leptin and Carcinoma--Papillary

To investigate the potential prognostic significance of leptin and its receptor (Ob-R) in thyroid carcinoma.. The study cohort consisted of 173 patients including 93 cases with papillary thyroid carcinoma (PTC), 41 cases with follicular thyroid carcinoma (FTC), 25 cases with medullary thyroid carcinoma (MTC) and 14 cases with anaplastic thyroid carcinoma (ATC). We investigated the correlation between clinicopathological features and leptin or Ob-R. The Kaplan-Meier method was used to analyse the survival rate.. There was a strong correlation of leptin expression with Ob-R expression in PTC, FTC and ATC. For PTC, leptin expression was strongly correlated with older age, larger tumour size, nodal metastasis and advanced stage. Ob-R was significantly correlated with larger tumour size, nodal metastasis and advanced stage. The 5-year disease-free survival (DFS) rate in patients with positive leptin or its receptor expression was lower than that in patients without expression (with statistical difference). For FTC, patients with positive leptin or Ob-R expression developed no recurrence or metastasis during the follow-up. For MTC, Ob-R was significantly correlated with nodal metastasis and advanced stage (P < 0·05). For ATC, patients with positive Ob-R expression had longer median DFS than those with negative expression (436 ± 185 vs 57 ± 71 days), and the difference in the survival rate was statistically significant (P < 0·05).. There was a strong correlation of leptin expression with Ob-R expression in PTC, FTC and ATC. Leptin and Ob-R had negative prognostic significance in PTC, while Ob-R may play a protective role in ATC.

Topics: Adenocarcinoma, Follicular; Carcinoma; Carcinoma, Neuroendocrine; Carcinoma, Papillary; Cohort Studies; Disease-Free Survival; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Leptin; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prognosis; Receptors, Leptin; Recurrence; Survival Rate; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Tissue Array Analysis

Obesity is associated with a higher incidence of thyroid cancer. Adiponectin is one of the most abundant adipokines with a pleiotropic role in metabolism and in the development and progression of cancer. It has been shown that circulating adiponectin level is inversely associated with the risk of thyroid cancer. This study aimed to investigate the possible association between the expression of adiponectin receptors (AdipoR1 and AdipoR2) and clinicopathological variables in papillary thyroid cancer. We found that protein levels of AdipoR1 and AdipoR2 were increased in some thyroid cancer specimens compared with adjacent normal thyroid tissues. Thyroid cancer cells expressed AdipoR1 and AdipoR2, which were attenuated by histone deacetylase inhibitors valproic acid and trichostatin A. Adiponectin stimulated AMP-activated protein kinase phosphorylation in thyroid cancer cells. We further determined the expression of AdipoR1 and AdipoR2 by immunohistochemical staining in primary tumor samples and metastatic lymph nodes. AdipoR1 was expressed in 27 % of primary tumors and AdipoR2 in 47 %. Negative expression of both adiponectin receptors was significantly associated with extrathyroidal invasion, multicentricity, and higher TNM stage. There was a trend toward decreased disease-free survival in patients with negative tumor expression of AdipoR1 and AdipoR2 (log-rank P = 0.051). Collectively, overexpression of adiponectin receptors was observed in some tumor tissues of papillary thyroid cancer and was associated with a better prognosis.

Topics: Adiponectin; Adult; AMP-Activated Protein Kinases; Blotting, Western; Carcinoma, Papillary; Cell Line, Tumor; Disease-Free Survival; Female; Humans; Immunohistochemistry; Leptin; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Phosphorylation; Receptors, Adiponectin; Receptors, Leptin; Thyroid Neoplasms

The incidence of thyroid cancer has remarkably increased in recent years. Epidemiologic data suggest that obesity is associated with an increased incidence of several types of malignancies, including thyroid cancer. Leptin, an adipocyte-derived cytokine, has been shown to be involved in cancer development and progression. We previously demonstrated that papillary thyroid cancer expressing leptin receptor and/or leptin has a higher incidence of lymph node metastasis. In this study, we investigated the effects of leptin on cell migration in K1 and B-CPAP papillary thyroid cancer cells. Expression of leptin receptor was observed in both cell lines. Leptin enhanced the migratory activity significantly in a dose-dependent manner. We showed that leptin induced AKT and extracellular signal-regulated kinase (ERK) phosphorylation. Inhibition of phosphatidylinositol 3-kinase and ERK activation using pharmacological inhibitors effectively blocked leptin-induced migration of K1 and B-CPAP cells. Taken together, this study provides new mechanistic evidence for a role of leptin in the regulation of papillary thyroid cancer progression by stimulating tumor cell migration.

Topics: Carcinoma; Carcinoma, Papillary; Cell Line, Tumor; Cell Movement; Extracellular Signal-Regulated MAP Kinases; Humans; Immunohistochemistry; Leptin; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Leptin; Signal Transduction; Thyroid Cancer, Papillary; Thyroid Neoplasms

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.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Papillary; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Genetic Linkage; Humans; Leptin; Male; Middle Aged; Neoplasm Invasiveness; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Prognosis; Receptors, Leptin; RNA, Small Interfering; Signal Transduction; Thyroid Neoplasms; Tumor Burden; Tumor Cells, Cultured

Epidemiologic studies have shown that obesity is associated with an increased risk of thyroid cancer. Leptin, an adipocyte-derived cytokine, can act as a growth factor on certain normal and transformed cells. Aberrant expression of leptin or leptin receptor has been detected in some types of cancer. The aim of this study is to determine immunohistochemical expression of leptin and leptin receptor in papillary thyroid cancer to investigate the relationship between their expression and clinicopathologic features.. The expression of leptin and leptin receptor was assessed in 49 primary neoplasms and 15 lymph node metastases using a semiquantitative immunohistochemical staining method.. Leptin and leptin receptor were expressed in 37% and 51% of papillary thyroid cancer, respectively. They were not expressed in normal follicles. In the primary neoplasms and the metastatic nodes, expression of leptin correlated closely with leptin receptor (P < .001 for the primary neoplasms and P = .017 for nodal metastases). Expression of either protein was associated with greater neoplasm size (leptin expression, 32.0 +/- 10.7 vs 20.5 +/- 8.4 mm; P = .001; leptin receptor expression, 27.9 +/- 11.5 vs 21.4 +/- 9.0 mm; P = .032). Coexpression of leptin and leptin receptor in primary neoplasms had greater incidence of lymph node metastasis (P = .038).. Expression of leptin and/or leptin receptor in papillary thyroid cancer is associated with neoplasm aggressiveness, including tumor size and lymph node metastasis.

Topics: Adult; Body Mass Index; Carcinoma, Papillary; Female; Humans; Immunohistochemistry; Leptin; Lymphatic Metastasis; Male; Middle Aged; Receptors, Leptin; Thyroid Neoplasms

Excess body weight is associated with a moderately increased risk of thyroid cancer. Adipocyte-derived hormone, leptin, has been shown to enhance cell growth and migration in many cancer types. Limited evidence suggests that leptin has direct actions on the thyroid gland, but there are no data available on the effect of leptin on thyroid cancer cells. We evaluated the action of leptin on gene expression, cell growth, cell cycle, and cell migration in anaplastic (ARO), follicular (WRO) and papillary (CGTH-W3) thyroid carcinoma cell lines. Expression of long-form leptin receptors was observed in all thyroid cancer cell lines. Leptin stimulation did not alter the expression levels of leptin, leptin receptor and sodium-iodide symporter. Cell growth and cell cycle were not changed after leptin treatment. However, leptin was able to promote cell migration of papillary thyroid cancer cells, but inhibited migration of anaplastic and follicular cancer cells. In summary, our study suggests that leptin modulates cell migration of thyroid cancer cells in a cell type-specific manner.

Topics: Adenocarcinoma, Follicular; Apoptosis; Blotting, Western; Carcinoma; Carcinoma, Papillary; Cell Cycle; Cell Movement; Cell Proliferation; Humans; Leptin; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thyroid Neoplasms

Leptin has physiological roles in multiple systems, and has possible effects on several carcinogenesis steps. The aim of this study was to investigate the leptin levels in thyroid papillary carcinoma (TPC) patients.. Forty-three female TPC patients and 30 healthy female control subjects were recruited for the study. TPC was diagnosed by fine needle aspiration biopsy. TPC patients had a bilateral total thyroidectomy operation and their leptin levels were measured before and 20 days after the operation.. Serum leptin levels of TPC patients were higher than in control group subjects (21.15 +/- 14.12 ng/mL vs. 9.89 +/- 0.21 ng/mL, p < 0.05). The leptin levels decreased after total thyroidectomy (13.92 +/- 10.55 ng/mL) compared to prethyroidectomy levels (22.94 +/- 14.67 ng/mL) in 34 patients who came to the follow-up visit (p < 0.05). However, the decreased post-thyroidectomy levels of leptin were still statistically significantly higher than the control group levels. Multivariate regression analysis showed that the leptin levels in TPC patients were not related to age, menopausal status or pathologic occult status but were directly related to the cancer group.. Leptin levels were elevated in thyroid cancer, decreased after total thyroidectomy, and might be associated with thyroid papillary carcinogenesis.

Topics: Adult; Carcinoma, Papillary; Female; Humans; Leptin; Thyroid Neoplasms; Thyroidectomy