Abstract
Background Obesity has been hypothesized to contribute to the aggressiveness of thyroid cancer through the production of abnormal levels of serum adipokines. Leptin receptor (OB-R) expression has also been documented in papillary thyroid cancer (PTC). Aim In this translational study, we analyzed in vitro the effects of leptin on the growth and migration of thyroid cancer cells (TPC-1 and K1), the molecular mechanisms underlying leptin's action, and the influence of prolonged leptin exposure on cell response to a protein kinase inhibitor lenvatinib. The expression levels of OB-R mRNA and protein were also investigated in vivo in a series of aggressive PTCs divided into two groups based on the presence of the BRAF mutation. Results In TPC-1 and K1 cells, prolonged treatment with leptin (500 ng/ml for 96 h) resulted in a mild increase in the proliferation (about 20% over control only in K1 cells, p < 0.05) and in the migration of both cancer cell lines. Immunoblot analysis revealed a slight increase in the phosphorylation of AKT, but no effect on β-catenin and phospho-ERK expressions. The inhibitory effects of lenvatinib on the viability of both cell lines were not influenced by the leptin treatment. OB-R transcript (in fresh tissues) and proteins (in formalin-fixed and paraffin-embedded specimens) were expressed in all PTC tissues examined, with no significant differences between BRAF-mutated and BRAF-wild-type tumors. Conclusions These results demonstrate leptin's role in mildly increasing the aggressive phenotype of PTC cells but without influencing the action of lenvatinib. Further studies will clarify whether it is possible to target OB-R, expressed in all aggressive PTCs, as an adjuvant treatment approach for these malignancies.
Highlights
While the majority of differentiated thyroid cancers are responsive to the current surgery/radioiodine treatments, there are subgroups of tumors which show a more aggressive behavior
Results are mean ± standard deviation (SD) of three independent experiments performed in eigthplicate. (b) After 96 h of treatment with 200 or 500 ng/ml leptin, cells were prepared for migration assays as indicated in Materials and Methods
In the present study, the role of prolonged leptin exposure in tumor progression and/or expansion, as it may occur in vivo in TC patients with high body mass index (BMI), was first analyzed in two papillary thyroid cancer (PTC)-derived cell lines carrying RET/PTC1 (TPC-1) and BRAF (K1) mutations which both express OB-R
Summary
While the majority of differentiated thyroid cancers are responsive to the current surgery/radioiodine treatments, there are subgroups of tumors which show a more aggressive behavior. We analyzed the effects of International Journal of Endocrinology leptin on two human papillary thyroid cancer (PTC) cell lines, focusing on the molecular mechanisms underlying leptin’s effects on cell viability and migration. We checked the influence of prolonged leptin treatment on cell response to the protein kinase inhibitor (PKI) lenvatinib. In this translational study, we analyzed in vitro the effects of leptin on the growth and migration of thyroid cancer cells (TPC-1 and K1), the molecular mechanisms underlying leptin’s action, and the influence of prolonged leptin exposure on cell response to a protein kinase inhibitor lenvatinib. These results demonstrate leptin’s role in mildly increasing the aggressive phenotype of PTC cells but without influencing the action of lenvatinib. Further studies will clarify whether it is possible to target OB-R, expressed in all aggressive PTCs, as an adjuvant treatment approach for these malignancies
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