Ritorto, Maria Stella;
Rhode, Heidrun;
Vogel, Arndt;
Borlak, Jürgen
Regulation of glycosylphosphatidylinositol-anchored proteins and GPI-phospholipase D in a c-Myc transgenic mouse model of hepatocellular carcinoma and human HCC
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Media type:
E-Article
Title:
Regulation of glycosylphosphatidylinositol-anchored proteins and GPI-phospholipase D in a c-Myc transgenic mouse model of hepatocellular carcinoma and human HCC
Contributor:
Ritorto, Maria Stella;
Rhode, Heidrun;
Vogel, Arndt;
Borlak, Jürgen
Published:
Walter de Gruyter GmbH, 2016
Published in:
Biological Chemistry, 397 (2016) 11, Seite 1147-1162
Language:
English
DOI:
10.1515/hsz-2016-0133
ISSN:
1437-4315;
1431-6730
Origination:
Footnote:
Description:
<jats:title>Abstract</jats:title>
<jats:p>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 <jats:italic>c-Myc</jats:italic> 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.</jats:p>