Esophageal adenocarcinoma essentially develops from esophageal inflammation caused by chronic GERD. During GERD episodes, the lower esophageal epithelium is repeatedly exposed to stomach acid, which often contains duodenal bile salts that prompt malignant transformation. TRAIL is one of the cytokines produced in response to such insults and targets the transformed cells exclusively. In this study, we simulated GERD episodes in vitro by exposing the cancer cells to acid or acid/bile combination and found that the cancer cells lived through acid attacks by expression of the decoy receptors and c-FLIP_R but died of TRAIL-mediated apoptosis when bile salts were present. Further investigation revealed that acid/bile exposure downregulated the decoy receptors and thereby facilitated TRAIL signaling; meantime, it inhibited protein kinase C activity and thus expedited c-FLIP_R degradation, allowing apoptosis to take place.

食道腺癌基本上是由慢性GERD引起的食道炎症发展而来。在GERD发作期间，食管下部上皮反复暴露于胃酸，胃酸通常含有提示恶性转化的十二指肠胆盐。TRAIL是对这种侮辱产生的细胞因子之一，并且仅靶向转化的细胞。在这项研究中，我们通过将癌细胞暴露于酸或酸/胆汁组合物中来模拟GERD发作，并通过诱饵受体和c-FLIP _R的表达发现癌细胞通过酸攻击而存活但当存在胆盐时，死于TRAIL介导的凋亡。进一步的研究表明，酸/胆汁暴露下调了诱饵受体，从而促进了TRAIL信号传导。同时，它抑制了蛋白激酶C的活性，从而加速了c-FLIP _R的降解，从而导致了细胞凋亡的发生。