title: Intercellular nanovesicle-mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth.
abstract: Hepatocellular carcinoma (HCC) is characterized by a propensity for multifocality, growth by local spread, and dysregulation of multiple signaling pathways. These features may be determined by the tumoral microenvironment. The potential of tumor cells to modulate HCC growth and behavior by secreted proteins has been extensively studied. In contrast, the potential for genetic modulation is poorly understood. We investigated the role and involvement of tumor-derived nanovesicles capable of altering gene expression and characterized their ability to modulate cell signaling and biological effects in other cells. We show that HCC cells can produce nanovesicles and exosomes that differ in both RNA and protein content from their cells of origin. These can be taken up and internalized by other cells and can transmit a functional transgene. The microRNA (miRNA) content of these exosomes was examined, and a subset highly enriched within exosomes was identified. A combinatorial approach to identify potential targets identified transforming growth factor β activated kinase-1 (TAK1) as the most likely candidate pathway that could be modulated by these miRNAs. Loss of TAK1 has been implicated in hepatocarcinogenesis and is a biologically plausible target for intercellular modulation. We show that HCC cell-derived exosomes can modulate TAK1 expression and associated signaling and enhance transformed cell growth in recipient cells.
  
  
  CONCLUSIONS
  Exosome-mediated miRNA transfer is an important mechanism of intercellular communication in HCC cells. These observations identify a unique intercellular mechanism that could potentially contribute to local spread, intrahepatic metastases, or multifocal growth in HCC.
authors: Mayo Clinic, Jacksonville, FL 32224, USA.
authors: Takayuki
authors: T
authors: Kogure
authors: Wen-Lang
authors: WL
authors: Lin
authors: Irene K
authors: IK
authors: Yan
authors: Chiara
authors: C
authors: Braconi
authors: Tushar
authors: T
authors: Patel
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D002450:Cell Communication / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D055354:Exosomes / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D012494:Sampling Studies; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D035683:MicroRNAs