Department of Thyroid Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, People's Republic of China.
Department of Thyroid Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, People's Republic of China.
Biochimie. 2018 May;148:1-11. doi: 10.1016/j.biochi.2018.02.009. Epub 2018 Feb 20.
Initiation of epithelial-to-mesenchymal transition (EMT) is common in papillary thyroid carcinoma (PTC) and may contribute to its metastasis. Aims of the present study are to investigate whether and how the C-X-C motif chemokine ligand (CXCL)-5/C-X-C motif receptor 2 (CXCR2) axis affects PTC metastasis, with a focus on the EMT process. Herein, two PTC cell lines, KTC-1 and B-CPAP cells, identified as CXCR2-positive cells were used as the cell model. We found that a 24-h stimulation of 1 or 10 nM recombinant human CXCL5 (rhCXCL5) enhanced the migration and invasion of both KTC-1 and B-CPAP cells without affecting their proliferation. The migration- and invasion-promoting effects of rhCXCL5 were attenuated if CXCR2 was silenced by its specific short hairpin RNAs (shRNAs). EMT initiation is defined as downregulation of epithelial-cadherin (E-cadherin) and upregulation of N-cadherin, Vimentin and Snail. Our data showed that rhCXCL5-induced EMT in PTC cells was suppressed by CXCR2 shRNA. Furthermore, the active CXCL5-CXCR2 axis enhanced the phosphorylation of Akt at Ser 473 residue and that of glycogen synthase kinase-3 (GSK-3β) at Ser 9 residue, and accelerated the nuclear accumulation of β-catenin in PTC cells. Re-expression of the active form of β-catenin in PTC cells rescued their impaired invasiveness caused by the blockade of CXCL5-CXCR2 axis. In addition, CXCL5 and CXCR2 were overexpressed in the metastatic lymph nodes obtained from 18 patients with PTC. In summary, our study demonstrates that the activated CXCL5-CXCR2 axis contributes to the metastatic phenotype of PTC cells by modulating Akt/GSK-3β/β-catenin pathway.
上皮间质转化 (EMT) 的启动在甲状腺乳头状癌 (PTC) 中很常见，可能导致其转移。本研究旨在探讨 C-X-C 基序趋化因子配体 (CXCL)-5/C-X-C 基序趋化因子受体 2 (CXCR2) 轴是否以及如何影响 PTC 转移，重点关注 EMT 过程。在此，使用 KTC-1 和 B-CPAP 细胞这两种 PTC 细胞系作为细胞模型，这些细胞被鉴定为 CXCR2 阳性细胞。我们发现，1 或 10 nM 重组人 CXCL5(rhCXCL5)刺激 24 小时可增强 KTC-1 和 B-CPAP 细胞的迁移和侵袭，而不影响其增殖。如果用其特异性短发夹 RNA(shRNA)沉默 CXCR2，则 rhCXCL5 的迁移和侵袭促进作用会减弱。EMT 启动被定义为上皮钙黏蛋白 (E-cadherin) 的下调和 N-钙黏蛋白、波形蛋白和 Snail 的上调。我们的数据显示，rhCXCL5 诱导的 PTC 细胞 EMT 被 CXCR2 shRNA 抑制。此外，活性 CXCL5-CXCR2 轴增强了 Akt 在 Ser 473 残基的磷酸化和糖原合酶激酶-3(GSK-3β)在 Ser 9 残基的磷酸化，并加速了 PTC 细胞中 β-连环蛋白的核积累。在 PTC 细胞中重新表达活性形式的 β-连环蛋白可挽救其因阻断 CXCL5-CXCR2 轴而导致的侵袭性受损。此外，在从 18 名 PTC 患者的转移性淋巴结中过度表达了 CXCL5 和 CXCR2。总之，我们的研究表明，激活的 CXCL5-CXCR2 轴通过调节 Akt/GSK-3β/β-连环蛋白通路促进 PTC 细胞的转移表型。
