The deregulation of microRNAs (miRNAs) plays an important role in human hepatocarcinogenesis. In this study, we highlight exosomes as mediators involved in modulating miRNA profiles in hepatocellular carcinoma (HCC) cells. First, we examined the different miRNA expression profiles in HCC cells and HCC cell–derived exosomes. Next, coculture experiments indicated that HCC cell–derived exosomes promoted the cell growth, migration, and invasion of HCC cells and had the ability to shuttle miRNAs to recipient cells. Further, our data showed that Vps4A, a key regulator of exosome biogenesis, was frequently down-regulated in HCC tissues. The reduction of Vps4A in HCC tissues was associated with tumor progression and metastasis. In vitro studies revealed that Vps4A repressed the growth, colony formation, migration, and invasion of HCC cells. We further investigated the role and involvement of Vps4A in suppressing the bioactivity of exosomes and characterized its ability to weaken the cell response to exosomes. By small RNA sequencing, we demonstrated that Vps4A facilitated the secretion of oncogenic miRNAs in exosomes as well as accumulation and uptake of tumor suppressor miRNAs in cells. A subset of Vps4A-associated miRNAs was identified. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that the phosphatidylinositol-3-kinase/Akt signaling pathway was the most likely candidate pathway for modulation by these miRNAs. Indeed, we proved that the phosphatidylinositol-3-kinase/Akt pathway was inactivated by Vps4A overexpression. Conclusion Exosome-mediated miRNA transfer is an important mechanism of self-modulation of the miRNA expression profiles in HCC cells, and Vps4A may function as a tumor suppressor, which utilizes exosomes as mediators to regulate the secretion and uptake of miRNAs in hepatoma cells; these observations provide new insights into the development of HCC.

Abstract. The expression of the long non-coding RNA (lncRNA) H19 is associated with proliferation in tumors. In order to investigate whether H19 may additionally mediate the proliferation of fibroblasts in human keloid disease, the present study collected samples from 24 subjects, including 8 with keloids, 8 with normal scars and 8 normal skin controls. Reverse transcription-polymerase chain reaction revealed that H19 levels were markedly increased in human keloids compared with normal scars and normal skin controls (P=0.017). In order to identify a potential role for H19 in the proliferative activity of human keloid fibroblasts, small interfering (si)RNA-mediated silencing experiments were performed. H19 siRNA treatment markedly inhibited the proliferation of keloid fibroblasts, as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (P= 0.008). In order to identify the signaling mediators that are regulated by H19 in keloid fibroblasts, the expression levels of mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF) were examined using western blotting. The results confirmed that knockdown of H19 inhibited mTOR and VEGF expression. In summary, the results indicate that H19 may be associated with increased proliferative activity of keloid fibroblasts, which may be mediated by mTOR and VEGF.

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