title: PDGF-D promotes dermal fibroblast invasion in 3-dimensional extracellular matrix via Snail-mediated MT1-MMP upregulation.
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.
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University Harbin, 157 Baojian Rd, Harbin, Heilongjiang, 150081, People's Republic of China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Department of General Surgery, Heilongjiang Province Hospital, Harbin, Heilongjiang, 150000, People's Republic of China.
authors.forename: Jinfa
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University Harbin, 157 Baojian Rd, Harbin, Heilongjiang, 150081, People's Republic of China.
authors.forename: Yusi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150081, People's Republic of China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Deng
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University Harbin, 157 Baojian Rd, Harbin, Heilongjiang, 150081, People's Republic of China. lclian@aliyun.com.
authors.forename: Changlian
authors.initials: C
authors.lastname: Lu
mesh_terms: D000818:Animals; D002465:Cell Movement; D020405:Dermis / Q000166:cytology*; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D008222:Lymphokines / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D008222:Lymphokines; C427493:PDGFD protein, human; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D020782:Matrix Metalloproteinases; D053511:Matrix Metalloproteinase 14
keywords: 3-dimensional extracellular matrix; Fibroblast; Invasion; MT1-MMP; PDGF-D; Snail