4921

DDR2

Discoidin domain receptor 2 (DDR2) is a collagen receptor that is expressed during epithelial-mesenchymal transition (EMT), a cellular transformation that mediates many stages of embryonic development and disease. However, the functional significance of this receptor in EMT is unknown. Here we show that Transforming Growth Factor-beta1 (TGF-beta1), a common stimulator of EMT, promotes increased expression of type I collagen and DDR2. Inhibiting expression of COL1A1 or DDR2 with siRNA is sufficient to perturb activity of the NF-kappaB and LEF-1 transcription factors and to inhibit EMT and cell migration induced by TGF-beta1. Furthermore, knockdown of DDR2 expression with siRNA inhibits EMT directly induced by type I collagen. These data establish a critical role for type I collagen-dependent DDR2 signaling in the regulation of EMT.CI - Copyright (c) 2011 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.

A wide range of genes involved in breast cancer metastasis have been reported to be related to the microenvironment. We studied the role of discoidin domain receptor 2 (DDR2), a collagen-binding receptor, in breast cancer progression under hypoxic conditions. We showed that DDR2 protein expression closely correlated with the expression of hypoxic marker HIF-1alpha in clinical breast cancer specimens. The in vitro data demonstrated that hypoxia treatment increased the levels of both expression and phosphorylation of DDR2 in human breast cancer cell lines. In vivo, orthotopic breast tumour xenografts with DDR2 knockdown displayed reduced dissemination and significant prevention in pulmonary and lymphatic metastasis; conversely, these processes were significantly facilitated by the enforced expression of the activated form of DDR2. Further mechanism studies indicated that DDR2 plays an indispensable role in a series of hypoxia-induced behaviours of breast cancer cells, including migration, invasion, and epithelial-mesenchymal transition (EMT). The transcription factor Snail was found to mediate DDR2-induced down-regulation of the cell-cell adhesion molecule E-cadherin. It was also documented that there is a correlation between DDR2 and E-cadherin expression with the presence of lymph node metastases in 160 cases of invasive human breast carcinoma. In addition, we provided evidence that DDR2 silencing in breast cancer cells prevents the hypoxia-induced activation of ERK MAPK, suggesting its potential involvement in mediating the effect of DDR2 on hypoxia-induced signalling. Based on the results of this study, we conclude that DDR2 participates in hypoxia-induced breast cancer metastasis through the regulation of cell migration, invasion, and EMT, and thus may serve as an accessible therapeutic target for the treatment of breast cancer.CI - Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

BACKGROUND/AIM: epithelial-mesenchymal transition (EMT) plays a role in cancer progression. Previous studies have suggested that discoidin domain receptor 2 (DDR2) is related to tumor progression and EMT. However, the role of DDR2 in regulating gastric cancer (GC) metastasis and in EMT has not been elucidated. In this study, we aimed to determine DDR2 expression and its clinical relation in GC and to investigate the effects of DDR2 on EMT and its underlying mechanisms. METHODS: DDR2 expression and the relation to patients' clinicopathological features were assayed by Western blot or immunohistochemical staining. The effects of DDR2 overexpression were investigated using in vivo tumorigenicity and xenograft models. The effects of DDR2 on EMT marker expression were assayed by Western blot and immunofluorescence. The possible role of the mTORC pathway in these processes was explored. RESULTS: DDR2 showed high expression in GC tissues and cells. DDR2 expression was negatively correlated with E-cadherin expression and positively correlated with N-cadherin and vimentin expression. High DDR2 expression is correlated with unfavorable pathoclinical features such as multiple tumor locations and intestinal-type GC. In xenograft models, DDR2 overexpression promoted tumor formation. Furthermore, DDR2 expression impacted on the invasion and motility of GC cells, accompanied by changes in EMT marker expression. Finally, our results revealed that DDR2 facilitates GC cell invasion and EMT through mTORC2 activation and AKT phosphorylation. CONCLUSION: DDR2 is upregulated and correlated with unfavorable clinical features of GC patients. DDR2 promotes tumor formation and invasion through facilitating EMT process via mTORC2 activation and AKT phosphorylation.

Increasing matrix stiffness caused by the extracellular matrix (ECM) deposition surrounding cancer cells is accompanied by epithelial-mesenchymal transition (EMT). Here, we show that expression levels of EMT marker genes along with discoidin domain receptor 2 (DDR2) can increase upon matrix stiffening. DDR2 silencing by short hairpin RNA downregulated EMT markers. Promoter analysis and chromatin immunoprecipitation revealed that c-Myb and LEF1 may be responsible for DDR2 induction during cell culture on a stiff matrix. Mechanistically, c-Myb acetylation by p300, which is upregulated on the stiff matrix, seems to be necessary for the c-Myb-and-LEF1-mediated DDR2 expression. Finally, we found that the c-Myb-DDR2 axis is crucial for lung cancer cell line proliferation and expression of EMT marker genes in a stiff environment. Thus, our results suggest that DDR2 regulation by p300 expression and/or c-Myb acetylation upon matrix stiffening may be necessary for regulation of EMT and invasiveness of lung cancer cells.

Discoidin Domain Receptor 2 (DDR2) is a receptor tyrosine kinase which has been shown to regulate cell migration upon binding its ligand, collagen. expression studies determined that DDR2 mRNA and protein are present in the atrioventricular canal during epithelial-mesenchymal transformation (EMT) and the receptor is expressed in both activated endothelial and migrating mesenchymal cells in vivo.