title: Endothelial progenitors promote hepatocarcinoma intrahepatic metastasis through monocyte chemotactic protein-1 induction of microRNA-21.
abstract: OBJECTIVE
  Endothelial progenitor cells (EPCs) circulate with increased numbers in the peripheral blood of patients with highly-vascularised hepatocellular carcinoma (HCC) and contribute to angiogenesis and neovascularisation. We hypothesised that angiogenic EPCs, that is, colony forming unit-endothelial cells (CFU-ECs), and outgrowth EPCs, that is, endothelial colony-forming cells, may exert paracrine effects on the behaviours and metastatic capacities of human hepatoma cells.
  
  
  METHODS
  Various molecular and functional approaches ranging from in vitro cell culture studies on molecular signalling to in vivo investigations on cell invasion and orthotropic transplantation models in mice and clinical specimens from patients with HCC were used.
  
  
  RESULTS
  Monocyte chemotactic protein-1 (MCP-1) was identified as a critical mediator released from CFU-ECs to contribute to the chemotaxis of Huh7 and Hep3B cells by inducing their microRNA-21 (miR-21) biogenesis through the C-C chemokine receptor-2/c-Jun N-terminal kinase/activator protein-1 signalling cascade. CFU-EC-induction of miR-21 in these cells activated their Rac1 and matrix metallopeptidase-9 by silencing Rho GTPase-activating protein-24 and tissue inhibitor of metalloproteinase-3, respectively, leading to increased cell mobility. MCP-1-induction of miR-21 induced epithelial-mesenchymal transformation of Huh7 cells in vitro and their intrahepatic metastatic capability in vivo. Moreover, increased numbers of MCP-1(+) EPCs and their positive correlations with miR-21 induction and metastatic stages in human HCC were found.
  
  
  CONCLUSIONS
  Our results provide new insights into the complexity of EPC-HCC interactions and indicate that anticancer therapies targeting either the MCP-1 released from angiogenic EPCs or the miR-21 biogenesis in HCC cells may prevent the malignant progression of primary tumours.
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Yu-Tsung
authors.initials: YT
authors.lastname: Shih
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Mei-Cun
authors.initials: MC
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, Basic Medical College, Peking University, Beijing, China Department of Bioengineering and Institute of Engineering in Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Hsin-Hsin
authors.initials: HH
authors.lastname: Peng
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Ding-Yu
authors.initials: DY
authors.lastname: Lee
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Jeng-Jiann
authors.initials: JJ
authors.lastname: Chiu
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000473:pathology* / Q000503:physiopathology*; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000502:physiology*; D002633:Chemotaxis / Q000502:physiology; D018920:Coculture Techniques; D066026:Endothelial Progenitor Cells / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D035683:MicroRNAs / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000502:physiology
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C107953:RAC1 protein, human; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D020830:rac1 GTP-Binding Protein
keywords: Endothelial Cells; Liver Metastases; Signal Transduction; Stem Cells