Abstract
Cancer secreted exosomal miRNAs are emerging as mediators between tumor-stoma crosstalk. Here, we show epithelial ovarian cancer (EOC)-derived exosomes activated macrophages to a tumor-associated macrophage (TAM)-like phenotype with SOCS3/STAT3 pathway involvement, which could facilitate the progression of cancer. MiR-222-3p was enrichment in exosomes released from EOC cells and it could be transferred to macrophages. Overexpression of miR-222-3p in macrophages induced polarization of the M2 phenotype. Luciferase assay verified miR-222-3p targeted SOCS3 genes and expression of SOCS3 was decreased after transfection with a miR-222-3p mimic. Down-regulation of SOCS3 correlated with an increased expression of STAT3 activation. MiR-222-3p could be detected in the exosomes from serum and its levels were related to EOC. These observations propose tumor-derived exosomal miR-222-3p is an effective regulator in the polarization of tumor-promoting M2 macrophages and may be a biomarker of EOC.
Highlights
Epithelial ovarian cancer (EOC) represents the fifth most common cause of cancer death in women [1]
Identification of exosomes derived from EOC cells and uptake of the exosomes in macrophages Exosomes extracted from the culture supernatant of Skov3 cells were isolated using a total exosome isolation reagent
We show cellular and molecular phenomena and mechanisms involve EOC-derived exosomes inducing the activation of macrophages to a tumor-associated macrophage (TAM)-like phenotype, which may promote progression of tumors
Summary
Epithelial ovarian cancer (EOC) represents the fifth most common cause of cancer death in women [1]. There is growing recognition cancer should be considered a complex microenvironment that plays a significant role in tumor progression and metastasis, rather than as single tumor cells [3]. Macrophages displaying diverse phenotypes and functions [4, 5] represent the largest number of immune-related stromal cells in the tumor environment [6]. Our previous study suggested Thrombin and coagulation factor XII could modulate the differentiation of monocytes toward tumor-associated macrophages that facilitate the peritoneal metastasis of EOC [7, 8]. Tumor-associated macrophages (TAMs) infiltrate tumors are generally considered to more closely resemble M2 phenotypes [10]. The mechanisms result in the changing phenotypes of macrophages remain to be explored
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