Research Papers:
Mutual amplification of HNF4α and IL-1R1 composes an inflammatory circuit in Helicobacter pylori associated gastric carcinogenesis
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Abstract
Lin Ma1, Jiping Zeng2, Qing Guo3, Xiuming Liang1, Li Shen1, Shuyan Li1, Yundong Sun1, Wenjuan Li1, Shili Liu1, Han Yu1, Chunyan Chen4, Jihui Jia1
1Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan 250012, Shandong, PR China
2Department of Biochemistry, School of Medicine, Shandong University, Jinan 250012, Shandong, PR China
3Department of Nursing, Ningxia People’s Hospital, Yinchuan 750021, Ningxia, PR China
4Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, Shandong, PR China
Correspondence to:
Jihui Jia, e-mail: [email protected]
Keywords: HNF4α, IL-1R1, NF-κB, Hp, gastric carcinogenesis
Received: September 30, 2015 Accepted: January 23, 2016 Published: February 08, 2016
ABSTRACT
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.
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