Insulin promotes HER2 signaling activation during Barrett's Esophagus carcinogenesis

Diletta Arcidiacono, Alessandro Antonello, Matteo Fassan, Daniele Nucci, Tiziana Morbin, Marco Agostini, Donato Nitti, Massimo Rugge, Alfredo Alberti, Giorgio Battaglia, Stefano Realdon

Research output: Contribution to journalArticle

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. Aims: 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.

Original languageEnglish
JournalDigestive and Liver Disease
DOIs
Publication statusAccepted/In press - Aug 28 2016

Keywords

  • C-peptide
  • Esophageal cancer
  • Human epidermal growth factor receptor 2
  • Hyperinsulinemia

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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