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Oncotarget. 2016 Feb 2;7(5):5892-908. doi: 10.18632/oncotarget.6824.

Gastro-duodenal fluid induced nuclear factor-κappaB activation and early pre-malignant alterations in murine hypopharyngeal mucosa.

Author information

1
Department of Surgery,Yale Larynx Laboratory Section of Otolaryngology, Yale School of Medicine, New Haven, CT, USA.
2
Pathology and of Surgery (Otolaryngology), Yale School of Medicine, New Haven, CT, USA.

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.

KEYWORDS:

NF-κB; bile acids; gastroduodenal reflux; hypopharyngeal cancer; in vivo

PMID:
26745676
PMCID:
PMC4868729
DOI:
10.18632/oncotarget.6824
[Indexed for MEDLINE]
Free PMC Article

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