title: Gastro-duodenal fluid induced nuclear factor-κappaB activation and early pre-malignant alterations in murine hypopharyngeal mucosa.
abstract: We recently described the role of gastro-duodenal fluids (GDFs) in generating changes consistent with hypopharyngeal neoplasia through activation of NF-κB pathway, using an in vitro model of human hypopharyngeal normal keratinocytes. Here, we further provide evidence that gastro-duodenal reflux is a risk factor for early pre-malignant alterations in hypopharyngeal mucosa (HM) related to an activated NF-κB oncogenic pathway, using both an in vitro and a novel in vivo model of C57Bl/6J mice. Histological, immunohistochemical and automated quantitative analysis documents significant NF-κB activation and early pre-malignant alterations in HM topically exposed to GDFs, compared to acid alone and other controls. Early pre-malignant histologic lesions exhibited increased Ki67, CK14 and ΔNp63, cell proliferation markers, changes of cell adhesion molecules, E-Cadherin and β-catenin, and STAT3 activation. The in vivo effect of NF-κB activation is positively correlated with p-STAT3, Ki67, CK14 or β-catenin expression, while GDFs induce significant transcriptional activation of RELA(p65), bcl-2, TNF-α, STAT3, EGFR and wnt5A, in vivo. Our in vivo model demonstrates selectively activated NF-κB in response to topically administrated GDFs, leading to early pre-malignant events in HM.
authors.affiliation: Department of Surgery,Yale Larynx Laboratory Section of Otolaryngology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Dimitra P
authors.initials: DP
authors.lastname: Vageli
authors.affiliation: Pathology and of Surgery (Otolaryngology), Yale School of Medicine, New Haven, CT, USA.
authors.forename: Manju L
authors.initials: ML
authors.lastname: Prasad
authors.affiliation: Department of Surgery,Yale Larynx Laboratory Section of Otolaryngology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Clarence T
authors.initials: CT
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D004386:Duodenum / Q000503:physiopathology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007012:Hypopharyngeal Neoplasms / Q000378:metabolism / Q000473:pathology*; D007013:Hypopharynx / Q000378:metabolism / Q000473:pathology*; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009092:Mucous Membrane / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013270:Stomach / Q000503:physiopathology*
chemical_list: D001647:Bile Acids and Salts; D016328:NF-kappa B; D012333:RNA, Messenger
keywords: NF-κB; bile acids; gastroduodenal reflux; hypopharyngeal cancer; in vivo