Abstract A19: Enhanced leptin receptor expression identifies an aggressive subset of Middle Eastern papillary thyroid cancer

Abstract

Abstract The putative role of leptin (Ob) and its receptor (Ob-R) in the pathogenesis of various primary human malignancies has been investigated in recent studies. However, the role of leptin and leptin receptor (Ob-R) in papillary thyroid cancer (PTC) has not yet been evaluated. In this study we investigated role of Ob-R in a large tissue microarray cohort of PTC followed by in vitro studies using a panel of PTC cell lines. Ob-R overexpression was seen in 80% PTCs and was significantly associated with poor disease free survival (p=0.0235). 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 histological subtype (p=0.0005, p=0.0006, p=0.0398, p= 0.0004, p=0.0111 and 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). In vitro analysis showed that leptin stimulated cell proliferation and inhibited apoptosis via activation of phosphatidylinisitol 3-kinase (PI3K)/AKT signalling pathway. Inhibition of PI3K activity by LY294002, a specific inhibitor of PI3K kinase abrogated leptin-mediated PI3K/AKT signalling. Gene silencing of Ob-R with Ob-R siRNA in PTC cells resulted in down regulation of phospho-AKT, Bcl-XL and XIAP expression suggesting that leptin mediated pathogenesis of PTC occur via involvement of these downstream targets. Altogether these data suggest that leptin plays a critical role in PTC pathogenesis through PI3K/AKT pathway via Ob-R and is a potential prognostic marker associated with an aggressive phenotype and poor disease free survival. Citation Information: Cancer Res 2009;69(23 Suppl):A19.