Forkhead Box M1 Transcription Factor Drives Liver Inflammation Linking to Hepatocarcinogenesis in Mice.
Animals
Apoptosis
/ immunology
Carbon Tetrachloride
/ administration & dosage
Carcinogenesis
/ immunology
Cells, Cultured
Chemokine CCL2
/ metabolism
Disease Models, Animal
Forkhead Box Protein M1
/ analysis
Hepatectomy
Hepatitis
/ diagnosis
Hepatocytes
/ immunology
Humans
Liver
/ immunology
Liver Cirrhosis, Experimental
/ chemically induced
Liver Function Tests
Liver Neoplasms
/ immunology
Mice
Mice, Transgenic
Primary Cell Culture
CCL2
FoxM1
Liver Inflammation
Journal
Cellular and molecular gastroenterology and hepatology
ISSN: 2352-345X
Titre abrégé: Cell Mol Gastroenterol Hepatol
Pays: United States
ID NLM: 101648302
Informations de publication
Date de publication:
2020
2020
Historique:
received:
15
04
2019
revised:
10
10
2019
accepted:
15
10
2019
pubmed:
2
11
2019
medline:
4
5
2021
entrez:
1
11
2019
Statut:
ppublish
Résumé
Liver inflammation has been recognized as a hallmark of hepatocarcinogenesis. Although Forkhead Box M1 (FoxM1) is a well-defined oncogenic transcription factor that is overexpressed in hepatocellular carcinoma (HCC), its role in liver inflammation has never been explored. We generated hepatocyte-specific FoxM1 conditional transgenic (TG) mice by using the Cre-loxP and Tetracycline (Tet)-on systems to induce FoxM1 expression in a hepatocyte-specific and time-dependent manner. After treatment of Tet-derivatives doxycycline (DOX) to induce FoxM1, TG mice exhibited spontaneous development of hepatocyte death with elevated serum alanine aminotransferase levels and hepatic infiltration of macrophages. The removal of DOX in TG mice completely removed this effect, suggesting that spontaneous inflammation in TG mice occurs in a hepatocyte FoxM1-dependent manner. In addition, liver inflammation in TG mice was associated with increased levels of hepatic and serum chemokine (C-C motif) ligand 2 (CCL2). In vitro transcriptional analysis confirmed that CCL2 is a direct target of FoxM1 in murine hepatocytes. After receiving FoxM1 induction since birth, all TG mice exhibited spontaneous HCC with liver fibrosis at 12 months of age. Hepatic expression of FoxM1 was significantly increased in liver injury models. Finally, pharmacologic inhibition of FoxM1 reduced liver inflammation in models of liver injury. Hepatocyte FoxM1 acts as a crucial regulator to orchestrate liver inflammation linking to hepatocarcinogenesis. Thus, hepatocyte FoxM1 may be a potential target not only for the treatment of liver injury but also for the prevention toward HCC.
Sections du résumé
BACKGROUND & AIMS
Liver inflammation has been recognized as a hallmark of hepatocarcinogenesis. Although Forkhead Box M1 (FoxM1) is a well-defined oncogenic transcription factor that is overexpressed in hepatocellular carcinoma (HCC), its role in liver inflammation has never been explored.
METHODS
We generated hepatocyte-specific FoxM1 conditional transgenic (TG) mice by using the Cre-loxP and Tetracycline (Tet)-on systems to induce FoxM1 expression in a hepatocyte-specific and time-dependent manner.
RESULTS
After treatment of Tet-derivatives doxycycline (DOX) to induce FoxM1, TG mice exhibited spontaneous development of hepatocyte death with elevated serum alanine aminotransferase levels and hepatic infiltration of macrophages. The removal of DOX in TG mice completely removed this effect, suggesting that spontaneous inflammation in TG mice occurs in a hepatocyte FoxM1-dependent manner. In addition, liver inflammation in TG mice was associated with increased levels of hepatic and serum chemokine (C-C motif) ligand 2 (CCL2). In vitro transcriptional analysis confirmed that CCL2 is a direct target of FoxM1 in murine hepatocytes. After receiving FoxM1 induction since birth, all TG mice exhibited spontaneous HCC with liver fibrosis at 12 months of age. Hepatic expression of FoxM1 was significantly increased in liver injury models. Finally, pharmacologic inhibition of FoxM1 reduced liver inflammation in models of liver injury.
CONCLUSIONS
Hepatocyte FoxM1 acts as a crucial regulator to orchestrate liver inflammation linking to hepatocarcinogenesis. Thus, hepatocyte FoxM1 may be a potential target not only for the treatment of liver injury but also for the prevention toward HCC.
Identifiants
pubmed: 31669262
pii: S2352-345X(19)30144-4
doi: 10.1016/j.jcmgh.2019.10.008
pmc: PMC7016284
pii:
doi:
Substances chimiques
Ccl2 protein, mouse
0
Chemokine CCL2
0
FOXM1 protein, human
0
Forkhead Box Protein M1
0
Foxm1 protein, mouse
0
Carbon Tetrachloride
CL2T97X0V0
Types de publication
Journal Article
Observational Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
425-446Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL084151
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL123490
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141174
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL149631
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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