title: Vps4A functions as a tumor suppressor by regulating the secretion and uptake of exosomal microRNAs in human hepatoma cells.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jin-xing
authors.initials: JX
authors.lastname: Wei
authors.forename: Li-hong
authors.initials: LH
authors.lastname: Lv
authors.forename: Yun-le
authors.initials: YL
authors.lastname: Wan
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.forename: Guo-lin
authors.initials: GL
authors.lastname: Li
authors.forename: Hao-ming
authors.initials: HM
authors.lastname: Lin
authors.forename: Rui
authors.initials: R
authors.lastname: Zhou
authors.forename: Chang-zhen
authors.initials: CZ
authors.lastname: Shang
authors.forename: Jun
authors.initials: J
authors.lastname: Cao
authors.forename: Hai
authors.initials: H
authors.lastname: He
authors.forename: Qing-fang
authors.initials: QF
authors.lastname: Han
authors.forename: Pei-qing
authors.initials: PQ
authors.lastname: Liu
authors.forename: Gang
authors.initials: G
authors.lastname: Zhou
authors.forename: Jun
authors.initials: J
authors.lastname: Min
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000502:physiology*; D055354:Exosomes / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D025262:Vacuolar Proton-Translocating ATPases / Q000502:physiology*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D035683:MicroRNAs; D025521:Tumor Suppressor Proteins; D025262:Vacuolar Proton-Translocating ATPases; D000074183:ATPases Associated with Diverse Cellular Activities; C490305:VPS4A protein, human