Leptin inhibits hepatocellular carcinoma proliferation via p38-MAPK-dependent signalling
Kyle J Thompson1, Kwan N Lau, Sarah Johnson
1Department of General Surgery, Carolinas Medical Center, Charlotte, NC 28203, USA.
Objectives:
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.
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