DDR2 facilitates papillary thyroid carcinoma epithelial mesenchymal transition by activating ERK2/Snail1 pathway

Abstract

Abstract. 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.

An Epithelial-to-Mesenchymal Transcriptional Switch Triggers Evolution of Pulmonary Sarcomatoid Carcinoma (PSC) and Identifies Dasatinib as New Therapeutic Option

“…This is a membrane tyrosine kinases receptor belonging to the same family of EGFR which binds specifically to the extracellular matrix collagens, working as sensor of the external microenvironment (43,44). DDR2 regulates several biological processes including cytoskeleton organization, cell movement and epithelial-mesenchymal transitions (EMT) (20,21,45).…”

“…Among the others, the observed upregulation of Discoidin domain-containing receptor 2 (DDR2) in S was of particular interest. DDR2 is a cell surface Tyrosine Kinase (TK) receptor for fibrillar collagen, which regulates remodeling of the extracellular matrix, facilitating cell migration and tumor cell invasion and has been previously linked to EMT activation (20)(21)(22)(23).…”

Mutations of genes including DNMT3A detected by next-generation sequencing in thyroid cancer

“…26 In general, molecular transcripts have been respectively associated with thyroid cancer, such as BRAF p.V600E, RAS, DNMT3 mutation, RET, NTRK1, NTRK3, ALK, PAX8 gene rearrangement, and other related oncogenes. [27][28][29][30] Besides diagnostic and genetic values, the detection of genetic changes in thyroid cancer has been becoming an effective way to search for new therapeutic targets. Recently, the RET inhibitors, including vandetanib 31 and cabozantinib, 32 have been approved by the US Food and Drug Administration (FDA) to treat metastatic MTC because they have anti-proliferative role in RET-mutant MTC.…”

The Yin and Yang of Discoidin Domain Receptors (DDRs): Implications in Tumor Growth and Metastasis Development

“…The role of DDR2 in EMT activation is less controversial. An association between DDR2 and Snail1 has been revealed in several studies on breast cancer [ 30 , 90 , 98 ], ovarian cancer [ 32 ], papillary thyroid carcinoma [ 107 ], and hepatocellular carcinoma [ 89 ] via different signaling pathways. Indeed, immunohistochemistry on breast cancer tissues revealed an association of DDR2 expression with nuclear localization of Snail1, as well as with a loss of E-cadherin expression.…”