Loss of TFF1 is associated with activation of NF-κB-mediated inflammation and gastric neoplasia in mice and humans
Loss of TFF1 is associated with activation of NF-κB-mediated inflammation and gastric neoplasia in mice and humans
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DOI：
10.1172/jci43922
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发表时间：
2011-05-01
影响因子：
15.9
通讯作者：
El-Rifai, Wael
中科院分区：
文献类型：
--
作者：
Soutto, Mohammed;Belkhiri, Abbes;El-Rifai, Wael
三叶因子1（TFF 1）是一种肿瘤抑制基因，其编码属于蛋白酶抗性肽的三叶因子家族的肽。虽然TFF 1表达在胃癌中经常丢失，但其影响的致瘤途径尚未确定。在这里，我们表明，Tff 1基因敲除小鼠表现出年龄依赖性的致癌组织学变化，在幽门窦的胃粘膜，从胃炎到增生，低度异型增生，高度异型增生，并最终恶性腺癌的进展。Tff 1基因敲除小鼠胃病变的组织学和分子特征与炎症表型一致。体内、离体和体外研究表明，TFF 1表达通过TNF受体1（TNFR 1）I κ B激酶（IKK）途径抑制TNF-α介导的NF-κ B活化。与这些小鼠数据一致，人胃组织样品显示沿着多步骤致癌级联反应，TFF 1表达逐渐降低，NF-κ B活化沿着增加。总的来说，这些结果提供的证据表明，TFF 1的损失导致IKK复合物调节的NF-κ B B转录因子的激活，是一个重要的事件，在形成NF-κ B介导的炎症反应在胃肿瘤发生的进展。
Trefoil factor 1 (TFF1) is a tumor suppressor gene that encodes a peptide belonging to the trefoil factor family of protease-resistant peptides. Although TFF1 expression is frequently lost in gastric carcinomas, the tumorigenic pathways this affects have not been determined. Here we show that Tff1-knockout mice exhibit age-dependent carcinogenic histological changes in the pyloric antrum of the gastric mucosa, progressing from gastritis to hyperplasia, low-grade dysplasia, high-grade dysplasia, and ultimately malignant adenocarcinoma. The histology and molecular signatures of gastric lesions in the Tff1-knockout mice were consistent with an inflammatory phenotype. In vivo, ex-vivo, and in vitro studies showed that TFF1 expression suppressed TNF-alpha-mediated NF-kappa B activation through the TNF receptor 1 (TNFR1)I kappa B kinase (IKK) pathway. Consistent with these mouse data, human gastric tissue samples displayed a progressive decrease in TFF1 expression and an increase in NF-kappa B activation along the multi-step carcinogenesis cascade. Collectively, these results provide evidence that loss of TFF1 leads to activation of IKK complex-regulated NF-kappa B transcription factors and is an important event in shaping the NF-kappa B-mediated inflammatory response during the progression to gastric tumorigenesis.