Abstract
Fibroblast growth factor (FGF) receptor (FGFR) substrate 2 (FRS2) is an adaptor protein that plays a critical role in FGFR signaling. FRS2 is located on chromosome 12q13-15 that is frequently amplified in liposarcomas. The significance of FRS2 and FGFR signaling in high-grade liposarcomas is unknown. Herein, we first comparatively examined the amplification and expression of FRS2 with CDK4 and MDM2 in dedifferentiated liposarcoma (DDLS) and undifferentiated high-grade pleomorphic sarcoma (UHGPS). Amplification and expression of the three genes were identified in 90% to 100% (9-11 of 11) of DDLS, whereas that of FRS2, CDK4, and MDM2 were observed in 55% (41 of 75), 48% (36 of 75), and 44% (33/75) of clinically diagnosed UHGPS, suggesting that these "UHGPS" may represent DDLS despite lacking histologic evidence of lipoblasts. Immunohistochemical analysis of phosphorylated FRS2 protein indicated that the FGFR/FRS2 signaling axis was generally activated in about 75% of FRS2-positive high-grade liposarcomas. Moreover, we found that FRS2 and FGFRs proteins are highly expressed and functional in three high-grade liposarcoma cell lines: FU-DDLS-1, LiSa-2, and SW872. Importantly, the FGFR selective inhibitor NVP-BGJ-398 significantly inhibited the growth of FU-DDLS-1 and LiSa-2 cells with a concomitant suppression of FGFR signal transduction. Attenuation of FRS2 protein in FU-DDLS-1 and LiSa-2 cell lines decreased the phosphorylated extracellular signal-regulated kinase 1/2 and AKT and repressed cell proliferation. These findings indicate that analysis of FRS2 in combination with CDK4 and MDM2 will more accurately characterize pathologic features of high-grade liposarcomas. Activated FGFR/FRS2 signaling may play a functional role in the development of high-grade liposarcomas, therefore, serve as a potential therapeutic target.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Arginine / analogs & derivatives
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Blotting, Western
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cyclin-Dependent Kinase 4 / genetics
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Cyclin-Dependent Kinase 4 / metabolism
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Gene Amplification
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Gene Expression Regulation, Neoplastic
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Humans
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Immunohistochemistry
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Liposarcoma / genetics*
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Liposarcoma / metabolism
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Liposarcoma / pathology
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Male
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism
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Middle Aged
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Neoplasm Grading
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Phenylurea Compounds / pharmacology
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Pyrimidines / pharmacology
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RNA Interference
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Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors
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Receptor, Fibroblast Growth Factor, Type 2 / genetics
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Receptor, Fibroblast Growth Factor, Type 2 / metabolism
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Receptor, Fibroblast Growth Factor, Type 3 / antagonists & inhibitors
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Receptor, Fibroblast Growth Factor, Type 3 / genetics
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Receptor, Fibroblast Growth Factor, Type 3 / metabolism
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Receptor, Fibroblast Growth Factor, Type 4 / antagonists & inhibitors
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Receptor, Fibroblast Growth Factor, Type 4 / genetics
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Receptor, Fibroblast Growth Factor, Type 4 / metabolism
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Receptors, Fibroblast Growth Factor / antagonists & inhibitors
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Receptors, Fibroblast Growth Factor / genetics*
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Receptors, Fibroblast Growth Factor / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction*
Substances
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Adaptor Proteins, Signal Transducing
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FRS2 protein, human
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Membrane Proteins
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Phenylurea Compounds
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Pyrimidines
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Receptors, Fibroblast Growth Factor
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N,N-dimethylarginine
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Arginine
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infigratinib
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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FGFR2 protein, human
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FGFR3 protein, human
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FGFR4 protein, human
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Receptor, Fibroblast Growth Factor, Type 2
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Receptor, Fibroblast Growth Factor, Type 3
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Receptor, Fibroblast Growth Factor, Type 4
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Proto-Oncogene Proteins c-akt
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Cyclin-Dependent Kinase 4
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Extracellular Signal-Regulated MAP Kinases