DDR2 inhibition reduces migration and invasion of murine metastatic melanoma cells by suppressing MMP2/9 expression through ERK/NF-κB pathway.
Metastatic melanoma is one of the most deadly and evasive cancers. Collagen I in the extracellular matrix promotes the migration and invasion of tumor cells through the production of matrix metalloproteinase (MMP) 2 and 9. Discoidin domain receptor (DDR) 2 is a collagen receptor that is implicated in several cancer types including breast and prostate cancers. However, the role of DDR2 in the migration and invasion of murine melanoma cells is less studied. In the present study, we investigated the effects and underlying mechanisms of DDR2 in migration and invasion of B16BL6 melanoma cells in response to collagen I. Results demonstrated that DDR2 is expressed and is phosphorylated by collagen I in the cells. Upon down-regulation of DDR2 using small-interfering RNA (siRNA) approach, both of the cell migratory and invasive phenotypes were significantly attenuated when compared with the control cells. This effect was mediated via suppression of MMP2/9 upon DDR2 inhibition. Furthermore, inhibition of DDR2 by specific siRNA markedly reduced the activation of extracellular regulated kinase (ERK) 1 and 2 and nuclear factor of kappa B (NF-κB) in the cells when compared with the control cells. Overall, these data demonstrated that DDR2 siRNA-mediated suppression of ERK1/2 and NF-κB could down-regulate the expressions of MMP2/9 in response to collagen I to reduce the migratory and invasive phenotypes of the cells.
Department of Immunology and Institute for Medical Sciences, Medical School, Chonbuk National University, Jeonju, Jeonbuk 561-756, Republic of Korea.
Barun
B
Poudel
Department of Oriental Pharmacy, College of Pharmacy and Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
Young-Mi
YM
Lee
Department of Immunology and Institute for Medical Sciences, Medical School, Chonbuk National University, Jeonju, Jeonbuk 561-756, Republic of Korea daekim@jbnu.ac.kr.
Dae-Ki
DK
Kim
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement; D000070818:Discoidin Domain Receptors; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D016328:NF-kappa B; D011975:Receptors, Mitogen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
B16BL6; ERK; NF-κB; collagen I; discoidin domain receptor 2; invasion; migration