PDGF-D promotes dermal fibroblast invasion in 3-dimensional extracellular matrix via Snail-mediated MT1-MMP upregulation.
Tumour Biol
; 37(1): 591-9, 2016 Jan.
Article
em En
| MEDLINE
| ID: mdl-26234766
ABSTRACT
Increasing attention has been focused on the malignant tumor microenvironment, which plays important roles in tumor occurrence, progression and metastasis. Fibroblasts are recruited by platelet-derived growth factor (PDGFs) and invade the tumor microenvironment. In the PDGF family, PDGF-B has been reported to play an important role in the recruitment and invasion programs. However, whether PDGF-D plays a role in these programs remains unclear. We generated a recombinant plasmid expressing human PDGF-D and transfected the plasmid to dermal fibroblasts to examine the effects on cell invasive activities in 3D type I collagen gels. PDGF-D plasmid transfection enhanced fibroblast invasive activities both in invasive cell numbers and invasion depth in 3D collagen gels. These effects were blocked by Snail-specific siRNA transfection. PDGF-D transfection significantly induced Snail expression at both mRNA and protein levels. PDGF-D further upregulated MT1-MMP mRNA and protein expressions and this was inhibited when Snail was knocked down by siRNA. Both Snail and MT1-MMP expressions in fibroblasts and cellular invasive activities in 3D collagen induced by PDGF-D were inhibited by LY294002, SP600125, and U1026, the inhibitors of PI3K, JNK, and ERK1/2 signaling pathways, respectively. However, no effects were observed in response to the P38MAPK signaling pathway inhibitor SB203580. These effects of PDGF-D were confirmed by using the culture supernatants of the transfectants. Taken together, these data demonstrate that PDGF-D plays important roles in the recruitment and invasion programs of fibroblasts via the activation of PI3K, JNK and ERK1/2 signaling pathways, and upregulation of Snail and downstream effecter MT1-MMP. These findings indicate that PDGF-D is an important player in the tumor microenvironment for fibroblast recruitment.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fator de Crescimento Derivado de Plaquetas
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Linfocinas
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Derme
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Metaloproteinases da Matriz
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Metaloproteinase 14 da Matriz
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Fibroblastos
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Fatores de Transcrição da Família Snail
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article