title: Interleukin-1β/Iinterleukin-1 receptor-associated kinase 1 inflammatory signaling contributes to persistent Gankyrin activation during hepatocarcinogenesis.
abstract: Hepatocellular carcinoma (HCC) is a prototype of inflammation-associated cancer. Oncoprotein Gankyrin, which mostly increases in HCC, plays a critical role in HCC development and metastasis. However, the exact mechanism of Gankyrin up-regulation in HCC remains unclear. A Gankyrin luciferase reporter was developed to screen a potential regulator for Gankyrin from a list of proinflammatory cytokines, and interleukin (IL)-1β was found as one of its activators. In clinical premalignant and malignant liver disease samples, enhanced IL-1β/interleukin-1 receptor-associated kinase 1 (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 polymerase chain reaction, or immunoblotting further confirmed the up-regulation 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 nuclear factor Y (NF-Y) family members, which can recruit histone acetyltransferase coactivator E1A-binding protein p300 (p300) or CREB-binding protein (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 recruitment of the p300/CBP/NF-Y complex to Gankyrin promoter. Inhibition of phospho-JNK impairs IL-1β/IRAK-1 signaling-mediated up-regulation of Gankyrin.
  
  
  CONCLUSIONS
  The finding of IL-1β/IRAK-1 signaling promoting Gankyrin expression through JNK and NF-Y/p300/CBP complex provides a fresh view on inflammation-enhanced hepatocarcinogenesis.
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, Shanghai, China; Central Laboratory, Thoracic Surgery Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Su
authors.forename: Tao
authors.initials: T
authors.lastname: Luo
authors.forename: Junjie
authors.initials: J
authors.lastname: Zhu
authors.forename: Jing
authors.initials: J
authors.lastname: Fu
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Zhao
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Huilu
authors.initials: H
authors.lastname: Zhang
authors.forename: Yibin
authors.initials: Y
authors.lastname: Ren
authors.forename: Lexing
authors.initials: L
authors.lastname: Yu
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Yang
authors.forename: Mengchao
authors.initials: M
authors.lastname: Wu
authors.forename: Gensheng
authors.initials: G
authors.lastname: Feng
authors.forename: Shao
authors.initials: S
authors.lastname: Li
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D023081:CCAAT-Binding Factor / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000821:virology; D016022:Case-Control Studies; D002417:Cattle; D004052:Diethylnitrosamine; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000150:complications / Q000378:metabolism; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008103:Liver Cirrhosis / Q000150:complications / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000821:virology; D008297:Male; D051379:Mice; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D055815:Young Adult
chemical_list: D023081:CCAAT-Binding Factor; D053583:Interleukin-1beta; C403591:PSMD10 protein, human; D011518:Proto-Oncogene Proteins; C402244:nuclear factor Y; D004052:Diethylnitrosamine; D050882:CREB-Binding Protein; D050881:E1A-Associated p300 Protein; D053592:Interleukin-1 Receptor-Associated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex