Dataset Information

Expression and function of methylthioadenosine phosphorylase in chronic liver disease.

ABSTRACT:

Unlabelled

To study expression and function of methylthioadenosine phosphorylase (MTAP), the rate-limiting enzyme in the methionine and adenine salvage pathway, in chronic liver disease.

Design

MTAP expression was analyzed by qRT-PCR, Western blot and immunohistochemical analysis. Levels of MTA were determined by liquid chromatography-tandem mass spectrometry.

Results

MTAP was downregulated in hepatocytes in murine fibrosis models and in patients with chronic liver disease, leading to a concomitant increase in MTA levels. In contrast, activated hepatic stellate cells (HSCs) showed strong MTAP expression in cirrhotic livers. However, also MTA levels in activated HSCs were significantly higher than in hepatocytes, and there was a significant correlation between MTA levels and collagen expression in diseased human liver tissue indicating that activated HSCs significantly contribute to elevated MTA in diseased livers. MTAP suppression by siRNA resulted in increased MTA levels, NF?B activation and apoptosis resistance, while overexpression of MTAP caused the opposite effects in HSCs. The anti-apoptotic effect of low MTAP expression and high MTA levels, respectively, was mediated by induced expression of survivin, while inhibition of survivin abolished the anti-apoptotic effect of MTA on HSCs. Treatment with a DNA demethylating agent induced MTAP and reduced survivin expression, while oxidative stress reduced MTAP levels but enhanced survivin expression in HSCs.

Conclusion

MTAP mediated regulation of MTA links polyamine metabolism with NF?B activation and apoptosis in HSCs. MTAP and MTAP modulating mechanisms appear as promising prognostic markers and therapeutic targets for hepatic fibrosis.

SUBMITTER: Czech B

PROVIDER: S-EPMC3855635 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Expression and function of methylthioadenosine phosphorylase in chronic liver disease.

Czech Barbara B Dettmer Katja K Valletta Daniela D Saugspier Michael M Koch Andreas A Stevens Axel P AP Thasler Wolfgang E WE Müller Martina M Oefner Peter J PJ Bosserhoff Anja-Katrin AK Hellerbrand Claus C

PloS one 20131206 12

<h4>Unlabelled</h4>To study expression and function of methylthioadenosine phosphorylase (MTAP), the rate-limiting enzyme in the methionine and adenine salvage pathway, in chronic liver disease.<h4>Design</h4>MTAP expression was analyzed by qRT-PCR, Western blot and immunohistochemical analysis. Levels of MTA were determined by liquid chromatography-tandem mass spectrometry.<h4>Results</h4>MTAP was downregulated in hepatocytes in murine fibrosis models and in patients with chronic liver disease, ...[more]

PMID: 24324622

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Project description:Identification of cancer-associated genes by genomic profiling contributes to the elucidation of tumor development and progression. The methylthioadenosine phosphorylase (MTAP) gene, located at chromosome 9p21, plays a critical role in tumorigenicity and disease progression in a wide variety of cancers. However, the prognostic impact of MTAP in patients with nasopharyngeal carcinoma (NPC) remains obscured. Through data mining from published transcriptomic database, MTAP was first identified as a differentially downregulated gene in NPC. In this study, our aim was to evaluate the expression of MTAP in NPC and to clarify its prognostic significance.MTAP immunohistochemistry was retrospectively performed and analyzed in biopsy specimens from 124 NPC patients who received standard treatment without distant metastasis at initial diagnosis. The immunoexpression status was correlated with the clinicopathological variables, disease-specific survival (DSS), distant metastasis-free survival (DMFS), and local recurrence-free survival (LRFS). Real-time quantitative polymerase chain reaction (PCR) was used to measure MTAP gene dosage. In some cases, we also performed methylation-specific PCR and pyrosequencing to assess the status of promoter methylation.MTAP deficiency was significantly associated with advanced tumor stages (P?=?0.023) and univariately predictive of adverse outcomes for DSS, DMFS, and LRFS. In the multivariate comparison, MTAP deficiency still remained prognostically independent to portend worse DSS (P?=?0.021, hazard ratio?=?1.870) and DMFS (P?=?0.009, hazard ratio?=?2.154), together with advanced AJCC stages III to IV. Homozygous deletion or promoter methylation of MTAP gene were identified to be significantly associated with MTAP protein deficiency (P?<?0.001).MTAP deficiency was correlated with an aggressive phenotype and independently predictive of worse DSS and DMFS, suggesting its role in disease progression and as an independent prognostic biomarker of NPC, which potentially offers new strategy of targeted treatment for patients lacking MTAP expression.

Dataset Information

Expression and function of methylthioadenosine phosphorylase in chronic liver disease.

Unlabelled

Design

Results

Conclusion

Publications

Expression and function of methylthioadenosine phosphorylase in chronic liver disease.

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