Deoxycholic acid (DCA) confers an intestinal phenotype on esophageal squamous epithelium via induction of the stemness-associated reprogramming factors OCT4 and SOX2

Barrett's esophagus (BE) is essentially a metaplasia in which the normal stratified squamous epithelium is replaced by columnar epithelium. This study focuses on the involvement of OCT4 and SOX2, 2 key cell-reprogramming factors, in the deoxycholic acid (DCA)-induced expression of the intestinal hallmarks Cdx2 and MUC2 using both in vivo and in vitro models. Up-regulated expression of OCT4 and down-regulated expression of SOX2 were observed in BE compared with normal esophagus and esophagitis. Consistent with the data in vivo, DCA induced time-dependent expression of OCT4 at both the mRNA and protein levels and decreased nuclear expression of SOX2 in Het-1A cells. Down-regulation of OCT4 expression by siRNA abrogated DCA-induced expression of Cdx2 and MUC2, whereas siRNA against SOX2 significantly upregulated the expression of both Cdx2 and MUC2. Our data indicate that both OCT4 and SOX2 play important roles in the development of BE triggered by bile acid reflux.

巴雷特食管（Barrett's esophagus，BE）本质上是一种化生现象，即正常的复层鳞状上皮被柱状上皮所替代。本研究借助体内（in vivo）与体外（in vitro）模型，探究两种关键细胞重编程因子OCT4与SOX2在脱氧胆酸（deoxycholic acid，DCA）诱导肠道标志物Cdx2及MUC2表达过程中的作用。与正常食管及食管炎组织相比，巴雷特食管组织中OCT4表达上调，而SOX2表达下调。体内实验数据与之相符：脱氧胆酸可在Het-1A细胞中以时间依赖性方式诱导OCT4在mRNA（信使RNA，messenger RNA）及蛋白水平的表达，并降低SOX2的核表达。通过小干扰RNA（small interfering RNA，siRNA）下调OCT4的表达，可阻断脱氧胆酸诱导的Cdx2与MUC2表达；而靶向SOX2的小干扰RNA则可显著上调这两个基因的表达。本研究数据表明，OCT4与SOX2均在胆汁酸反流诱发的巴雷特食管发生发展过程中发挥关键调控作用。