Insulin promotes HER2 signaling activation during Barrett's Esophagus carcinogenesis

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.