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Article

Pepsin Promotes Activation of Epidermal Growth Factor Receptor and Downstream Oncogenic Pathways, at Slightly Acidic and Neutral pH, in Exposed Hypopharyngeal Cells

The Yale Larynx Laboratory, Department of Surgery (Otolaryngology), Yale School of Medicine, New Haven, CT 06510, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Larry Fliegel
Int. J. Mol. Sci. 2021, 22(8), 4275; https://doi.org/10.3390/ijms22084275
Received: 30 March 2021 / Revised: 16 April 2021 / Accepted: 17 April 2021 / Published: 20 April 2021
(This article belongs to the Special Issue Role of Dysregulation of pH in Cancer)
Pepsin refluxate is considered a risk factor for laryngopharyngeal carcinogenesis. Non-acidic pepsin was previously linked to an inflammatory and tumorigenic effect on laryngopharyngeal cells in vitro. Yet there is no clear evidence of the pepsin-effect on a specific oncogenic pathway and the importance of pH in this process. We hypothesized that less acidic pepsin triggers the activation of a specific oncogenic factor and related-signalling pathway. To explore the pepsin-effect in vitro, we performed intermittent exposure of 15 min, once per day, for a 5-day period, of human hypopharyngeal primary cells (HCs) to pepsin (1 mg/mL), at a weakly acidic pH of 5.0, a slightly acidic pH of 6.0, and a neutral pH of 7.0. We have documented that the extracellular environment at pH 6.0, and particularly pH 7.0, vs. pH 5.0, promotes the pepsin-effect on HCs, causing increased internalized pepsin and cell viability, a pronounced activation of EGFR accompanied by NF-κB and STAT3 activation, and a significant upregulation of EGFR, AKT1, mTOR, IL1β, TNF-α, RELA(p65), BCL-2, IL6 and STAT3. We herein provide new evidence of the pepsin-effect on oncogenic EGFR activation and its related-signaling pathway at neutral and slightly acidic pH in HCs, opening a window to further explore the prevention and therapeutic approach of laryngopharyngeal reflux disease. View Full-Text
Keywords: pepsin; EGFR; STAT3; NF-κB; laryngopharyngeal reflux; non-acidic reflux; pH; hypopharyngeal primary cells; hypopharyngeal cancer; head and neck cancer pepsin; EGFR; STAT3; NF-κB; laryngopharyngeal reflux; non-acidic reflux; pH; hypopharyngeal primary cells; hypopharyngeal cancer; head and neck cancer
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MDPI and ACS Style

Doukas, P.G.; Vageli, D.P.; Sasaki, C.T.; Judson, B.L. Pepsin Promotes Activation of Epidermal Growth Factor Receptor and Downstream Oncogenic Pathways, at Slightly Acidic and Neutral pH, in Exposed Hypopharyngeal Cells. Int. J. Mol. Sci. 2021, 22, 4275. https://doi.org/10.3390/ijms22084275

AMA Style

Doukas PG, Vageli DP, Sasaki CT, Judson BL. Pepsin Promotes Activation of Epidermal Growth Factor Receptor and Downstream Oncogenic Pathways, at Slightly Acidic and Neutral pH, in Exposed Hypopharyngeal Cells. International Journal of Molecular Sciences. 2021; 22(8):4275. https://doi.org/10.3390/ijms22084275

Chicago/Turabian Style

Doukas, Panagiotis G., Dimitra P. Vageli, Clarence T. Sasaki, and Benjamin L. Judson. 2021. "Pepsin Promotes Activation of Epidermal Growth Factor Receptor and Downstream Oncogenic Pathways, at Slightly Acidic and Neutral pH, in Exposed Hypopharyngeal Cells" International Journal of Molecular Sciences 22, no. 8: 4275. https://doi.org/10.3390/ijms22084275

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