title: 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.
authors.forename: Maria Stella
authors.initials: MS
authors.lastname: Ritorto
authors.forename: Heidrun
authors.initials: H
authors.lastname: Rhode
authors.forename: Arndt
authors.initials: A
authors.lastname: Vogel
authors.forename: Jürgen
authors.initials: J
authors.lastname: Borlak
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D058851:GPI-Linked Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008074:Lipoproteins / Q000494:pharmacology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D010739:Phospholipase D / Q000097:blood / Q000378:metabolism*; D055550:Protein Stability; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes / Q000235:genetics
chemical_list: D058851:GPI-Linked Proteins; D008074:Lipoproteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D010739:Phospholipase D; C065017:glycoprotein phospholipase D