Forkhead Box M1 Transcription Factor Drives Liver Inflammation Linking to Hepatocarcinogenesis in MiceSummary

Tomohide Kurahashi; Yuichi Yoshida; Satoshi Ogura; Mayumi Egawa; Kunimaro Furuta; Hayato Hikita; Takahiro Kodama; Ryotaro Sakamori; Shinichi Kiso; Yoshihiro Kamada; I-Ching Wang; Hidetoshi Eguchi; Eiichi Morii; Yuichiro Doki; Masaki Mori; Vladimir V. Kalinichenko; Tomohide Tatsumi; Tetsuo Takehara

Cellular and Molecular Gastroenterology and Hepatology (Jan 2020)

Forkhead Box M1 Transcription Factor Drives Liver Inflammation Linking to Hepatocarcinogenesis in MiceSummary

Tomohide Kurahashi,
Yuichi Yoshida,
Satoshi Ogura,
Mayumi Egawa,
Kunimaro Furuta,
Hayato Hikita,
Takahiro Kodama,
Ryotaro Sakamori,
Shinichi Kiso,
Yoshihiro Kamada,
I-Ching Wang,
Hidetoshi Eguchi,
Eiichi Morii,
Yuichiro Doki,
Masaki Mori,
Vladimir V. Kalinichenko,
Tomohide Tatsumi,
Tetsuo Takehara

Affiliations

Tomohide Kurahashi: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Yuichi Yoshida: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; Yuichi Yoshida, MD, PhD, Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan. fax: (81) 6-6879-3629.
Satoshi Ogura: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Mayumi Egawa: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Kunimaro Furuta: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Hayato Hikita: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Takahiro Kodama: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Ryotaro Sakamori: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Shinichi Kiso: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Yoshihiro Kamada: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; Department of Molecular Biochemistry and Clinical Investigation, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
I-Ching Wang: Center for Lung Regenerative Medicine, Divisions of Pulmonary Biology and Developmental Biology, Cincinnati Children’s Hospital Medical Center, College of Medicine of the University of Cincinnati, Cincinnati, Ohio; Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan
Hidetoshi Eguchi: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Eiichi Morii: Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Yuichiro Doki: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Masaki Mori: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Vladimir V. Kalinichenko: Center for Lung Regenerative Medicine, Divisions of Pulmonary Biology and Developmental Biology, Cincinnati Children’s Hospital Medical Center, College of Medicine of the University of Cincinnati, Cincinnati, Ohio
Tomohide Tatsumi: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
Tetsuo Takehara: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; Correspondence Address correspondence to: Tetsuo Takehara, MD, PhD, Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan. fax: (81) 6-6879-3629.

Journal volume & issue: Vol. 9, no. 3
pp. 425 – 446

Abstract

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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. Keywords: FoxM1, Liver Inflammation, CCL2

Published in Cellular and Molecular Gastroenterology and Hepatology

ISSN: 2352-345X (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the digestive system. Gastroenterology
Website: https://www.journals.elsevier.com/cellular-and-molecular-gastroenterology-and-hepatology/

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