Leptin-R and its association with PI3K/AKT signaling pathway in papillary thyroid carcinoma
Document Type
Article
Department
Centre for Regenerative Medicine
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.
Publication (Name of Journal)
Endocrine-Related Cancer
Recommended Citation
Shahabuddin, .,
Bavi, P.,
Siraj, A.,
Ahmed, M.,
Al-Rasheed, M.,
Hussain, A.,
Ahmed, M.,
Amin, T.,
Alzahrani, A.,
Al-Dayel, F.,
Abubaker, J.,
Bu, R.,
Al-Kuraya, K.
(2010). Leptin-R and its association with PI3K/AKT signaling pathway in papillary thyroid carcinoma. Endocrine-Related Cancer, 17, 191-202.
Available at:
https://ecommons.aku.edu/crm/39
Comments
This work was published before the author joined Aga Khan University.