1. Forkhead Box M1 Transcription Factor Drives Liver Inflammation Linking to Hepatocarcinogenesis in Mice
- Author
-
Tomohide Kurahashi, Satoshi Ogura, Takahiro Kodama, Yoshihiro Kamada, I-Ching Wang, Ryotaro Sakamori, Yuichiro Doki, Eiichi Morii, Kunimaro Furuta, Mayumi Egawa, Masaki Mori, Yuichi Yoshida, Hidetoshi Eguchi, Tomohide Tatsumi, Tetsuo Takehara, Shinichi Kiso, Hayato Hikita, and Vladimir V. Kalinichenko
- Subjects
bp, base pair ,0301 basic medicine ,Chemokine ,Tet, tetracycline ,Mice ,0302 clinical medicine ,GalNAc, N-acetylgalactosamine ,TG, transgenic ,CCl4, carbon tetrachloride ,HFHC, high-fat/high-cholesterol ,Original Research ,Liver injury ,biology ,Liver Neoplasms ,Gastroenterology ,CCL2, chemokine (C-C motif) ligand 2 ,medicine.anatomical_structure ,GAPDH, glyceraldehyde-3-phosphate dehydrogenase ,Hepatocyte ,Hepatocellular carcinoma ,AS, antisense ,030211 gastroenterology & hepatology ,FoxM1, Forkhead Box M1 transcription factor ,medicine.symptom ,CCL2 ,Transgene ,DOX, doxycycline ,PBS, phosphate-buffered saline ,Inflammation ,03 medical and health sciences ,RT-PCR, reverse transcription polymerase chain reaction ,ALT, alanine aminotransferase ,medicine ,Animals ,lcsh:RC799-869 ,Hepatology ,business.industry ,medicine.disease ,WT, wild-type ,Fibrosis ,030104 developmental biology ,S, sense ,FoxM1 ,Hepatocytes ,Cancer research ,FOXM1 ,biology.protein ,lcsh:Diseases of the digestive system. Gastroenterology ,NPC, nonparenchymal cell ,HCC, hepatocellular carcinoma ,business ,TUNEL, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling ,Liver Inflammation ,Transcription Factors - Abstract
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., Graphical abstract
- Published
- 2020