| Summary: | 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 (<i>Mus musculus</i> 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 <i>Tnf</i>, <i>Il6</i>, <i>Bcl2</i>, <i>Egfr</i>, <i>Rela</i>, <i>Stat3</i>, and the deregulation of <i>miR-21</i>, <i>miR-155</i>, <i>miR-192</i>, <i>miR-34a</i>, <i>miR-375</i>, and <i>miR-451a</i>. 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.
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