Regulation of glycosylphosphatidylinositol-anchored proteins and GPI-phospholipase D in a c-Myc transgenic mouse model of hepatocellular carcinoma and human HCC
Abstract
Recent research implicated glycosylphosphatidylinositol-anchored proteins (GPI-AP) and GPI-specific phospholipase D (GPI-PLD) in the pathogenesis of fatty liver disease and hepatocellular carcinoma (HCC). Given that c-Myc is frequently amplified in HCC, we investigated their regulation in a c-Myc transgenic disease model of liver cancer and HCC patient samples. Whole genome scans defined 54 significantly regulated genes coding for GPI-AP of which 29 and 14 were repressed in expression in transgenic tumors and steatotic human hepatocyte cultures, respectively, to influence lipid-mediated signal transduction, extracellular matrix and immunity pathways. Analysis of gene specific promoter revealed >95% to carry c-Myc binding sites thus establishing a link between c-Myc activity and transcriptional response. Alike, serum GPI-PLD activity was increased 4-fold in transgenic mice; however its tissue activity was reduced by 70%. The associated repression of the serine/threonine phosphatase 2A (PP2A), i.e. a key player of c-Myc proteolysis, indicates co-ordinate responses aimed at impairing tissue GPI-PLD anti-proliferative activities. Translational research identified >4-fold increased GPI-PLD serum protein expression though enzyme activities were repressed by 60% in NASH and HCC patients. Taken collectively, c-Myc influences GPI-AP signaling transcriptionally and posttranslational and represses GPI-AP anti-proliferative signaling in tumors. The findings broaden the perspective of molecular targeted therapies and disease monitoring.
Acknowledgments
The authors thank Dr. Roman Halter for maintaining c-Myc transgenic mice and Dr. Tatiana Meier and Kerstin Wiesner for support in the microarray studies.
Funding: German Federal Ministry of Education and Research (BMBF), (“The Virtual Liver Network”, Grant/Award Number: ‘031 6154’).
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©2016 Walter de Gruyter GmbH, Berlin/Boston
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Articles in the same Issue
- Frontmatter
- Reviews
- Dynamic organization of the mitochondrial protein import machinery
- Common therapeutic strategies for prion and Alzheimer’s diseases
- IL-1 family cytokines in cancer immunity – a matter of life and death
- Research Articles/Short Communications
- Genes and Nucleic Acids
- Epigenetic regulation of KLK7 gene expression in pancreatic and cervical cancer cells
- Molecular Medicine
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- Biological characteristics of renal cancer cells after CTP-mediated cancer suppressor gene NPRL2 protein treatment
- Cell Biology and Signaling
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