title: Insulin promotes HER2 signaling activation during Barrett's Esophagus carcinogenesis.
abstract: BACKGROUND
  Insulin-resistance and hyperinsulinemia could have a role in the growing incidence of esophageal adenocarcinoma (EAC) and its pre-cancerous lesion Barrett's Esophagus (BE). HER2 activation has also a pivotal role in EAC carcinogenesis but no data correlate these two phenomena in this disease context.
  
  
  OBJECTIVE
  To investigate the role of hyperinsulinemia in BE-dysplasia-adenocarcinoma sequence and the possible relationship between insulin-mediated and HER2 signaling in EAC development.
  
  
  METHODS
  Serum insulin, C-peptide, IGF1, glucagon, IL-6, TNF-alpha, leptin, adiponectin and Insulin-Resistance-index were analyzed in 19 patients with gastro-esophageal reflux disease, 51 with BE, 24 with dysplastic-BE and 14 with EAC. Insulin/IGF1/HER2 pathways were analyzed in esophageal biopsies using Luminex®Technology. Insulin effect was also evaluated in EAC-derived OE19 cells. Data were analyzed by Fisher's exact test, Kruskal-Wallis test, Mann-Whitney U-test, Cuzick's test and Spearman correlation coefficient calculation.
  
  
  RESULTS
  Insulin-Resistance-index, insulin and C-peptide levels increased along with disease progression (p=0.019, p=0.002, p<0.0001, respectively) and correlated with HER2 expression and with downstream mediators phospho-Akt and phospho-mTOR in esophageal tissue. In vitro, insulin was also able to induce cell proliferation through HER2 activation.
  
  
  CONCLUSIONS
  Our data pinpoint a possible role of hyperinsulinemia in the Barrett's Esophagus metaplasia-dysplasia-adenocarcinoma sequence through HER2 activation in esophageal epithelial cells.
authors.affiliation: Digestive Endoscopy Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. Electronic address: diddiarci@gmail.com.
authors.forename: Diletta
authors.initials: D
authors.lastname: Arcidiacono
authors.affiliation: Digestive Endoscopy Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. Electronic address: alessandro.antonello@gmail.com.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Antonello
authors.affiliation: Department of Medicine, Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy. Electronic address: matteo.fassan@unipd.it.
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.affiliation: Digestive Endoscopy Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. Electronic address: daniele.nucci@unipg.it.
authors.forename: Daniele
authors.initials: D
authors.lastname: Nucci
authors.affiliation: Digestive Endoscopy Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. Electronic address: tiziana.morbin@ioveneto.it.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Morbin
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; Istituto di Ricerca Pediatrica-Città della Speranza, Padua, Italy; Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, TX, USA. Electronic address: m.agostini@unipd.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Agostini
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy. Electronic address: donato.nitti@unipd.it.
authors.forename: Donato
authors.initials: D
authors.lastname: Nitti
authors.affiliation: Department of Medicine, Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy. Electronic address: massimo.rugge@unipd.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Rugge
authors.affiliation: Department of Molecular Medicine, University of Padua, Padua, Italy; Venetian Institute of Molecular Medicine-VIMM, Padua, Italy. Electronic address: alfredo.alberti@unipd.it.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Alberti
authors.affiliation: Digestive Endoscopy Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy. Electronic address: giorgio.battaglia@unipd.it.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Battaglia
authors.affiliation: Digestive Endoscopy Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. Electronic address: stefano.realdon@ioveneto.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Realdon
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000328:Adult; D000368:Aged; D001471:Barrett Esophagus / Q000473:pathology*; D002096:C-Peptide / Q000097:blood; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000473:pathology*; D004947:Esophagus / Q000473:pathology; D005260:Female; D005764:Gastroesophageal Reflux / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000378:metabolism; D007558:Italy; D008297:Male; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D002096:C-Peptide; D007328:Insulin; D015850:Interleukin-6; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; C508600:IL6 protein, human; C546842:MTOR protein, human; C508053:ERBB2 protein, human
keywords: C-peptide; Esophageal cancer; Human epidermal growth factor receptor 2; Hyperinsulinemia