Leptin stimulates the proliferation of human oesophageal adenocarcinoma cells via HB-EGF and Tgfalpha mediated transactivation of the epidermal growth factor receptor.
Obesity increases the risk of developing oesophageal adenocarcinoma (OAC) as well as several other cancers. Leptin is secreted by adipocytes and serum leptin levels rise with body mass index. Leptin stimulates proliferation and inhibits apoptosis in OAC cells but the mechanisms are not fully elucidated, Transactivation of the epidermal growth factor receptor (EGFR) is an important signalling mechanism for G-protein-coupled receptors, but the relationship with leptin-type receptors has not been examined and the authors hypothesise that leptin-induced proliferation involves EGFR signalling. This study examines the effect of leptin on EGFR signalling in cultured cell lines. Leptin stimulated proliferation in four OAC lines expressing leptin receptors (OE33, OE19, BIC-1 and FLO) and this was abolished by specific EGFR inhibitors (PD153035 and AG1478). Leptin-induced proliferation was inhibited by neutralising antibodies to transforming growth factor-alpha (TGFalpha and HB-EGF) but not by anti-amphiregulin. Leptin significantly increased gene expression of HB-EGF and TGFalpha as measured by a quantitative real-time polymerase chain reaction (PCR) method but did not alter amphiregulin and EGFR gene expression. Leptin increased extracellular release of HB-EGF and TGFalpha and this was blocked by matrix metalloproteinase (MMP) inhibitors. The MMP inhibitors also abolished leptin-induced proliferation as well as leptin-induced EGFR tyrosine phosphorylation, but did not affect proliferation or EGFR activation induced by TGFalpha. The authors conclude that leptin stimulates OAC proliferation via increased gene expression of HB-EGF and TGFalpha, MMP-mediated extracellular release of HB-EGF and TGFalpha and subsequent activation of EGFR.
Ogunwobi
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OO
Biomedical Research Centre, School of Medicine, Health Policy and Practice, University of East Anglia, Norwich NR4 7TJ, United Kingdom.
Beales
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IL
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D066258:Amphiregulin; D001323:Autoantibodies / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000473:pathology*; D006023:Glycoproteins / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015533:Transcriptional Activation; D016211:Transforming Growth Factor alpha / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology
C587848:AREG protein, human; D066258:Amphiregulin; D001323:Autoantibodies; D066255:EGF Family of Proteins; D006023:Glycoproteins; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D011799:Quinazolines; D016211:Transforming Growth Factor alpha; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors; D020782:Matrix Metalloproteinases; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline