Inhibition of NF-B prevents the acidic bile-induced oncogenic mRNA phenotype, in human hypopharyngeal cells.

Bile-containing gastro-duodenal reflux has been clinically considered an independent risk factor in hypopharyngeal carcinogenesis. We recently showed that the chronic effect of acidic bile, at pH 4.0, selectively induces NF-B activation and accelerates the transcriptional levels of genes, linked to head and neck cancer, in normal hypopharyngeal epithelial cells. Here, we hypothesize that NF-B inhibition is capable of preventing the acidic bile-induced and cancer-related mRNA phenotype, in treated normal human hypopharyngeal cells. In this setting we used BAY 11-7082, a specific and well documented pharmacologic inhibitor of NF-B, and we observed that BAY 11-7082 effectively inhibits the acidic bile-induced gene expression profiling of the NF-B signaling pathway (down-regulation of 72 out of 84 analyzed genes). NF-B inhibition significantly prevents the acidic bile-induced transcriptional activation of NF-B transcriptional factors, RELA (p65) and c-REL, as well as genes related to and commonly found in established HNSCC cell lines. These include anti-apoptotic bcl-2, oncogenic STAT3, EGFR, ∆Np63, TNF-α and WNT5A, as well as cytokines IL-1β and IL-6. Our findings are consistent with our hypothesis demonstrating that NF-B inhibition effectively prevents the acidic bile-induced cancer-related mRNA phenotype in normal human hypopharyngeal epithelial cells supporting an understanding that NF-B may be a critical link between acidic bile and early preneoplastic events in this setting.