Department of Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Endocr Relat Cancer. 2010 Feb 18;17(1):191-202. doi: 10.1677/ERC-09-0153. Print 2010 Mar.
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.
瘦素及其受体（Ob-R）在各种原发性人类恶性肿瘤发病机制中的假定作用已被报道；然而，其在甲状腺乳头状癌（PTC）中的作用尚未得到评估。我们通过对大量 PTC 组织微阵列队列进行研究，然后使用一系列 PTC 细胞系进行体外研究，来探讨 Ob-R 在 PTC 中的作用。80%的 PTC 中观察到 Ob-R 过表达，且与无病生存期不良显著相关（P=0.0235）。过表达 Ob-R 的 PTC 表现出侵袭性表型，其特征为年龄较大、甲状腺外扩展、肿瘤较大、淋巴结转移、晚期、高细胞变异组织学亚型和无病生存期不良（P=0.0005，P=0.0006，P=0.0398，P=0.0004，P=0.0111，P=0.0003，P=0.0235）。然而，在多变量分析中，Ob-R 表达并不是预测无病生存期的独立预后标志物。过表达 Ob-R 的 PTC 与 XIAP（P<0.0001）和 Bcl-XL（P<0.0001）的过表达呈显著直接关联。体外分析表明，瘦素通过激活磷脂酰肌醇 3'激酶（PI3K）/蛋白激酶 B（AKT）信号通路刺激细胞增殖并抑制细胞凋亡。其抑制剂 LY294002 抑制 PI3K 活性可阻断瘦素介导的 PI3K/AKT 信号。PTC 细胞中 Ob-R 的基因沉默导致磷酸化 AKT、Bcl-XL 和 XIAP 表达下调，提示瘦素介导的 PTC 发病机制通过涉及这些下游靶点发生。总之，这些数据表明，瘦素通过 Ob-R 通过 PI3K/AKT 通路在 PTC 发病机制中发挥重要作用，是与侵袭性表型和不良无病生存期相关的潜在预后标志物。
