Circulating microRNAs, miR-939, miR-595, miR-519d and miR-494, Identify Cirrhotic Patients with HCC.
The performance of circulating biomarkers for the diagnosis of hepatocellular carcinoma (HCC) is sub-optimal. In this study we tested circulating microRNAs as biomarkers for HCC in cirrhotic patients by performing a two stage study: a discovery phase conducted by microarray and a validation phase performed by qRT-PCR in an independent series of 118 patients. Beside miRNAs emerged from the discovery phase, miR-21, miR-221, miR-519d were also tested in the validation setting on the basis of literary and tissue findings. Deregulated microRNAs were assayed in HCC-derived cells in the intracellular compartment, cell culture supernatant and exosomal fraction. Serum and tissue microRNA levels were compared in 14 patients surgically treated for HCC. From the discovery study, it emerged that seven circulating microRNAs were differentially expressed in cirrhotic patients with and without HCC. In the validation set, miR-939, miR-595 and miR-519d were shown to differentiate cirrhotic patients with and without HCC. MiR-939 and miR-595 are independent factors for HCC. ROC curves of miR-939, miR-595 and miR-519d displayed that AUC was higher than AFP. An exosomal secretion of miR-519d, miR-21, miR-221 and miR-1228 and a correlation between circulating and tissue levels of miR-519d, miR-494 and miR-21 were found in HCC patients. Therefore, we show that circulating microRNAs deserve attention as non-invasive biomarkers in the diagnostic setting of HCC and that exosomal secretion contributes to discharging a subset of microRNAs into the extracellular compartment.
Centro di Ricerca Biomedica Applicata (CRBA), Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi e Università di Bologna, Bologna, Italy.
Francesca
F
Fornari
Dipartimento di Medicina Sperimentale e Diagnostica e Centro Interdipartimentale per la Ricerca sul Cancro, Università di Ferrara, Ferrara, Italy.
Manuela
M
Ferracin
Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale Università di Bologna, Bologna, Italy.
Davide
D
Trerè
Centro di Ricerca Biomedica Applicata (CRBA), Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi e Università di Bologna, Bologna, Italy.
Maddalena
M
Milazzo
Centro di Ricerca Biomedica Applicata (CRBA), Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi e Università di Bologna, Bologna, Italy.
Sara
S
Marinelli
Centro di Ricerca Biomedica Applicata (CRBA), Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi e Università di Bologna, Bologna, Italy.
Marzia
M
Galassi
Centro di Ricerca Biomedica Applicata (CRBA), Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi e Università di Bologna, Bologna, Italy.
Laura
L
Venerandi
Centro di Ricerca Biomedica Applicata (CRBA), Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi e Università di Bologna, Bologna, Italy.
Daniela
D
Pollutri
Centro di Ricerca Biomedica Applicata (CRBA), Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi e Università di Bologna, Bologna, Italy.
Clarissa
C
Patrizi
Centro di Ricerca Biomedica Applicata (CRBA), Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi e Università di Bologna, Bologna, Italy.
Alberto
A
Borghi
Dipartimento di Medicina Interna, Ospedale per gli Infermi, Faenza, Italy.
Francesco G
FG
Foschi
Dipartimento di Medicina Interna, Ospedale per gli Infermi, Faenza, Italy.
Giuseppe F
GF
Stefanini
Dipartimento di Medicina Sperimentale e Diagnostica e Centro Interdipartimentale per la Ricerca sul Cancro, Università di Ferrara, Ferrara, Italy.
Massimo
M
Negrini
Centro di Ricerca Biomedica Applicata (CRBA), Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi e Università di Bologna, Bologna, Italy.
Luigi
L
Bolondi
Centro di Ricerca Biomedica Applicata (CRBA), Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi e Università di Bologna, Bologna, Italy.
Laura
L
Gramantieri
D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000473:pathology; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D055354:Exosomes; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood / Q000150:complications* / Q000235:genetics*; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D009367:Neoplasm Staging; D012372:ROC Curve; D015203:Reproducibility of Results
D015415:Biomarkers; C547168:MIRN494 microRNA, human; C546194:MIRN519 microRNA, human; C000604729:MIRN939 microRNA, human; D035683:MicroRNAs