Back to Search
Start Over
Monoamine oxidase A expression is suppressed in human cholangiocarcinoma via coordinated epigenetic and IL-6-driven events
- Source :
- Laboratory investigation; a journal of technical methods and pathology
- Publication Year :
- 2012
- Publisher :
- Elsevier BV, 2012.
-
Abstract
- Objectives The secretion of dopamine and serotonin is increased in cholangiocarcinoma, which has growth-promoting effects. Monoamine oxidase A (MAOA), the degradation enzyme of serotonin and dopamine, is suppressed in cholangiocarcinoma via an unknown mechanism. The aims of this study were to (i) correlate MAOA immunoreactivity with pathophysiological parameters of cholangiocarcinoma, (ii) determine the mechanism by which MAOA expression is suppressed and (iii) evaluate the consequences of restored MAOA expression in cholangiocarcinoma. Design MAOA expression was assessed in cholangiocarcinoma and non-malignant controls. The control of MAOA expression by promoter hypermethylation was evaluated and the contribution of IL-6 signaling to the suppression of MAOA expression was determined. The effects of MAOA overexpression on cholangiocarcinoma growth and invasion were also assessed. Results MAOA expression is correlated with differentiation, invasion and survival in cholangiocarcinoma. The MAOA promoter was hypermethylated immediately upstream of the start codon in cholangiocarcinoma samples and cell lines but not in non-malignant counterparts. IL-6 signaling also decreased MAOA expression via a mechanism independent of hypermethylation, involving the regulation of the balance between SP-1 transcriptional activity and its inhibitor, R1 repressor. Inhibition of both IL-6 signaling and DNA methylation restored MAOA levels to those observed in cholangiocytes. Forced MAOA overexpression inhibited cholangiocarcinoma growth and invasion. Conclusions MAOA expression is suppressed by the coordinated control of promoter hypermethylation and IL-6 signaling. MAOA may be a useful prognostic marker in the management of cholangiocarcinoma, and therapies designed to increase MAOA expression might prove beneficial in the treatment of cholangiocarcinoma.
- Subjects :
- Male
Chromatin Immunoprecipitation
Serotonin
Cell Survival
Sp1 Transcription Factor
Dopamine
Mice, Nude
Repressor
digestive system
Gene Expression Regulation, Enzymologic
Article
Pathology and Forensic Medicine
Cholangiocarcinoma
Mice
Cell Line, Tumor
medicine
Animals
Humans
Epigenetics
Promoter Regions, Genetic
Interleukin 6
Monoamine Oxidase
neoplasms
Molecular Biology
R1 repressor
DNA methylation
biology
Interleukin-6
Cell Biology
Immunohistochemistry
digestive system diseases
Gene Expression Regulation, Neoplastic
Repressor Proteins
Bile Ducts, Intrahepatic
SP-1
Bile Duct Neoplasms
Cell culture
Case-Control Studies
Choledochal Cyst
biliary cancer
biology.protein
Cancer research
Monoamine oxidase A
medicine.drug
Subjects
Details
- ISSN :
- 00236837
- Volume :
- 92
- Database :
- OpenAIRE
- Journal :
- Laboratory Investigation
- Accession number :
- edsair.doi.dedup.....26222bb026e48b5b8e4f0f872f7e874e