derived exosomal microRNA‑369 potentiates migration and invasion of lung squamous cell carcinomacells via NF1‑mediated MAPK signaling pathway.

Abstract

Cancer-associated fibroblasts (CAFs) exhibit tumor-stimulating properties and are associated with poor survival in several types of cancer, making them potential therapeutic targets. The present study aimed to determine whether CAFs were associated with cell migration and invasion in lung squamous cell carcinoma (LUSC), as well as their association with microRNA-369 (miR-369) in these processes. Firstly, the changes of the malignant biological behavior were observed by treating the LUSC cells with the CAFs-derived extracellular vesicles (CAFs-EVs). Subsequently, the differentially expressed miRNAs in the cells treated with CAFs-EVs were analyzed by microarray analysis. Following inhibition of miR-369 expression in CAFs-EVs, LUSC cells were co-cultured, and the malignant biological behavior of the cells was re-examined. Then, through bioinformatics analysis and verification, the mRNA targets of miR-369 and the corresponding downstream signaling pathway were screened out. Finally, the effects of CAFs-EVs on the growth and metastasis of LUSC were demonstrated by in vivo tumor formation and metastasis experiments. It was identified that miR-369 was expressed at a relatively high level in the CAFs-EVs. Neurofibromin-1 (NF1) was hypothesized as a direct target of miR-369 in LUSC. Also, the overexpression of miR-369 activated the mitogen-activated protein kinase signaling pathway by interacting with NF1, consequently potentiating LUSC cell growth. The present study provided novel insights into the action of miR-369 in CAFs-EVs in controlling LUSC cell migration, invasion and tumorigenesis, and identified miR-369 in CAFs-EVs as an important prognostic marker and therapeutic target.