Leptin-R and its association with PI3K/AKT signaling pathway in papillary thyroid carcinoma

Shahab Uddin, Prashant Bavi, Abdul K. Siraj, Maqbool Ahmed, Maha Al-Rasheed, Azhar R. Hussain, Mohammed Ahmed, Tarek Amin, Ali Alzahrani, Fouad Al-Dayel, Jehad Abubaker, Rong Bu, Khawla S. Al-Kuraya

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Abstract

The putative role of leptin and its receptor (Ob-R) in the pathogenesis of various primary human malignancies has been reported; however, their role in papillary thyroid cancer (PTC) has not yet been evaluated. We investigated the 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, tall cell variant histological subtype, and a poor disease-free survival (P=0.0005, P=0.0006, P=0.0398, P=0.0004, P=0.0111, P=0.0003, and P=0.0235 respectively). However, Ob-R expression was not an independent prognostic marker to predict disease-free survival in multivariate analysis. PTCs with overexpression of Ob-R showed a significant direct association with overexpression of 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)/protein kinase B (AKT) signaling pathway. Inhibition of PI3K activity by its inhibitor LY294002 abrogated leptin-mediated PI3K/AKT signaling. Gene silencing of Ob-R in PTC cells resulted in downregulation of phospho-AKT, Bcl-XL, and XIAP expression suggesting that leptin-mediated pathogenesis of PTC occurs via involvement of these downstream targets. Altogether, these data show that leptin plays an important 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.

Original languageEnglish
Pages (from-to)191-202
Number of pages12
JournalEndocrine-Related Cancer
Volume17
Issue number1
DOIs
Publication statusPublished - 1 Mar 2010

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    Uddin, S., Bavi, P., Siraj, A. K., Ahmed, M., Al-Rasheed, M., Hussain, A. R., Ahmed, M., Amin, T., Alzahrani, A., Al-Dayel, F., Abubaker, J., Bu, R., & Al-Kuraya, K. S. (2010). Leptin-R and its association with PI3K/AKT signaling pathway in papillary thyroid carcinoma. Endocrine-Related Cancer, 17(1), 191-202. https://doi.org/10.1677/ERC-09-0153