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首页> 外文期刊>The journal of clinical investigation >Loss of TFF1 is associated with activation of NF-κB–mediated inflammation and gastric neoplasia in mice and humans
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Loss of TFF1 is associated with activation of NF-κB–mediated inflammation and gastric neoplasia in mice and humans

机译：TFF1的丧失与小鼠和人类中NF-κB介导的炎症和胃肿瘤的活化有关

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摘要

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-α–mediated NF-κB activation through the TNF receptor 1 (TNFR1)/IκB kinase (IKK) pathway. Consistent with these mouse data, human gastric tissue samples displayed a progressive decrease in TFF1 expression and an increase in NF-κB activation along the multi-step carcinogenesis cascade. Collectively, these results provide evidence that loss of TFF1 leads to activation of IKK complex–regulated NF-κB transcription factors and is an important event in shaping the NF-κB–mediated inflammatory response during the progression to gastric tumorigenesis.
机译：三叶因子1（TFF1）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。尽管TFF1表达在胃癌中经常丢失，但尚未确定这种影响的致癌途径。在这里，我们显示了敲除Tff1-的小鼠在胃粘膜幽门窦内显示出年龄依赖性的致癌组织学变化，从胃炎发展到增生，低度增生，高度增生，最后是恶性腺癌。 Tff1基因敲除小鼠的胃病变的组织学和分子特征与炎性表型一致。体内，离体和体外研究表明，TFF1表达通过TNF受体1（TNFR1）/IκB激酶（IKK）途径抑制了TNF-α介导的NF-κB活化。与这些小鼠数据一致，人类胃组织样品显示出TFF1表达逐渐降低，而NF-κB激活沿多步致癌级联反应增加。总而言之，这些结果提供了证据，即TFF1的缺失会导致IKK复合物调节的NF-κB转录因子的激活，并且是在胃癌发生过程中塑造NF-κB介导的炎症反应的重要事件。

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