Liang Zhong, Xie Wen-Jun, Zhao Ming, Cheng Guo-Ping, Wu Mei-Juan
Department of Head and Neck Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China.
Department of Pathology, Integrated Chinese and Western Medicine Hospital of Zhejiang Affiliated Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310000, P.R. China.
Oncol Lett. 2017 Dec;14(6):8114-8121. doi: 10.3892/ol.2017.7250. Epub 2017 Oct 23.
The upregulation of discoidin domain receptor tyrosine kinase 2 (DDR2) has been reported to be associated with poor prognosis and metastasis in numerous tumor types by inducing epithelial-mesenchymal transition (EMT); however, the expression profile of DDR2 in papillary thyroid carcinoma (PTC) with local metastasis and the effect of DDR2 on PTC cells remain unknown. The aim of the present study was to investigate the expression levels of DDR2 in tumor tissues of patients with PTC with local metastasis and cell lines and to determine the effect of DDR2 on EMT in PTC cells. In the present study, it was demonstrated that DDR2 was significantly increased in tumor tissues of patients with PTC with local metastasis and human PTC cell lines. The overexpression of DDR2 by lentiviral transfection decreased E-cadherin protein, increased Vimentin protein, and promoted cell migration and invasion. The inhibition of DDR2 reversed transforming growth factor-β- and collagen I-induced EMT. EMT induced by DDR2 overexpression was suggested to be dependent on increased Snail1 protein level following extracellular signal-regulated kinase (ERK)2 activation. The inhibition of Snail1 or ERK2 was sufficient to abrogate DDR2-induced PTC cell EMT. In conclusion, these results indicate that DDR2 is upregulated in PTC tissues with local metastasis. Overexpression of DDR2 induced EMT in PTC cells by activating ERK2 and stabilizing Snail1, making it a promising therapeutic target for reducing PTC local or distant metastasis.
据报道，盘状结构域受体酪氨酸激酶2（DDR2）的上调通过诱导上皮-间质转化（EMT）与多种肿瘤类型的不良预后和转移相关；然而，DDR2在伴有局部转移的甲状腺乳头状癌（PTC）中的表达谱以及DDR2对PTC细胞的影响仍不清楚。本研究的目的是调查DDR2在伴有局部转移的PTC患者肿瘤组织和细胞系中的表达水平，并确定DDR2对PTC细胞中EMT的影响。在本研究中，结果表明DDR2在伴有局部转移的PTC患者肿瘤组织和人PTC细胞系中显著升高。通过慢病毒转染过表达DDR2可降低E-钙黏蛋白水平，增加波形蛋白水平，并促进细胞迁移和侵袭。抑制DDR2可逆转转化生长因子-β和I型胶原诱导 的EMT 。DDR2过表达诱导的EMT被认为依赖于细胞外信号调节激酶（ERK）2激活后Snail1蛋白水平增加。抑制Snail1或ERK2足以消除DDR2诱导的PTC细胞EMT。总之，这些结果表明DDR2在伴有局部转移 的PTC组织中上调。DDR2的过表达通过激活ERK2和稳定Snail1诱导PTC细胞发生EMT，使其成为减少PTC局部或远处转移的有希望 的治疗靶点。
