Enhanced Leptin Receptor Expression Identifies an Aggressive Subset of Middle Eastern Papillary Thyroid Cancer

A number of studies published recently focused on putative role of leptin in the pathogenesis of various primary human malignancies. However, the role of leptin and leptin receptor (Ob-R) in papillary thyroid cancer (PTC) has not yet been evaluated. The current study was aimed first at investigating Ob-R protein expression, and its clinicopathological correlation in a large cohort of Middle Eastern PTC. Then we investigated the effect of leptin on proliferation and apoptosis of PTC cells and the early signaling events involved. Ob-R immunostaining was detected in 410/512 (80.1 %) PTCs. PTCs that overexpressed Ob-R showed a aggressive phenotype characterized by older age, extrathyroid extension, larger tumor size, nodal metastasis, advanced stage and tall cell variant histologic subtype (p=0.0005, p=0.0006, p=0.0398, p= 0.0004, p=0.0111and p= 0.0003 respectively). Further PTCs with overexpression of Ob-R showed a significant direct association with overexpression of leptin (p=0.0004), XIAP (p<0.0001) and BCL-XL (p<0.0001). Interestingly, PTCs with Ob-R overexpression showed a statistically significant poor disease free survival (p=0.0235) as compared to PTCs with low expression of Ob-R. In vitro analysis showed that leptin stimulated cell proliferation and inhibit apoptosis via activation of phosphatidylinositol 3\#8217; kinase (PI3K)/AKT signaling pathway. The proliferation and anti-apoptotic effects of leptin were abolished by inhibition of Ob-R with small interference RNA (siRNA) and PI3K/AKT with LY294.So our data showed that Ob-R is commonly expressed in Middle Eastern PTC and leptin stimulates proliferation inhibits apoptosis in human PTC via PI3K/AKT pathway activation. These effects of leptin provide a link between obesity and PTC and may represent a target for anti cancer drug development.