Department of Veterans Affairs, Miami Healthcare System, Miami, FL, USA.
Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
Nat Commun. 2019 Jul 10;10(1):3039. doi: 10.1038/s41467-019-11011-4.
TFF1, a secreted protein, plays an essential role in keeping the integrity of gastric mucosa and its barrier function. Loss of TFF1 expression in the TFF1-knockout (KO) mouse leads to a pro-inflammatory phenotype with a cascade of gastric lesions that include low-grade dysplasia, high-grade dysplasia, and adenocarcinomas. In this study, we demonstrate nuclear localization of p-STAT, with significant overexpression of several STAT3 target genes in gastric glands from the TFF1-KO mice. We also show frequent loss of TFF1 with nuclear localization of STAT3 in human gastric cancers. The reconstitution of TFF1 protein in human gastric cancer cells and 3D gastric glands organoids from TFF1-KO mice abrogates IL6-induced nuclear p-STAT3 expression. Reconstitution of TFF1 inhibits IL6-induced STAT3 transcription activity, suppressing expression of its target genes. TFF1 blocks IL6Rα-GP130 complex formation through interfering with binding of IL6 to its receptor IL6Rα. These findings demonstrate a functional role of TFF1 in suppressing gastric tumorigenesis by impeding the IL6-STAT3 pro-inflammatory signaling axis.
TFF1 是一种分泌蛋白，在维持胃黏膜完整性及其屏障功能方面发挥着重要作用。TFF1 敲除（KO）小鼠中 TFF1 表达的缺失导致炎症表型，胃黏膜出现一系列病变，包括低级别上皮内瘤变、高级别上皮内瘤变和腺癌。在这项研究中，我们证明了 p-STAT 的核定位，以及 TFF1-KO 小鼠胃腺中几个 STAT3 靶基因的显著过表达。我们还发现 TFF1 在人类胃癌中经常发生核定位丢失，同时伴有 STAT3 的核定位。在人类胃癌细胞和 TFF1-KO 小鼠的 3D 胃腺类器官中重建 TFF1 蛋白可消除 IL6 诱导的核 p-STAT3 表达。TFF1 抑制 IL6 诱导的 STAT3 转录活性，抑制其靶基因的表达。TFF1 通过干扰 IL6 与其受体 IL6Rα 的结合，阻止 IL6Rα-GP130 复合物的形成。这些发现表明 TFF1 通过抑制 IL6-STAT3 促炎信号轴在抑制胃肿瘤发生方面具有功能作用。
