Abstract
Metastasis is associated with poor prognosis in cancers. Exosomes, which are packed with RNA and proteins and are released in all biological fluids, are emerging as an important mediator of intercellular communication. However, the function of exosomes remains poorly understood in cancer metastasis. Here, we demonstrate that exosomes isolated by size-exclusion chromatography from a highly metastatic human oral cancer cell line, HOC313-LM, induced cell growth through the activation of ERK and AKT as well as promoted cell motility of the poorly metastatic cancer cell line HOC313-P. MicroRNA (miRNA) array analysis identified two oncogenic miRNAs, miR-342–3p and miR-1246, that were highly expressed in exosomes. These miRNAs were transferred to poorly metastatic cells by exosomes, which resulted in increased cell motility and invasive ability. Moreover, miR-1246 increased cell motility by directly targeting DENN/MADD Domain Containing 2D (DENND2D). Taken together, our findings support the metastatic role of exosomes and exosomal miRNAs, which highlights their potential for applications in miRNA-based therapeutics.
Highlights
Metastasis is associated with poor prognosis in cancers
We focused on seven miRNAs, miR-17, miR-30a-3p, miR-30a-5p, miR92a, miR-181a, miR-342–3p and miR-1246, all of which have been reported as oncogenic miRNAs22–28
We found that DENN/MADD Domain Containing 2D (DENND2D) was downregulated 6.2-fold in miR-1246-transfected cells compared with control-transfected cells
Summary
Metastasis is associated with poor prognosis in cancers. Exosomes, which are packed with RNA and proteins and are released in all biological fluids, are emerging as an important mediator of intercellular communication. Exosomes are 30–100-nm-diameter vesicles of endosomal origin that are secreted in all biological fluids, including blood, urine, saliva, cerebrospinal fluid and in vitro cell culture medium[6,7,8] These vesicles form part of an intercellular communication system, which makes them potentially useful for therapy as well as biomarkers of diseases, such as cancer[6,9]. The authors found that exosomes from tumors drive the formation of the pre-metastatic niche and determine organotropic metastasis through the integrins of exosomes[11] Exosomes play such biological and pathological roles in intercellular communication through their cargo molecules, which includes protein and genetic material, such as microRNA (miRNA)[12,13]. Despite many studies on exosomes function, the exact molecular basis behind the biological and pathological function of exosomes is poorly understood
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