Serum AP-endonuclease 1 (sAPE1) as novel biomarker for hepatocellular carcinoma

// Devis Pascut 1, * , Caecilia Hapsari Ceriapuri Sukowati 1, 2, * , Giulia Antoniali 2 , Giovanna Mangiapane 2 , Silvia Burra 2 , Luca Giovanni Mascaretti 4 , Matteo Rossano Buonocore 3 , Lory Saveria Croce 3, 5, 1 , Claudio Tiribelli 1 and Gianluca Tell 2 1 Liver Research Center, Fondazione Italiana Fegato, ONLUS, AREA Science Park, Basovizza, Trieste, Italy 2 Laboratory of Molecular Biology and DNA Repair, Department of Medicine (DAME), University of Udine, Udine, Italy 3 Department of Medical Sciences, University of Trieste, Trieste, Italy 4 Transfusion Medicine Department, Azienda Sanitaria Universitaria Integrata di Trieste (ASUITS), Trieste, Italy 5 Clinica Patologie Fegato, Azienda Sanitaria Universitaria Integrata di Trieste (ASUITS), Trieste, Italy * These authors contributed equally to this work Correspondence to: Gianluca Tell, email: gianluca.tell@uniud.it Claudio Tiribelli, email: ctliver@fegato.it Keywords: APE1; hepatocellular carcinoma; diagnosis; biomarker; DNA repair Received: November 12, 2018      Accepted: December 27, 2018      Published: January 08, 2019 ABSTRACT Late diagnosis for Hepatocellular Carcinoma (HCC) remains one of the leading causes for the high mortality rate. The apurinic/apyrimidinic endonuclease 1 (APE1), an essential member of the base excision DNA repair (BER) pathway, contributes to cell response to oxidative stress and has other non-repair activities. In this study, we evaluate the role of serum APE1 (sAPE1) as a new diagnostic biomarker and we investigate the biological role for extracellular APE1 in HCC. sAPE1 level was quantified in 99 HCC patients, 50 non-HCC cirrhotic and 100 healthy controls. The expression level was significantly high in HCC (75.8 [67.3–87.9] pg/mL) compared to cirrhosis (29.8 [18.3–36.5] pg/mL] and controls (10.8 [7.5–13.2] pg/mL) ( p < 0.001). The sAPE1 level corresponded with its protein expression in HCC tissue. sAPE1 had high diagnostic accuracy to differentiate HCC from cirrhotic (AUC = 0.87, sensitivity 88%, specificity 71%, cut-off of 36.3 pg/mL) and healthy subjects (AUC 0.98, sensibility 98% and specificity 83%, cut-off of 19.0 pg/mL). Recombinant APE1, exogenously added to JHH6 cells, significantly promotes IL-6 and IL-8 expression, suggesting a role of sAPE1 as a paracrine pro-inflammatory molecule, which may modulate the inflammatory status in cancer microenvironment. We described herein, for the first time to our knowledge, that sAPE1 might be considered as a promising diagnostic biomarker for HCC.