title: Disruption of a regulatory loop between DUSP1 and p53 contributes to hepatocellular carcinoma development and progression.
abstract: OBJECTIVE
  Altered expression of dual specificity phosphatase 1 (DUSP1) is common in tumors including hepatocellular carcinoma (HCC), and is predictive of tumor progression and poor prognosis. However, the tumor suppressive role of DUSP1 has yet to be clearly elucidated.
  
  
  METHODS
  The molecular mechanisms of tumor suppression that were investigated were induction of apoptosis, cell cycle inhibition, and regulation of p53. Additionally, the antitumor effect of DUSP1 was assessed using a mouse model. Associated signaling pathways in HCC cells and tissues were examined.
  
  
  RESULTS
  Downregulation of DUSP1 expression was significantly correlated with poor differentiation (p<0.001) and advanced HCC stage (p=0.023). DUSP1 expression resulted in HCC suppression and longer survival (p=0.0002) in a xenoplant mice model. DUSP1 inhibited p38 MAPK phosphorylation and subsequently suppressed HSP27 activation, resulting in enhanced p53 phosphorylation at sites S15, S20, and S46 in HCC cells. Enhanced p53 activation induced the expression of target genes p21 and p27, which are linked to cell cycle arrest and apoptosis. Thus, DUSP1 was potentially linked to p53 activation via the p38 MAPK/HSP27 pathway. Wild-type but not mutant p53 transcriptionally upregulated DUSP1 via its DNA-binding domain. DUSP1 and p53 might collaborate to suppress tumors in hepatocarcinogenesis via a positive regulatory loop.
  
  
  CONCLUSIONS
  Our results revealed that disruption of a positive regulatory loop between DUSP1 and p53 promoted HCC development and progression, providing a rationale for a therapeutic agent that restores DUSP1 in HCC.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Research Institute of Clinical Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Jeonbuk, Republic of Korea.
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Hao
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Research Institute of Clinical Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Jeonbuk, Republic of Korea.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Research Institute of Clinical Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Jeonbuk, Republic of Korea.
authors.forename: Mi-Jin
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Research Institute of Clinical Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Jeonbuk, Republic of Korea.
authors.forename: Yun-Peng
authors.initials: YP
authors.lastname: Wang
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Research Institute of Clinical Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Jeonbuk, Republic of Korea.
authors.forename: Jong-Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Research Institute of Clinical Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Jeonbuk, Republic of Korea.
authors.forename: Goung-Ran
authors.initials: GR
authors.lastname: Yu
authors.affiliation: Division of Life Science Research, Korea Basic Science Institute, Daejeon, 305-806 Daejeon, Republic of Korea.
authors.forename: Sang-Yeop
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Biological Science, Dong-A University, Busan, Republic of Korea.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Leem
authors.affiliation: Department of Pathology, Chonbuk National University Medical School, Jeonju, Jeonbuk, Republic of Korea.
authors.forename: Kyu-Yun
authors.initials: KY
authors.lastname: Jang
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Research Institute of Clinical Medicine, Chonbuk National University Medical School and Hospital, Jeonju, Jeonbuk, Republic of Korea. Electronic address: daeghon@chonbuk.ac.kr.
authors.forename: Dae-Ghon
authors.initials: DG
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D018450:Disease Progression; D015536:Down-Regulation; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D056945:Hep G2 Cells; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D012334:RNA, Neoplasm; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1
keywords: DUSP1; HSP27; Hepatocellular carcinoma; p38 MAPK; p53