MicroRNA 196a contributes to the aggressiveness of esophageal adenocarcinoma through the MYC/TERT/NF?B axis

Abstract

Barrett's esophagus (BE) is a premalignant lesion that can lead to an invasive esophageal adenocarcinoma (EAC), a type of cancer that usually has a poor outcome. We have previously described a set of four microRNAs (miR-192, 194, 196a and b) that are markers of the disease's progression. To determine whether these miRNAs might also be drivers of invasive EAC development, their overexpression in EAC cells was analyzed. Only the overexpression of miR-196a and miR-196b induced a phenotype switch in non-invasive EAC cells, resembling epithelial-to-mesenchymal transition (EMT). The overexpression of miR-196a promoted EMT and increased cell motility and NF?B signaling. Mechanistically, miR-196a targets the inhibitor of NF?B alpha NFKBIa and also leads to c-MYC protein accumulation by down-regulating VCP expression. This in turn up-regulated TERT expression and reinforced NF?B signaling. NF?B signaling, TERT, and c-MYC inhibition resulted in a reversed-EMT phenotype, with decreased EMT hallmarks and cell motility in miR-196a overexpressing cells. Finally, an immunohistochemical analysis of BE tissue samples showed that c-MYC, TERT, and NF?B signaling increased in BE patients who developed EAC, more so than in patients that did not. The high expression of miR-196a induces aggressive features in non-invasive EAC cells. These effects are dependent on the c-MYC/TERT/NF?B signaling molecular axis. BE patients and non-invasive EAC patients with high miR-196a expression could benefit from therapeutic interventions to prevent EMT or activation of the molecular pathway described in this study.