Abstract
BackgroundRecent epidemiological studies have suggested that obesity is associated with ovarian cancer. Obesity hormone leptin and its receptor (Ob-R) contribute to tumor development by enhancing cell growth and survival. This study was design to investigate the prevalence of leptin and Ob-R in Middle Eastern epithelial ovarian cancer (EOC) and to analyze the role of leptin and the mechanisms under its action in EOC tissue sample and cell lines.MethodsThe expression of leptin and Ob-R was examined by immunohistochemistry in a tissue microarray of 156 EOC samples. Proliferation of EOC cells in response to leptin was assessed by MTT assays, and its anti-apoptotic effects were determined by flow cytometry. Effect of leptin on PI3K/AKT signaling pathway was further determined by western blotting.ResultsIn clinical samples, Ob-R overexpression was seen in 59.2% EOCs and was significantly associated with poor progression free survival (p = 0.0032). Furthermore, Ob-R expression was associated with anti apoptotic proteins Bcl-XL (p = 0.0035) and XIAP (p = 0.0001). In vitro analysis using EOC cell lines showed that leptin stimulated cell proliferation and inhibits apoptosis via activation of PI3K/AKT signaling pathway. Inhibition of PI3K activity by LY294002, a specific inhibitor of PI3-kinase abrogated leptin mediated PI3K/AKT signaling. Gene silencing of Ob-R with Ob-R siRNA in EOC cells resulted in down regulation of phospho-AKT and its down stream targets.ConclusionOur findings have potential clinical implication for EOC development and progression.
Highlights
Recent epidemiological studies have suggested that obesity is associated with ovarian cancer
We examined the expression of leptin and Obesity hormone leptin and its receptor (Ob-R) using epithelial ovarian cancer (EOC) cell lines
Immunohistochemical detection of obesity gene (Ob)-R expression and its association with clinicopathological parameters Ob-R expression was seen in 59.2% (90/152) of the EOCs analyzed (Figure 1)
Summary
Recent epidemiological studies have suggested that obesity is associated with ovarian cancer. This study was design to investigate the prevalence of leptin and Ob-R in Middle Eastern epithelial ovarian cancer (EOC) and to analyze the role of leptin and the mechanisms under its action in EOC tissue sample and cell lines. The product of obesity gene (Ob) is suggested to be associated with cancer development and progression in many epithelial cancers including EOC [5,6,7,8]. Leptin mediated signaling pathways play an important role in cancer cell proliferation, invasion and metastasis [5]. Previous study [8] has suggested that leptin signaling pathway is transmitted via MAP kinase pathway. The interaction between leptin signaling and PI3K/AKT pathway in ovarian cancer remains unknown
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