Abstract
Cancers of the laryngopharynx represent the most devastating of the head and neck malignancies and additional risk factors are now epidemiologically linked to this disease. Using an in vivo model (Mus musculus C57Bl/6J), we provide novel evidence that acidic bile (pH 3.0) progressively promotes invasive cancer in the hypopharynx. Malignant lesions are characterized by increasing: (i) oxidative DNA-damage, (ii) γH2AX expression, (iii) NF-κB activation, and (iv) p53 expression. Histopathological changes observed in murine hypopharyngeal mucosa exposed to acidic bile were preceded by the overexpression of Tnf, Il6, Bcl2, Egfr, Rela, Stat3, and the deregulation of miR-21, miR-155, miR-192, miR-34a, miR-375, and miR-451a. This is the first study to document that acidic bile is carcinogenic in the upper aerodigestive tract. We showed that oxidative DNA-damage produced by acidic bile in combination with NF-κB-related anti-apoptotic deregulation further supports the underlying two-hit hypothesized mechanism. Just as importantly, we reproduced the role of several biomarkers of progression that served as valuable indicators of early neoplasia in our experimental model. These findings provide a sound basis for proposing translational studies in humans by exposing new opportunities for early detection and prevention.
Highlights
It is estimated that head and neck cancer will account for approximately 53,000 new cases and10,860 deaths in the United States in 2019 [1]
We recently focused our research on the role of laryngopharyngeal reflux (LPR) and the role of bile refluxate in laryngopharyngeal carcinogenesis
To suggest that bile may be etiologically implicated in supraesophageal squamous cell carcinoma (SCC) in humans, we have recently shown that unlike tumors of patients without biliary esophageal reflux, NF-κB is highly activated in patients with bile-related hypopharyngeal SCC, accompanied by characteristic premalignant mRNA and miRNA phenotypes [40] that we had previously identified in acidic-bile-treated murine hypopharyngeal mucosa (HM) [16,17]
Summary
It is estimated that head and neck cancer will account for approximately 53,000 new cases and10,860 deaths in the United States in 2019 [1]. It is estimated that head and neck cancer will account for approximately 53,000 new cases and. Laryngopharyngeal tumors that mainly represent squamous cell carcinoma account for almost 50% of all head and neck cancers (HNSCC). Because of the elevated risk of recurrent disease and lower quality of life, patients with hypopharyngeal cancer carry a 13-fold increased risk of suicide [2], identifying it among the most devastating cancers. Known risk factors, such as smoking, alcohol consumption, and HPV16 infection have been associated with laryngopharyngeal carcinogenesis [3], additional risk factors, such as laryngopharyngeal reflux (LPR), have been epidemiologically linked to the disease [4,5]. There is growing evidence that approximately 50%
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