Oncotarget

Research Papers:

The temporal effects of topical NF-κB inhibition, in the in vivo prevention of bile-related oncogenic mRNA and miRNA phenotypes in murine hypopharyngeal mucosa: a preclinical model

Dimitra P. Vageli, David Kasle, Sotirios G. Doukas, Panagiotis G. Doukas and Clarence T. Sasaki _

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Oncotarget. 2020; 11:3303-3314. https://doi.org/10.18632/oncotarget.27706

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Abstract

Dimitra P. Vageli1, David Kasle1, Sotirios G. Doukas1, Panagiotis G. Doukas1 and Clarence T. Sasaki1

1 The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT, USA

Correspondence to:

Clarence T. Sasaki,email: [email protected]

Keywords: NF-κB inhibition; BAY 11-7082; bile; laryngopharyngeal reflux; hypopharyngeal cancer

Received: May 07, 2020     Accepted: July 27, 2020     Published: September 01, 2020

ABSTRACT

Supraesophageal bile reflux at strongly acidic pH can cause hypopharyngeal squamous cell cancer, through activation of the oncogenic NF-κB-related pathway. We hypothesize that topical pre- or post-application of pharmacologic NF-κB inhibitor, BAY 11-7082 (0.25 μmol), on murine (C57BL/6J) HM (twice a day for 10 days) can effectively inhibit acidic bile (10 mmol/l; pH 3.0) induced oncogenic molecular events, similar to prior in vitro findings. We demonstrate that the administration of BAY 11-7082, either before or after acidic bile, eliminates NF-κB activation, prevents overexpression of Bcl2, Rela, Stat3, Egfr, Tnf, Wnt5a, and deregulations of miR-192, miR-504, linked to bile reflux-related hypopharyngeal cancer. Pre- but not post-application of NF-κB inhibitor, significantly blocks overexpression of Il6 and prostaglandin H synthases 2 (Ptgs2), and reverses miR-21, miR-155, miR-99a phenotypes, supporting its early bile-induced pro-inflammatory effect. We thus provide novel evidence that topical administration of a pharmacological NF-κB inhibitor, either before or after acidic bile exposure can successfully prevent its oncogenic mRNA and miRNA phenotypes in HM, supporting the observation that co-administration of NF-κB inhibitor may not be essential in preventing early bile-related oncogenic events and encouraging a capacity for further translational exploration.


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