TY - JOUR
T1 - Forkhead Box M1 Transcription Factor Drives Liver Inflammation Linking to Hepatocarcinogenesis in Mice
AU - Kurahashi, Tomohide
AU - Yoshida, Yuichi
AU - Ogura, Satoshi
AU - Egawa, Mayumi
AU - Furuta, Kunimaro
AU - Hikita, Hayato
AU - Kodama, Takahiro
AU - Sakamori, Ryotaro
AU - Kiso, Shinichi
AU - Kamada, Yoshihiro
AU - Wang, I. Ching
AU - Eguchi, Hidetoshi
AU - Morii, Eiichi
AU - Doki, Yuichiro
AU - Mori, Masaki
AU - Kalinichenko, Vladimir V.
AU - Tatsumi, Tomohide
AU - Takehara, Tetsuo
N1 - Funding Information:
Funding Supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science.
Publisher Copyright:
© 2020 The Authors
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
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U2 - 10.1016/j.jcmgh.2019.10.008
DO - 10.1016/j.jcmgh.2019.10.008
M3 - Article
C2 - 31669262
AN - SCOPUS:85079869543
VL - 9
SP - 425
EP - 446
JO - Cellular and Molecular Gastroenterology and Hepatology
JF - Cellular and Molecular Gastroenterology and Hepatology
SN - 2352-345X
IS - 3
ER -