CD90+ liver cancer cells modulate endothelial cell phenotype through the release of exosomes containing H19 lncRNA.
BACKGROUND
CD90+ liver cancer cells have been described as cancer stem-cell-like (CSC), displaying aggressive and metastatic phenotype. Using two different in vitro models, already described as CD90+ liver cancer stem cells, our aim was to study their interaction with endothelial cells mediated by the release of exosomes.


METHODS
Exosomes were isolated and characterized from both liver CD90+ cells and hepatoma cell lines. Endothelial cells were treated with exosomes, as well as transfected with a plasmid containing the full length sequence of the long non-coding RNA (lncRNA) H19. Molecular and functional analyses were done to characterize the endothelial phenotype after treatments.


RESULTS
Exosomes released by CD90+ cancer cells, but not by parental hepatoma cells, modulated endothelial cells, promoting angiogenic phenotype and cell-to-cell adhesion. LncRNA profiling revealed that CD90+ cells were enriched in lncRNA H19, and released this through exosomes. Experiments of gain and loss of function of H19 showed that this LncRNA plays an important role in the exosome-mediated phenotype of endothelial cells.


CONCLUSIONS
Our data indicate a new exosome-mediated mechanism by which CSC-like CD90+ cells could influence their tumor microenvironment by promoting angiogenesis. Moreover, we suggest the lncRNA H19 as a putative therapeutic target in hepatocellular carcinoma.
Dipartimento di Biotecnologie Cellulari ed Ematologia, Sapienza University of Rome, c/o Policlinico Umberto I, V Clinica Medica Viale Regina Elena, Rome, 324-00161, Italy. alice.conigliaro@uniroma1.it.
Alice
A
Conigliaro
Laboratory of Tissue Engineering - Innovative Technology Platforms for Tissue Engineering (PON01-00829), Rizzoli Orthopedic Institute, Palermo, Italy.
Viviana
V
Costa
Dipartimento di Biopatologia e Biotecnologie Mediche, University of Palermo, Via Divisi 83-90133, Palermo, Italy.
Alessia
A
Lo Dico
Dipartimento di Biopatologia e Biotecnologie Mediche, University of Palermo, Via Divisi 83-90133, Palermo, Italy.
Laura
L
Saieva
Dipartimento di Biopatologia e Biotecnologie Mediche, University of Palermo, Via Divisi 83-90133, Palermo, Italy.|Servizio di Diabetologia, Dipartimento per la cura e lo studio della patologie addominali e dei trapianti addominali, ISMETT IRCCS, Palermo, Italy.
Simona
S
Buccheri
Dipartimento di Biopatologia e Biotecnologie Mediche, University of Palermo, Via Divisi 83-90133, Palermo, Italy.
Francesco
F
Dieli
Institute of Biophysics, National Research Council of Italy, Palermo, Italy.
Mauro
M
Manno
Institute of Biophysics, National Research Council of Italy, Palermo, Italy.
Samuele
S
Raccosta
Dipartimento di Biotecnologie Cellulari ed Ematologia, Sapienza University of Rome, c/o Policlinico Umberto I, V Clinica Medica Viale Regina Elena, Rome, 324-00161, Italy.|National Institute for Infectious Diseases L. Spallanzani, IRCCS, Rome, Italy.
Carmine
C
Mancone
National Institute for Infectious Diseases L. Spallanzani, IRCCS, Rome, Italy.|Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Biotecnologie Cellulari ed Ematologia, Sapienza University of Rome, Rome, Italy.
Marco
M
Tripodi
Dipartimento di Biopatologia e Biotecnologie Mediche, University of Palermo, Via Divisi 83-90133, Palermo, Italy.
Giacomo
G
De Leo
Dipartimento di Biopatologia e Biotecnologie Mediche, University of Palermo, Via Divisi 83-90133, Palermo, Italy. riccardo.alessandro@unipa.it.|Institute of Biomedicine and Molecular Immunology (IBIM), National Research Council of Italy, Palermo, Italy. riccardo.alessandro@unipa.it.
Riccardo
R
Alessandro
D002448:Cell Adhesion; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000378:metabolism*; D055354:Exosomes / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D062085:RNA, Long Noncoding / Q000235:genetics*; D018800:Thy-1 Antigens / Q000378:metabolism*
C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D018800:Thy-1 Antigens