Prohibitin 1 suppresses liver cancer tumorigenesis in mice and human hepatocellular and cholangiocarcinoma cells

Autor: Jiaohong Wang, María L. Martínez-Chantar, Wei Fan, Gregory J. Gores, Nirmala Mavila, José M. Mato, Shelly C. Lu, Anuradha Krishnan, Jin Won Yang, Tony W.H. Li, Yuanyuan Tang, Mazen Noureddin, Heping Yang, Jian Tu, Ting Liu, Hui Peng, Alagappan Annamalai
Rok vydání: 2016
Předmět:
0301 basic medicine
Oncology
Male
Carcinogenesis
Biopsy
Messenger
Bile Duct Neoplasm
Medical Biochemistry and Metabolomics
medicine.disease_cause
Cell Transformation
Polymerase Chain Reaction
Cholangiocarcinoma
E-Box Elements
Mice
Random Allocation
Needle
2.1 Biological and endogenous factors
Prohibitin
Aetiology
Cancer
Mice
Knockout
Tumor
Bile duct
Blotting
Liver Disease
Biopsy
Needle
Liver Neoplasms
Immunohistochemistry
medicine.anatomical_structure
Cell Transformation
Neoplastic
Knockout mouse
Liver cancer
Western
Liver Cancer
medicine.medical_specialty
Carcinoma
Hepatocellular
Knockout
Chronic Liver Disease and Cirrhosis
Clinical Sciences
Immunology
Blotting
Western
Down-Regulation
Biology
Sensitivity and Specificity
Article
Cell Line
03 medical and health sciences
Rare Diseases
Internal medicine
Cell Line
Tumor
Prohibitins
medicine
Genetics
Animals
Humans
RNA
Messenger
Neoplastic
Hepatology
Gastroenterology & Hepatology
Animal
Gene Expression Profiling
Carcinoma
Hepatocellular
medicine.disease
Bile duct proliferation
Repressor Proteins
Disease Models
Animal
030104 developmental biology
Bile Duct Neoplasms
Cancer cell
Disease Models
Cancer research
RNA
Digestive Diseases
Zdroj: Hepatology (Baltimore, Md.), vol 65, iss 4
ISSN: 1527-3350
Popis: Prohibitin 1 (PHB1) is best known as a mitochondrial chaperone, and its role in cancer is conflicting. Mice lacking methionine adenosyltransferase α1 (MATα1) have lower PHB1 expression, and we reported that c-MYC interacts directly with both proteins. Furthermore, c-MYC and MATα1 exert opposing effects on liver cancer growth, prompting us to examine the interplay between PHB1, MATα1, and c-MYC and PHB1's role in liver tumorigenesis. We found that PHB1 is highly expressed in normal hepatocytes and bile duct epithelial cells and down-regulated in most human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). In HCC and CCA cells, PHB1 expression correlates inversely with growth. PHB1 and MAT1A positively regulate each other's expression, whereas PHB1 negatively regulates the expression of c-MYC, MAFG, and c-MAF. Both PHB1 and MATα1 heterodimerize with MAX, bind to the E-box element, and repress E-box promoter activity. PHB1 promoter contains a repressive E-box element and is occupied mainly by MAX, MNT, and MATα1 in nonmalignant cholangiocytes and noncancerous tissues that switched to c-MYC, c-MAF, and MAFG in cancer cells and human HCC/CCA. All 8-month-old liver-specific Phb1 knockout mice developed HCC, and one developed CCA. Five-month-old Phb1 heterozygotes, but not Phb1 flox mice, developed aberrant bile duct proliferation; and one developed CCA 3.5 months after left and median bile duct ligation. Phb1 heterozygotes had a more profound fall in the expression of glutathione synthetic enzymes and higher hepatic oxidative stress following left and median bile duct ligation. Conclusion: We have identified that PHB1, down-regulated in most human HCC and CCA, heterodimerizes with MAX to repress the E-box and positively regulates MAT1A while suppressing c-MYC, MAFG, and c-MAF expression; in mice, reduced PHB1 expression predisposes to the development of cholestasis-induced CCA. (Hepatology 2017;65:1249-1266).
Databáze: OpenAIRE
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