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Neoplasia. 2018 Apr;20(4):374-386. doi: 10.1016/j.neo.2018.02.001. Epub 2018 Mar 9.

In Vivo Short-Term Topical Application of BAY 11-7082 Prevents the Acidic Bile-Induced mRNA and miRNA Oncogenic Phenotypes in Exposed Murine Hypopharyngeal Mucosa.

Author information

1
Department of Surgery, Yale Larynx Laboratory, Yale School of Medicine, New Haven, CT, USA.
2
Department of Surgery, Yale Larynx Laboratory, Yale School of Medicine, New Haven, CT, USA. Electronic address: dimitra.vangeli@yale.edu.

Abstract

PURPOSE:

Bile-containing gastroesophageal reflux may promote cancer at extraesophageal sites. Acidic bile can accelerate NF-κB activation and molecular events, linked to premalignant changes in murine hypopharyngeal mucosa (HM). We hypothesize that short-term in vivo topical application of NF-κB inhibitor BAY 11-7082 can prevent acidic bile-induced early preneoplastic molecular events, suggesting its potential role in disease prevention.

EXPERIMENTAL DESIGN:

We topically exposed HM (C57Bl/6j wild-type) to a mixture of bile acids at pH 3.0 with and without BAY 11-7082 3 times/day for 7 days. We used immunofluorescence, Western blotting, immunohistochemistry, quantitative polymerase chain reaction, and polymerase chain reaction microarrays to identify NF-κB activation and its associated oncogenic mRNA and miRNA phenotypes, in murine hypopharyngeal cells in vitro and in murine HM in vivo.

RESULTS:

Short-term exposure of HM to acidic bile is a potent stimulus accelerating the expression of NF-κB signaling (70 out of 84 genes) and oncogenic molecules. Topical application of BAY 11-7082 sufficiently blocks the effect of acidic bile. BAY 11-7082 eliminates NF-κB activation in regenerating basal cells of acidic bile-treated HM and prevents overexpression of molecules central to head and neck cancer, including bcl-2, STAT3, EGFR, TNF-α, and WNT5A. NF-κB inhibitor reverses the upregulated "oncomirs" miR-155 and miR-192 and the downregulated "tumor suppressors" miR-451a and miR-375 phenotypes in HM affected by acidic bile.

CONCLUSION:

There is novel evidence that acidic bile-induced NF-κB-related oncogenic mRNA and miRNA phenotypes are generated after short-term 7-day mucosal exposure and that topical mucosal application of BAY 11-7082 can prevent the acidic bile-induced molecular alterations associated with unregulated cell growth and proliferation of hypopharyngeal cells.

PMID:
29529473
PMCID:
PMC5909679
DOI:
10.1016/j.neo.2018.02.001
[Indexed for MEDLINE]
Free PMC Article

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