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

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 (PZ0.0235). 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 (PZ0.0005, PZ0.0006, PZ0.0398, PZ0.0004, PZ0.0111, PZ0.0003, and PZ0.0235 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 0 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 diseasefree survival.

Leptin enhances migration of human papillary thyroid cancer cells through the PI3K/AKT and MEK/ERK signaling pathways

“…This is in keeping with the observation of others (13)(14)(15)(16)(17). We and others have shown that papillary thyroid cancer with expression of leptin receptor and/or leptin is associated with the risk of nodal metastasis (21,22). The same oncogenic signaling cascade initiating transforming events in thyroid cancer cells also sustains their motile and invasive properties (33).…”

“…Although papillary thyroid cancer expressing leptin receptor and/or leptin is associated with larger tumor size (21,22), this study does not support the hypothesis that leptin promotes cell proliferation in thyroid cancer. Uddin et al (22) demonstrated that leptin could stimulate cell proliferation and inhibit apoptosis in B-CPAP and 8505C cell lines via the activation of PI3K/AKT signaling pathway.…”

“…Using immunohistochemical analysis, we and others have reported that leptin and leptin receptor were overexpressed in papillary thyroid cancer and metastatic lymph nodes (21,22). Expression of leptin receptor and/or leptin in primary tumors was associated with higher incidence of lymph node metastasis.…”

MECHANISMS IN ENDOCRINOLOGY: The crosstalk between thyroid gland and adipose tissue: signal integration in health and disease

“…Leptin was shown to promote cell migration in PTC cells, while inhibiting the migration of follicular and anaplastic thyroid cancer cells (157). Other in vitro studies demonstrated that leptin stimulates a more aggressive PTC phenotype by putative activation of the PI3K/AKT pathway (158), and also promotes the de-differentiation of thyroid tumor cells via the JAK2/ STAT3 signaling pathway (159). The possibility that these effects might result in distinct tumor presentations and disease courses remains purely theoretical.…”

The Src/PI3K/Akt signal pathway may play a key role in decreased drug efficacy in obesity‐associated cancer

“…There are many evidences that obesity can cause poor prognosis of many cancers such as ovarian cancer, leukemia, papillary thyroid cancer, and colon cancer [Dignam et al, 2006;Uddin et al, 2010]. Epidemic studies showed that severe obesity (BMI >35 kg/m 2 ) caused increased mortality and recurrence of colon cancer [Dignam et al, 2006;Jacobs et al, 2007].…”