Research Papers:

Circulating miR-106b-3p, miR-101-3p and miR-1246 as diagnostic biomarkers of hepatocellular carcinoma

Farzaneh Moshiri _, Alessandro Salvi, Laura Gramantieri, Angelo Sangiovanni, Paola Guerriero, Giuseppina De Petro, Cristian Bassi, Laura Lupini, Arash Sattari, Douglas Cheung, Dario Veneziano, Giovanni Nigita, Ram C. Shankaraiah, Nazario Portolani, Paolo Carcoforo, Francesca Fornari, Luigi Bolondi, Antonio Frassoldati, Silvia Sabbioni, Massimo Colombo, Carlo M. Croce and Massimo Negrini

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Oncotarget. 2018; 9:15350-15364. https://doi.org/10.18632/oncotarget.24601

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Farzaneh Moshiri1,2, Alessandro Salvi3, Laura Gramantieri4, Angelo Sangiovanni5, Paola Guerriero1, Giuseppina De Petro3, Cristian Bassi1, Laura Lupini1, Arash Sattari2, Douglas Cheung2, Dario Veneziano2, Giovanni Nigita2, Ram C. Shankaraiah1, Nazario Portolani6, Paolo Carcoforo1, Francesca Fornari4,7, Luigi Bolondi4,7, Antonio Frassoldati8, Silvia Sabbioni9, Massimo Colombo5, Carlo M. Croce2 and Massimo Negrini1

1Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy

2Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA

3Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, Brescia, Italy

4Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, Bologna, Italy

5Gastroenterology and Hepatology Division, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milano, Milan, Italy

6Department of Medical and Surgical Sciences, Surgical Clinic, University of Brescia, Brescia, Italy

7Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy

8Oncology Division, University Hospital of Ferrara, Cona (FE), Italy

9Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy

Correspondence to:

Massimo Negrini, email: [email protected]

Carlo M. Croce, email: [email protected]

Keywords: hepatocellular carcinoma; cirrhosis; circulating microRNA; diagnostic biomarkers

Received: March 09, 2017     Accepted: November 05, 2017     Epub: February 27, 2018     Published: March 16, 2018


Hepatocellular carcinoma (HCC) is the most common liver cancer and second leading cause of cancer related death worldwide. Most HCCs occur in a damaged cirrhotic background and it may be difficult to discriminate between regenerative nodules and early HCCs. No dependable molecular biomarker exists for the early detection of HCC. MicroRNAs (miRNAs) have attracted attention as potential blood-based biomarkers. To identify circulating miRNAs with diagnostic potential in HCC, we performed preliminary RNAseq studies on plasma samples from a small set of HCC patients, cirrhotic patients and healthy controls. Then, out of the identified miRNAs, we investigated miR-101-3p, miR-106b-3p, miR-1246 and miR-411-5p in plasma of independent HCC patients’ cohorts. The use of droplet digital PCR (ddPCR) confirmed the aberrant levels of these miRNAs. The diagnostic performances of each miRNA and their combinations were measured using Receiver Operating Characteristic (ROC) curve analyses: a classifier consisting of miR-101-3p, miR-1246 and miR-106b-3p produced the best diagnostic precision in plasma of HCC vs. cirrhotic patients (AUC = 0.99). A similar performance was found when the levels of miRNAs of HCC patients were compared to healthy controls (AUC = 1.00). We extended the analyses of the same miRNAs to serum samples. In serum of HCC vs. cirrhotic patients, the combination of miR-101-3p and miR-106b-3p exhibited the best diagnostic accuracy with an AUC = 0.96. Thus, circulating miR-101-3p, miR-106b-3p and miR-1246, either individually or in combination, exhibit a considerable potential value as diagnostic biomarkers of HCC.

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