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Interleukin-1β/IRAK-1 inflammatory signaling contributes to persistent gankyrin activation during hepatocarcinogenesis.
MedLine Citation:
PMID:  25294684     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Hepatocellular carcinoma (HCC) is a prototype of inflammation-associated cancer. Oncoprotein Gankyrin, mostly increases in HCC, plays a critical role in HCC development and metastasis. However, the exact mechanism of Gankyrin upregulation in HCC remains unclear. A Gankyrin luciferase reporter was developed to screen potential regulator for Gankyrin from a list of pro-inflammatory cytokines, and IL-1β was found as one of its activators. In clinical pre-malignant and malignant liver diseases samples, enhanced IL-1β/IRAK-1 signaling accompanied by increased Gankyrin was observed. Lower expression of Gankyrin and phospho-IRAK-1 are favorable prognostic markers for HCC. A similar correlation was observed in the diethylnitrosamine (DEN) model of rat hepatocarcinogenesis. The results from Gankyrin reporter activity, real-time PCR, or immunoblot further confirmed the upregulation of Gankyrin by IL-1β/IRAK-1 inflammatory signaling. Moreover, a series of Gankyrin's truncated reporters were constructed, and electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) were performed to analyze the properties of Gankyrin promoter. Mechanistically, the core promoter of Gankyrin contains the binding site of NF-Y family members, which can recruit histone acetyltransferase (HAT) co-activator p300 or CBP to promote Gankyrin transcription. Conversely, knockdown of NF-Y, p300, or CBP inhibits Gankyrin expression. IL-1β stimulation causes sequential phosphorylation of IRAK-1, c-Jun N-terminal kinase (JNK) and p300, and enhances the recruitment of the p300/CBP/NF-Y complex to Gankyrin promoter. Inhibition of phospho-JNK impairs IL-1β/IRAK-1 signaling-mediated upregulation of Gankyrin. Thus, the finding of IL-1β/IRAK-1 signaling promoting Gankyrin expression via JNK and NF-Y/p300/CBP complex provides a fresh view on inflammation-enhanced hepatocarcinogenesis. (Hepatology 2014;).
Authors:
Bo Su; Tao Luo; Junjie Zhu; Jing Fu; Xiaofang Zhao; Lei Chen; Huilu Zhang; Yibin Ren; Lexing Yu; Xiaojun Yang; Mengchao Wu; Gensheng Feng; Shao Li; Yao Chen; Hongyang Wang
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-10-7
Journal Detail:
Title:  Hepatology (Baltimore, Md.)     Volume:  -     ISSN:  1527-3350     ISO Abbreviation:  Hepatology     Publication Date:  2014 Oct 
Date Detail:
Created Date:  2014-10-8     Completed Date:  -     Revised Date:  2014-10-9    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2014 American Association for the Study of Liver Diseases.
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