Cancer-associated fibroblasts contribute to oral cancer cells proliferation and metastasis via exosome-mediated paracrine miR-34a-5p

Abstract

BackgroundCancer-associated fibroblasts (CAFs) play an important role in regulating tumor progression by transferring exosomes to neighboring cells. Our aim was to clarify the role of microRNA encapsulated in the exosomes derived from CAFs in oral squamous cell carcinoma (OSCC).MethodsWe examined the microRNA expression profiles of exosomes derived from CAFs and donor-matched normal fibroblasts (NFs) from patients with OSCC. We used confocal microscopy to examine the transportation of exosomal miR-34a-5p between CAFs and OSCC cells. Next, luciferase reporter and its mutant plasmids were used to confirm direct target gene of miR-34a-5p. Phenotypic assays and in vivo tumor growth experiments were used to investigate the functional significance of exosomal miR-34a-5p.FindingsWe found that the expression of miR-34a-5p in CAF-derived exosomes was significantly reduced, and fibroblasts could transfer exosomal miR-34a-5p to OSCC cells. In xenograft experiments, miR-34a-5p overexpression in CAFs could inhibit the tumorigenesis of OSCC cells. We further revealed that miR-34a-5p binds to its direct downstream target AXL to suppress OSCC cell proliferation and metastasis. Stable ectopic expression of AXL in OSCC cells overexpressing miR-34a-5p restored proliferation and motility abolished by the miRNA. The miR-34a-5p/AXL axis promoted OSCC progression via the AKT/GSK-3β/β-catenin signaling pathway, which could induce the epithelial-mesenchymal transition (EMT) to promote cancer cells metastasis. The miR-34a-5p/AXL axis enhanced nuclear translocation of β-catenin and then induced transcriptional upregulation of SNAIL, which in turn activated both MMP-2 and MMP-9.InterpretationThe miR-34a-5p/AXL axis confers aggressiveness in oral cancer cells through the AKT/GSK-3β/β-catenin/Snail signaling cascade and might represent a therapeutic target for OSCC.FundNational Natural Science Foundation of China.

Human airway epithelial extracellular vesicle miRNA signature is altered upon asthma development

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Oral cancer‐associated fibroblasts predict poor survival: Systematic review and meta‐analysis

“…The ongoing research on the role of CAFs in the expansion of the adjacent malignant tumors, in general and in OSCC, in particular, has been revealing new ways of molecular cross‐talk between these inseparable partners. Among these, transportation of specific micro‐RNAs and proteins from CAFs via extracellular vesicles (i.e., exosomes and secretomes) was found to increase the biological aggressiveness of the OSCC cells in terms of proliferation and metastasis (Li et al, ; Principe et al, ). In addition, it was also found that CAFs and OSCC cells co‐operate to modify the quality of the extracellular tissues, for example, by regulating lymphangiogenesis (Gao, Li, Chang, Wang, & Xuan, ).…”

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