Fibroblast‑derived exosomal microRNA‑369 potentiates migration and invasion of lung squamous cell carcinoma cells 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.

Proteomics reveals the function reverse of MPSSS‐treated prostate cancer‐associated fibroblasts to suppress PC‐3 cell viability via the FoxO pathway

“…So, in this study, we just focused on how the low molecular weight secretome affect the proliferation of PC‐3 cells using comparative proteomics. Since EVs were the important components of the secretome and the researches have revealed that EVs derived from CAFs could mediated the proliferation, migration, and invasion of cancer cells, 57–59 the high molecular weight secretome might have other unknown influence on PC‐3 cells, which need to be further studied.…”

Apoptosis Deregulation and the Development of Cancer Multi-Drug Resistance

“…CAFs secrete various extracellular matrix proteins, chemokines, cytokines, as well as growth factors and extensively contribute to tumor progression, invasion and metastasis [145,146]. CAFs are also linked to poor survival in most cancers and are considered potential therapeutic targets [147]. Factors released by CAFs increase tumor cell survival via the activation of anti-apoptotic pathways or by induction of the epithelial to mesenchymal transition (EMT) and cancer stem cell (CSC) phenotype, as demonstrated in melanoma, non-small cell lung cancer (NSCLC) and colorectal cancer [148][149][150][151][152][153].…”

Extracellular vesicle-orchestrated crosstalk between cancer-associated fibroblasts and tumors

“…CAF-derived EVs deliver miR-1228 to promote the invasion and migration of osteosarcoma by targeting ScaI [80] . Similarly, CAFs can improve tumor migration and invasion by delivering miR-382–5p (OSCC) [81] , miR-139 (gastric cancer) [82] , and miR-369 (lung squamous cell carcinoma) [83] . Using these miRNAs as therapeutic targets may improve the inhibitory effect of cancer metastasis in clinical practice.…”

“… [91] Lung cancer miR-369 Cancer‑associated fibroblast‑derived extracellular vesicle microRNA‑369 potentiates migration and invasion of lung squamous cell carcinoma cells via NF1‑mediated MAPK signaling pathway. [83] Breast cancer miR-221 Cancer‑associated fibroblast-secreted extracellular vesicle microRNA221 is directly involved in ER-repression, and may contribute to the MAPK-induced ER repression in breast cancer cells. [86] Gastric cancer miR-139 Extracellular vesicle miRNA-139 in cancer-associated fibroblasts inhibits gastric cancer progression by repressing MMP11 expression.…”