{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T16:02:56Z","timestamp":1784822576476,"version":"3.55.0"},"reference-count":44,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2018,4,14]],"date-time":"2018-04-14T00:00:00Z","timestamp":1523664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hyperinsulinemia could have a role in the growing incidence of esophageal adenocarcinoma (EAC) and its pre-cancerous lesion, Barrett\u2019s Esophagus, a possible consequence of Gastro-Esophageal Reflux Disease. Obesity is known to mediate esophageal carcinogenesis through different mechanisms including insulin-resistance leading to hyperinsulinemia, which may mediate cancer progression via the insulin\/insulin-like growth factor axis. We used the hyperinsulinemic non-obese FVB\/N (Friend leukemia virus B strain) MKR (muscle (M)-IGF1R-lysine (K)-arginine (R) mouse model to evaluate the exclusive role of hyperinsulinemia in the pathogenesis of EAC related to duodeno-esophageal reflux. FVB\/N wild-type (WT) and MKR mice underwent jejunum-esophageal anastomosis side\u2014to end with the exclusion of the stomach. Thirty weeks after surgery, the esophagus was processed for histological, immunological and insulin\/Insulin-like growth factor 1 (IGF1) signal transduction analyses. Most of the WT mice (63.1%) developed dysplasia, whereas most of the MKR mice (74.3%) developed squamous cell and adenosquamous carcinomas, both expressing Human Epidermal growth factor receptor 2 (HER2). Hyperinsulinemia significantly increased esophageal cancer incidence in the presence of duodenal-reflux. Insulin receptor (IR) and IGF1 receptor (IGF1R) were overexpressed in the hyperinsulinemic condition. IGF1R, through ERK1\/2 mitogenic pattern activation, seems to be involved in cancer onset. Hyperinsulinemia-induced IGF1R and HER2 up-regulation could also increase the possibility of forming of IGF1R\/HER2 heterodimers to support cell growth\/proliferation\/progression in esophageal carcinogenesis.<\/jats:p>","DOI":"10.3390\/ijms19041198","type":"journal-article","created":{"date-parts":[[2018,4,16]],"date-time":"2018-04-16T03:12:09Z","timestamp":1523848329000},"page":"1198","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Hyperinsulinemia Promotes Esophageal Cancer Development in a Surgically-Induced Duodeno-Esophageal Reflux Murine Model"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4417-6513","authenticated-orcid":false,"given":"Diletta","family":"Arcidiacono","sequence":"first","affiliation":[{"name":"Digestive Endoscopy Unit, Veneto Institute of Oncology IOV-IRCCS, via Gattamelata, 64, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arben","family":"Dedja","sequence":"additional","affiliation":[{"name":"Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, via Giustiniani 2, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5313-0971","authenticated-orcid":false,"given":"Cinzia","family":"Giacometti","sequence":"additional","affiliation":[{"name":"Anatomic Pathology Unit, ULSS 6 Euganea, via Cosma, 1, Camposampiero, 35012 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6515-5482","authenticated-orcid":false,"given":"Matteo","family":"Fassan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgical Pathology &amp; Cytopathology Unit, University of Padua, via Giustiniani 2, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4546-213X","authenticated-orcid":false,"given":"Daniele","family":"Nucci","sequence":"additional","affiliation":[{"name":"Digestive Endoscopy Unit, Veneto Institute of Oncology IOV-IRCCS, via Gattamelata, 64, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Francia","sequence":"additional","affiliation":[{"name":"Venetian Institute of Molecular Medicine-VIMM, via Orus, 2, 35129 Padua, Italy"},{"name":"Department of Biomedical Sciences, University of Padua, via Bassi, 58\/B, 35131, Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Fabris","sequence":"additional","affiliation":[{"name":"Venetian Institute of Molecular Medicine-VIMM, via Orus, 2, 35129 Padua, Italy"},{"name":"Department of Molecular Medicine, University of Padua, via Gabelli, 63, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Zaramella","sequence":"additional","affiliation":[{"name":"Venetian Institute of Molecular Medicine-VIMM, via Orus, 2, 35129 Padua, Italy"},{"name":"Department of Molecular Medicine, University of Padua, via Gabelli, 63, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Gallagher","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Cassaro","sequence":"additional","affiliation":[{"name":"Anatomic Pathology Unit, ULSS 6 Euganea, via Cosma, 1, Camposampiero, 35012 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Rugge","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgical Pathology &amp; Cytopathology Unit, University of Padua, via Giustiniani 2, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek","family":"LeRoith","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Alberti","sequence":"additional","affiliation":[{"name":"Venetian Institute of Molecular Medicine-VIMM, via Orus, 2, 35129 Padua, Italy"},{"name":"Department of Molecular Medicine, University of Padua, via Gabelli, 63, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Realdon","sequence":"additional","affiliation":[{"name":"Digestive Endoscopy Unit, Veneto Institute of Oncology IOV-IRCCS, via Gattamelata, 64, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1136\/gutjnl-2012-302412","article-title":"A global assessment of the oesophageal adenocarcinoma epidemic","volume":"62","author":"Edgren","year":"2013","journal-title":"Gut"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1056\/NEJMoa1103042","article-title":"Incidence of adenocarcinoma among patients with Barrett\u2019s esophagus","volume":"365","author":"Pedersen","year":"2011","journal-title":"N. 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