KMID : 1141520210360051095
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Endocrinology and Metabolism 2021 Volume.36 No. 5 p.1095 ~ p.1110
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Lobeglitazone, A Peroxisome Proliferator-Activated Receptor-Gamma Agonist, Inhibits Papillary Thyroid Cancer Cell Migration and Invasion by Suppressing p38 MAPK Signaling Pathway
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Jin Jun-Qing
Han Jeong-Sun Ha Jeong-Hoon Baek Han-Sang Lim Dong-Jun
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Abstract
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Background: Peroxisome proliferator-activated receptor-gamma (PPAR-¥ã) ligands have been widely shown to correlate with epithelial-mesenchymal transition (EMT) and cancer progression. Lobeglitazone (LGZ) is a novel ligand of PPAR-¥ã; and its role in EMT and metastasis in papillary thyroid carcinoma (PTC) is poorly understood. We aimed to investigate the role of LGZ in metastatic behavior of PTC cells.
Methods: Half maximal inhibitory concentration (IC50) values of LGZ in BRAF-mutated PTC cell lines (BCPAP and K1) were determined using MTT assay. Rosiglitazone (RGZ), the PPAR-¥ã ligand was used as a positive control. The protein expression of PPAR-¥ã, cell-surface proteins (E-cadherin, N-cadherin), cytoskeletal protein (Vimentin), transcription factor (Snail), p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK) 1/2 pathway, and matrix metalloproteinase (MMP)-2 expression were measured using Western blotting. Changes in E-cadherin expression were also determined using immunocytochemistry. Cell migration and invasion were analyzed using wound healing and Matrigel invasion assays.
Results: Treatment with LGZ or RGZ significantly inhibited transforming growth factor-beta1 (TGF-¥â1)-induced EMT-associated processes such as fibroblast-like morphological changes, EMT-related protein expression, and increased cell migration and invasion in BCPAP and K1 cells. LGZ restored TGF-¥â1-induced loss of E-cadherin, as observed using immunocytochemistry. Furthermore, LGZ and RGZ suppressed TGF-¥â1-induced MMP-2 expression and phosphorylation of p38 MAPK, but not ERK1/2. Although there was no change in PPAR-¥ã expression after treatment with LGZ or RGZ, the effect of downstream processes mediated by LGZ was hampered by GW9662, a PPAR-¥ã antagonist.
Conclusion: LGZ inhibits TGF-¥â1-induced EMT, migration, and invasion through the p38 MAPK signaling pathway in a PPAR-¥ã-dependent manner in PTC cells.
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KEYWORD
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Thyroid cancer, papillary, PPAR gamma, Neoplasm metastasis
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