Leptin stimulates the proliferation of human oesophageal adenocarcinoma cells via HB-EGF and TGFα 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 (EGER) is ail 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 EGER signalling. This study examines the effect of leptin on EGER 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 EGER inhibitors (PD153035 and AG1478). Leptin-induced proliferation was inhibited by neutralising antibodies to transforming growth factor-alpha (TGF alpha and HB-EGF) but not by anti-amphiregulin. Leptin significantly increased gene expression of HB-EGF and TGF alpha 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 TGF alpha, and this was blocked by matrix rnetalloproteinase (MMP) inhibitors. The MMP inhibitors also abolished leptin-induced proliferation as well as leptin-induced EGER tyrosine phosphorylation, but did not affect proliferation or EGER activation induced by TGF alpha. The authors conclude that leptin stimulates OAC proliferation via increased gene expression of HB-EGF and TGF alpha, MMP-mediated extracellular release of HB-EGF and TGF alpha and subsequent activation of EGER.