hERG1 behaves as biomarker of progression to adenocarcinoma in Barrett’s esophagus and can be exploited for a novel endoscopic surveillance

// Elena Lastraioli 1 , Tiziano Lottini 1 , Jessica Iorio 1 , Giancarlo Freschi 2 , Marilena Fazi 2 , Claudia Duranti 1 , Laura Carraresi 3 , Luca Messerini 1 , Antonio Taddei 2 , Maria Novella Ringressi 2 , Marianna Salemme 4 , Vincenzo Villanacci 4 , Carla Vindigni 5 , Anna Tomezzoli 6 , Roberta La Mendola 7 , Maria Bencivenga 7 , Bruno Compagnoni 8 , Mariella Chiudinelli 9 , Luca Saragoni 10 , Ilaria Manzi 11 , Giovanni De Manzoni 7 , Paolo Bechi 2 , Luca Boni 12, * , Annarosa Arcangeli 1, * 1 Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy 2 Department of Surgery and Translational Medicine, University of Florence, 50134 Florence, Italy 3 DI.V.A.L Toscana Srl, 50019 Sesto Fiorentino, Italy 4 Institute of Pathology, Spedali Civili, 25123 Brescia, Italy 5 Pathology Division, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy 6 Pathology Division, Borgo Trento Hospital, 37134 Verona, Italy 7 Division of Surgery, University of Verona, 37134 Verona, Italy 8 Surgery Division, Esine Hospital, ASL Vallecamonica Sebino, 25040 Esine (BS), Italy 9 Pathology Division, Esine Hospital, ASL Vallecamonica Sebino, 25040 Esine (BS), Italy 10 Pathology Division, Morgagni-Pierantoni Hospital, 47121 Forli, Italy 11 Gastroenterology and Endoscopy Unit, Morgagni-Pierantoni Hospital, 47121 Forli, Italy 12 Clinical Trials Coordinating Center, Azienda Ospedaliero-Universitaria Careggi/Istituto Toscano Tumori, 50134 Florence, Italy * These authors contributed equally to this work Correspondence to: Annarosa Arcangeli, email: annarosa.arcangeli@unifi.it Keywords: hERG1, Barrett’s esophagus, adenocarcinoma progression, surveillance, optical imaging Received: March 13, 2016      Accepted: July 09, 2016      Published: August 09, 2016 ABSTRACT Barrett’s esophagus (BE) is the only well-known precursor lesion of esophageal adenocarcinoma (EA). The exact estimates of the annual progression rate from BE to EA vary from 0.07% to 3.6%. The identification of BE patients at higher risk to progress to EA is hence mandatory, although difficult to accomplish. In search of novel BE biomarkers we analyzed the efficacy of hERG1 potassium channels in predicting BE progression to EA. Once tested by immunohistochemistry (IHC) on bioptic samples, hERG1 was expressed in BE, and its expression levels increased during progression from BE to esophageal dysplasia (ED) and EA. hERG1 was also over-expressed in the metaplastic cells arising in BE lesions obtained in different BE mouse models, induced either surgically or chemically. Furthermore, transgenic mice which over express hERG1 in the whole gastrointestinal tract, developed BE lesions after an esophago-jejunal anastomosis more frequently, compared to controls. A case-control study was performed on 104 bioptic samples from newly diagnosed BE patients further followed up for at least 10 years. It emerged a statistically significant association between hERG1 expression status and risk of progression to EA. Finally, a novel fluorophore- conjugated recombinant single chain variable fragment antibody (scFv-hERG1-Alexa488) was tested on freshly collected live BE biopsies: it could recognize hERG1 positive samples, perfectly matching IHC data. Overall, hERG1 can be considered a novel BE biomarker to be exploited for a novel endoscopic surveillance protocol, either in biopsies or through endoscopy, to identify those BE patients with higher risk to progress to EA.