Exosomal miR-122-5p for regulation of secretory functions of fibroblasts and promotion of breast cancer metastasis by targeting MKP-2: an experimental study.

Abstract

Tumor metastasis is a major obstacle for the effective treatment of breast cancer. Some studies showed that exosomes could promote tumor distant metastasis by establishing pre-metastasis niches (PMN). MicroRNAs (miRNAs) in exosomes play a critical role in tumor development and invasion. We aimed to investigate the effects of exosomal miRNAs derived from breast cancer cells on metastasis. MiRNA sequencing and RT-PCR approach were used to screen potential exosomal miRNAs. We compared the levels of serum exosomal miRNAs from breast cancer patients and those from MCF10A/MCF7/MDA-MB-231 cells. We found that differential exosomal miRNAs screened from patients with metastasis have higher expression levels in exosomes secreted by MDA-MB-231 cells. Using miRNA mimics or inhibitors, exosomal miR-122-5p was found to enhance the secretion levels of chemokine MCP-1 and SDF-1 from WI-38 lung fibroblast cells. In vitro luciferase assay and western blot confirmed the targeting of 3'-untranslated region of MKP-2 and suppression of MKP-2 expression by miR-122-5p in WI-38 cells. Treatment of xenograft mice with exosomal miR-122-5p increased the levels of MCP-1 and SDF-1 in serum, and promoted lung metastasis of breast cancer. In conclusion, we identified exosomal miR-122-5p from breast cancer cells that could promote the chemokine secretion of lung fibroblasts, which might facilitate the chemotaxis and colonization of breast cancer cells in lung tissue.