Nuclear expression of FLT1 and its ligand PGF in FUS-DDIT3 carrying myxoid liposarcomas suggests the existence of an intracrine signaling loop

Autor: Carola Andersson, Anita Olofsson, Melker Göransson, Pierre Åman, Mattias K Andersson
Rok vydání: 2010
Předmět:
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor B
Cancer Research
Intracrine
Oncogene Proteins
Fusion
Fibrosarcoma
Recombinant Fusion Proteins
Blotting
Western
Fluorescent Antibody Technique
chemical and pharmacologic phenomena
Mice
SCID
Pregnancy Proteins
Biology
Ligands
Transfection
lcsh:RC254-282
Mice
Cell Line
Tumor
Genetics
Animals
Humans
Protein Kinase Inhibitors
Tissue homeostasis
Cell Proliferation
Placenta Growth Factor
Cell Nucleus
Vascular Endothelial Growth Factor Receptor-1
Dose-Response Relationship
Drug
Oncogene
Reverse Transcriptase Polymerase Chain Reaction
Cell growth
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Immunohistochemistry
Molecular biology
Liposarcoma
Myxoid
Oncology
Cell culture
RNA-Binding Protein FUS
RNA Interference
HT1080
Signal transduction
Neoplasm Transplantation
Transcription Factor CHOP
Research Article
Signal Transduction
Zdroj: BMC Cancer
BMC Cancer, Vol 10, Iss 1, p 249 (2010)
ISSN: 1471-2407
DOI: 10.1186/1471-2407-10-249
Popis: Background The FUS-DDIT3 fusion oncogene encodes an abnormal transcription factor that has a causative role in the development of myxoid/round-cell liposarcomas (MLS/RCLS). We have previously identified FLT1 (VEGFR1) as a candidate downstream target gene of FUS-DDIT3. The aim of this study was to investigate expression of FLT1 and its ligands in MLS cells. Methods HT1080 human fibrosarcoma cells were transiently transfected with FUS-DDIT3-GFP variant constructs and FLT1 expression was measured by quantitative real-time PCR. In addition, FLT1, PGF, VEGFA and VEGFB expression was measured in MLS/RCLS cell lines, MLS/RCLS tumors and in normal adiopocytes. We analyzed nine cases of MLS/RCLS and one cell line xenografted in mice for FLT1 protein expression using immunohistochemistry. MLS/RCLS cell lines were also analyzed for FLT1 by immunofluorescence and western blot. MLS/RCLS cell lines were additionally treated with FLT1 tyrosine kinase inhibitors and assayed for alterations in proliferation rate. Results FLT1 expression was dramatically increased in transfected cells stably expressing FUS-DDIT3 and present at high levels in cell lines derived from MLS. The FLT1 protein showed a strong nuclear expression in cells of MLS tissue as well as in cultured MLS cells, which was confirmed by cellular fractionation. Tissue array analysis showed a nuclear expression of the FLT1 protein also in several other tumor and normal cell types including normal adipocytes. The FLT1 ligand coding gene PGF was highly expressed in cultured MLS cells compared to normal adipocytes while the other ligand genes VEGFA and VEGFB were expressed to lower levels. A more heterogeneous expression pattern of these genes were observed in tumor samples. No changes in proliferation rate of MLS cells were detected at concentrations for which the kinase inhibitors have shown specific inhibition of FLT1. Conclusions Our results imply that FLT1 is induced as an indirect downstream effect of FUS-DDIT3 expression in MLS. This could be a consequence of the ability of FUS-DDIT3 to hijack parts of normal adipose tissue development and reprogram primary cells to a liposarcoma-like phenotype. The findings of nuclear FLT1 protein and expression of corresponding ligands in MLS and normal tissues may have implications for tissue homeostasis and tumor development through auto- or intracrine signaling.
Databáze: OpenAIRE
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