title: Leptin inhibits hepatocellular carcinoma proliferation via p38-MAPK-dependent signalling.
abstract: OBJECTIVE
  Obesity is a significant risk factor for many liver diseases, including hepatocellular carcinoma (HCC). Leptin has been identified as a central mediator of factors that regulate energy intake and expenditure, including appetite, metabolism and fat storage. The role of leptin in the initiation, development and progression of HCC remains poorly understood. The aims of this study were to determine the effect(s) of leptin on HCC cell proliferation and to identify potential signalling mechanism(s) by which leptin exerts these effects.
  
  
  METHODS
  Rat H4IIE HCC cells and H4IIE-derived HCC tumours were analysed for leptin receptor (LR) expression. H4IIE cells were treated with leptin (0-100 ng/ml) in the absence or presence of pharmacological inhibitors of p42/p44 mitogen-activated protein kinase (MAPK) (PD98059), p38-MAPK (SB202190) or Janus kinase-signal transducers and activators of transcription (JAK-STAT) (AG490; 10 µM) signalling. Cell proliferation was determined and signal pathway activity analysed.
  
  
  RESULTS
  Immunohistochemistry identified increased LR expression in HCC in human tissue. Leptin did not significantly affect H4IIE cell numbers in serum-depleted (0.1% [v/v] foetal bovine serum [FBS]) medium. However, leptin significantly inhibited serum-stimulated (1.0% [v/v] FBS) H4IIE proliferation. Immunoblot analysis demonstrated that leptin significantly activated p42/p44-MAPK, p38-MAPK and STAT3 signalling in a time-dependent manner. Pretreatment of H4IIE cells with SB202190 abrogated leptin-dependent inhibition of H4IIE proliferation, an effect not observed in cells pretreated with PD98059 or AG490.
  
  
  CONCLUSIONS
  Leptin inhibits HCC cell growth in vitro via a p38-MAPK-dependent signalling pathway. Identifying similar effects on tumour growth in vivo may provide an attractive therapeutic target for slowing HCC progression.
authors.affiliation: Department of General Surgery, Carolinas Medical Center, Charlotte, NC 28203, USA.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Thompson
authors.forename: Kwan N
authors.initials: KN
authors.lastname: Lau
authors.forename: Sarah
authors.initials: S
authors.lastname: Johnson
authors.forename: John B
authors.initials: JB
authors.lastname: Martinie
authors.forename: David A
authors.initials: DA
authors.lastname: Iannitti
authors.forename: Iain H
authors.initials: IH
authors.lastname: McKillop
authors.forename: David
authors.initials: D
authors.lastname: Sindram
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D020738:Leptin / Q000378:metabolism*; D008113:Liver Neoplasms / Q000201:enzymology* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D054411:Receptors, Leptin / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C515448:LEPR protein, human; D020738:Leptin; D047428:Protein Kinase Inhibitors; D054411:Receptors, Leptin; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases