Exosomal transfer of miR‐124 inhibits normal fibroblasts to cancer‐associated fibroblasts transition by targeting sphingosine kinase 1 in ovarian cancer

Abstract

The interaction between tumor microenvironment and tumor cells plays a key role in tumor progression. However, the mechanisms by which this interaction promotes the transdifferentiation of normal fibroblasts (NFs) to cancer-associated fibroblasts (CAFs) are still unclear. The aim of this study was to investigate whether ovarian cancer (OvCa) cells-derived microRNAs were involved in the transition of resident fibroblasts to CAFs, and in promoting tumorigenesis. CAFs and NFs were isolated from the same ovarian site in OvCa and noncancerous prophylactic oophorectomy specimens. The effect of exosomes on the motility of CAFs or NFs was analyzed by wound healing and Transwell assays. The expression of CAFs marker α-smooth muscle actin (α-SMA) and fibroblast activated protein (FAP) were determined by quantitative real-time PCR and Western blotting. A luciferase reporter assay was used to test the interaction between miR-124 and sphingosine kinase 1 (SPHK1). NFs with downregulated miR-124 displayed the characteristics of CAFs, including overexpression of α-SMA and FAP and increased migratory and invasive ability. Overexpression of miR-124 in CAFs reversed some traits of NFs. Human ovarian surface epithelial cells-secreted miR-124 could be transferred via exosomes to CAFs and resulted in decreased α-SMA and FAP expression and attenuated cell motility. Moreover, our finding showed that the expression of SPHK1, a potential target of miR-124, was significantly elevated in CAFs. The present study provides important and novel perspective into OvCa CAF differentiation and extracellular matrix remodeling, which trigger the tumor progression.