title: p53 promotes inflammation-associated hepatocarcinogenesis by inducing HMGB1 release.
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) develops in response to chronic hepatic injury. Although induced cell death is regarded as the major component of p53 tumor-suppressive activity, we recently found that sustained p53 activation subsequent to DNA damage promotes inflammation-associated hepatocarcinogenesis. Here we aim at exploring the mechanism linking p53 activation and hepatic inflammation during hepatocarcinogenesis.
  
  
  METHODS
  p53(-/-) hepatocytes expressing inducible p53 and primary wild type hepatocytes were treated to induce p53 expression. The supernatants were collected and analyzed for the presence of released inflammatory cytokines. Ethyl pyruvate was used in a rat model of carcinogen-induced hepatocarcinogenesis to examine its effect on p53-dependent chronic hepatic injury, inflammation, and tumorigenesis.
  
  
  RESULTS
  Here we show that cytoplasmic translocation and circulating levels of potent inflammatory molecule high-mobility group protein 1 (HMGB1) were greater in wild type rats than in p53(+/-) rats following carcinogen administration. Restoration of p53 expression in p53-null hepatocytes or induction of endogenous p53 in wild type hepatocytes gives rise to the release of HMGB1. Administration of the HMGB1 release inhibitor ethyl pyruvate, which does not affect p53-mediated hepatic apoptosis, substantially prevented carcinogen-induced cirrhosis and tumorigenesis in rat livers.
  
  
  CONCLUSIONS
  These results suggest that although p53 is usually regarded as a tumor suppressor, its constant activation can promote pro-tumorigenic inflammation, at least in part, via inducing HMGB1 release. Application of HMGB1 inhibitors when restoring p53 in cancer therapy might protect against pro-tumorigenic effects while leaving p53-mediated clearance of malignant cells intact.
authors.affiliation: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200433, China; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: hexiny@yahoo.com.
authors.forename: He-Xin
authors.initials: HX
authors.lastname: Yan
authors.forename: Hong-Ping
authors.initials: HP
authors.lastname: Wu
authors.forename: Hui-Lu
authors.initials: HL
authors.lastname: Zhang
authors.forename: Charles
authors.initials: C
authors.lastname: Ashton
authors.forename: Chang
authors.initials: C
authors.lastname: Tong
authors.forename: Han
authors.initials: H
authors.lastname: Wu
authors.forename: Qi-Jun
authors.initials: QJ
authors.lastname: Qian
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Wang
authors.forename: Qi-Long
authors.initials: QL
authors.lastname: Ying
mesh_terms: D000818:Animals; D002460:Cell Line; D004052:Diethylnitrosamine / Q000633:toxicity; D055786:Gene Knockout Techniques; D016158:Genes, p53; D024243:HMGB1 Protein / Q000378:metabolism*; D006521:Hepatitis, Chronic / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D018836:Inflammation Mediators; D016159:Tumor Suppressor Protein p53; D004052:Diethylnitrosamine
keywords: DEN; HCC; HMGB1; Inflammation; diethylnitrosamine; hepatocellular carcinoma; high-mobility group protein 1; p53