Mutual amplification of HNF4α and IL-1R1 composes an inflammatory circuit in Helicobacter pylori associated gastric carcinogenesis.
Mutual amplification of HNF4α and IL-1R1 composes an inflammatory circuit in Helicobacter pylori associated gastric carcinogenesis.
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HNF4α 和 IL-1R1 的相互放大构成幽门螺杆菌相关胃癌发生中的炎症回路
DOI：
10.18632/oncotarget.7239
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发表时间：
2016-03-08
期刊：
影响因子：
--
通讯作者：
Jia J
中科院分区：
文献类型：
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作者：
Ma L;Zeng J;Guo Q;Liang X;Shen L;Li S;Sun Y;Li W;Liu S;Yu H;Chen C;Jia J
幽门螺杆菌（Helicobacter pylori，Hp）是胃炎和胃癌的环境诱发因子。对Hp的免疫应答和相关的体细胞基因表达变化是控制胃炎向GC转变的关键决定因素。我们发现，Hp感染通过NF-κB信号上调肝细胞核因子4α（HNF 4 α），并且其蛋白和mRNA水平在GC中升高。HNF 4 α反过来刺激白细胞介素-1受体1（IL-1 R1）的表达，从而放大其配体IL-1β诱发的炎症反应。IL-1β/IL-1 R1激活NF-κB信号传导，从而增加HNF 4 α表达并形成反馈环，维持NF-κB通路的激活并将炎症推向GC。对临床标本的检测显示，HNF 4 α和IL-1 R1水平随着Hp诱导的胃炎的严重程度增加而增加，并在GC中达到最高水平。HNF 4 α和IL-1 R1的共同表达是胃炎向胃癌恶变的重要指标，与胃癌患者预后不良相关。在Hp感染过程中阻断HNF 4 α/IL 1 R1/IL 1β/NF κB通路可能是预防相关性胃癌的有效手段。
Helicobacter pylori (Hp) is an environmental inducer of gastritis and gastric cancer (GC). The immune response to Hp and the associated changes in somatic gene expression are key determinants governing the transition from gastritis to GC. We show that hepatocyte nuclear factor 4α (HNF4α) is upregulated by Hp infection via NF-κB signaling and that its protein and mRNA levels are elevated in GC. HNF4α in turn stimulates expression of interleukin-1 receptor 1(IL-1R1), which amplifies the inflammatory response evoked by its ligand IL-1β. IL-1β/IL-1R1 activates NF-κB signaling, thereby increasing HNF4α expression and forming a feedback loop that sustains activation of the NF-κB pathway and drives the inflammation towards GC. Examination of clinical samples revealed that HNF4α and IL-1R1 levels increase with increasing severity of Hp-induced gastritis and reach their highest levels in GC. Co-expression of HNF4α and IL-1R1 was a crucial indicator of malignant transformation from gastritis to GC, and was associated with a poorer prognosis in GC patients. Disruption of the HNF4α/IL-1R1/IL-1β/NF-κB circuit during Hp infection maybe an effective means of preventing the associated GC.