Deregulated methionine adenosyltransferase α1, c‐Myc, and Maf proteins together promote cholangiocarcinoma growth in mice and humans‡

Autor: Gregory J. Gores, Hui Peng, Heping Yang, Wei Fan, Ting Liu, Shelly C. Lu, Tony W.H. Li, Jiaohong Wang, Anuradha Krishnan, José M. Mato
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
Medical Biochemistry and Metabolomics
Inbred C57BL
medicine.disease_cause
Oral and gastrointestinal
Cholangiocarcinoma
E-Box Elements
Mice
chemistry.chemical_compound
Maf Transcription Factors
2.1 Biological and endogenous factors
Aetiology
Cancer
Liver injury
Regulation of gene expression
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Liver Disease
Hep G2 Cells
Biochemistry
Salivary alpha-Amylases
Proto-Oncogene Proteins c-maf
Liver Cancer
MafG Transcription Factor
Lithocholic acid
1.1 Normal biological development and functioning
Chronic Liver Disease and Cirrhosis
Clinical Sciences
Immunology
Biology
03 medical and health sciences
Rare Diseases
Cholestasis
Underpinning research
Genetics
medicine
Animals
Humans
Digestive Diseases - (Gallbladder)
Gastroenterology & Hepatology
Hepatology
Methionine Adenosyltransferase
DNA Methylation
medicine.disease
Mice
Inbred C57BL
Repressor Proteins
030104 developmental biology
Bile Duct Neoplasms
Gene Expression Regulation
chemistry
Cancer research
Digestive Diseases
Carcinogenesis
Zdroj: Hepatology (Baltimore, Md.), vol 64, iss 2
ISSN: 1527-3350
0270-9139
Popis: Unlabelledc-Myc induction drives cholestatic liver injury and cholangiocarcinoma (CCA) in mice, and induction of Maf proteins (MafG and c-Maf) contributes to cholestatic liver injury, whereas S-adenosylmethionine (SAMe) administration is protective. Here, we determined whether there is interplay between c-Myc, Maf proteins, and methionine adenosyltransferase α1 (MATα1), which is responsible for SAMe biosynthesis in the liver. We used bile duct ligation (BDL) and lithocholic acid (LCA) treatment in mice as chronic cholestasis models, a murine CCA model, human CCA cell lines KMCH and Huh-28, human liver cancer HepG2, and human CCA specimens to study gene and protein expression, protein-protein interactions, molecular mechanisms, and functional outcomes. We found that c-Myc, MATα1 (encoded by MAT1A), MafG, and c-Maf interact with one another directly. MAT1A expression fell in hepatocytes and bile duct epithelial cells during chronic cholestasis and in murine and human CCA. The opposite occurred with c-Myc, MafG, and c-Maf expression. MATα1 interacts mainly with Mnt in normal liver, but this switches to c-Maf, MafG, and c-Myc in cholestatic livers and CCA. Promoter regions of these genes have E-boxes that are bound by MATα1 and Mnt in normal liver and benign bile duct epithelial cells that switched to c-Myc, c-Maf, and MafG in cholestasis and CCA cells. E-box positively regulates c-Myc, MafG, and c-Maf, but it negatively regulates MAT1A. MATα1 represses, whereas c-Myc, MafG, and c-Maf enhance, E-box-driven promoter activity. Knocking down MAT1A or overexpressing MafG or c-Maf enhanced CCA growth and invasion in vivo.ConclusionThere is a novel interplay between MATα1, c-Myc, and Maf proteins, and their deregulation during chronic cholestasis may facilitate CCA oncogenesis. (Hepatology 2016;64:439-455).
Databáze: OpenAIRE
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