title: Ganglioside GD1a negatively regulates hepatocyte growth factor expression through caveolin-1 at the transcriptional level in murine osteosarcoma cells.
abstract: BACKGROUND
  Hepatocyte growth factor (HGF) is a mesenchyme-derived, multifunctional protein that is implicated in tumor growth and invasive behavior. Some tumor cells express both HGF and its receptor MET, forming an autocrine loop that permanently activates it. Ganglioside GD1a suppresses metastatic capacity in murine FBJ osteosarcoma cells and MET phosphorylation activated by HGF binding, but the signaling pathway controlling HGF production has not been fully explored.
  
  
  METHODS
  Expression of HGF, caveolins, or MET of the cells that had been transfected with siRNA or cDNA directed to GM2/GD2 synthase, caveolin-1 or HGF was determined by semi-quantitative RT-PCR and Western blots.
  
  
  RESULTS
  HGF expression in highly metastatic, GD1a-deficient FBJ-LL cells was higher than that in the poorly metastatic, GD1a-rich FBJ-S1 cells. Transfection with GM2/GD2 synthase cDNA increased GD1a levels in FBJ-LL cells and suppressed HGF expression. Treatment with siRNAs directed toward GM2/GD2 synthase in FBJ-S1 cells reduced gangliosides and augmented HGF expression. GD1a was found to be the only ganglioside species suppressing HGF expression upon addition to FBJ-LL cells. HGF expression was decreased by GD1a addition to FBJ-LL cells after 48h, enough to induce caveolin-1 expression. Silencing caveolin-1 up-regulated HGF, and the re-introduction of caveolin-1 cDNA decreased HGF expression. Caveolin-1 suppressed MET phosphorylation. We also found GD1a regulation of HGF in Lewis lung carcinoma cells.
  
  
  CONCLUSIONS
  HGF expression was negatively regulated by GD1a through caveolin-1 at the transcriptional level via the suppression of MET phosphorylation.
  
  
  CONCLUSIONS
  This is the first report that ganglioside GD1a negatively regulates HGF expression through caveolin-1.
authors.affiliation: Laboratory of Tumor Biology and Glycobiology, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.forename: Yinan
authors.initials: Y
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Ting
authors.initials: T
authors.lastname: Cao
authors.forename: Sumiko
authors.initials: S
authors.lastname: Hyuga
authors.forename: Toshinori
authors.initials: T
authors.lastname: Sato
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
authors.forename: Sadako
authors.initials: S
authors.lastname: Yamagata
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamagata
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005732:Gangliosides / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D017350:N-Acetylgalactosaminyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism
chemical_list: C495541:Cav1 protein, mouse; D051242:Caveolin 1; D005732:Gangliosides; C553307:HGF protein, mouse; C021298:ganglioside, GD1a; D017228:Hepatocyte Growth Factor; D017350:N-Acetylgalactosaminyltransferases; C023220:(N-acetylneuraminyl)-galactosylglucosylceramide N-acetylgalactosaminyltransferase; D019859:Proto-Oncogene Proteins c-met