FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent Pathway1

Autor: Tornin, Juan, Hermida-Prado, Francisco, Padda, Ranjit Singh, Gonzalez, M. Victoria, Alvarez-Fernandez, Carlos, Rey, Veronica, Martinez-Cruzado, Lucia, Estupiñan, Oscar, Menendez, Sofia T., Fernandez-Nevado, Lucia, Astudillo, Aurora, Rodrigo, Juan P., Lucien, Fabrice, Kim, Yohan, Leong, Hon S., Garcia-Pedrero, Juana Maria, Rodriguez, Rene
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Original article
Oncogene Proteins
Fusion
CHOP
C/EBP homologous protein
hemic and lymphatic diseases
ROCK
Rho-associated coiled-coil-containing protein kinases 1 and 2
Humans
MRCLS
myxoid/round cell liposarcoma
RNA
Small Interfering
RHO
RHOA/C GTPases
FFPE
formalin-fixed
paraffin-embedded
rho-Associated Kinases
Gene Expression Profiling
MLC2
myosin light chain 2
BMSC
bone marrow–derived mesechymal stem/stromal cell
CSC
cancer stem cell
Liposarcoma
Myxoid
Gene Expression Regulation
Neoplastic
src-Family Kinases
SFK
Src-family of protein kinases
FAK
focal adhesion kinase
Focal Adhesion Kinase 1
Neoplastic Stem Cells
RNA-Binding Protein FUS
CAM
chorioallantoic membrane
biological phenomena
cell phenomena
and immunity
Transcription Factor CHOP
FUS
fused in sarcoma
Acute-Phase Proteins
Signal Transduction
Zdroj: Neoplasia (New York, N.Y.)
ISSN: 1476-5586
1522-8002
Popis: Deregulated SRC/FAK signaling leads to enhanced migration and invasion in many types of tumors. In myxoid and round cell liposarcoma (MRCLS), an adipocytic tumor characterized by the expression of the fusion oncogene FUS-CHOP, SRC have been found as one of the most activated kinases. Here we used a cell-of-origin model of MRCLS and an MRCLS cell line to thoroughly characterize the mechanisms of cell invasion induced by FUS-CHOP using in vitro (3D spheroid invasion assays) and in vivo (chicken chorioallantoic membrane model) approaches. FUS-CHOP expression activated SRC-FAK signaling and increased the invasive ability of MRCLS cells. In addition, FAK expression was found to significantly correlate with tumor aggressiveness in sarcoma patient samples. The involvement of SRC/FAK activation in FUS-CHOP-mediated invasion was further confirmed using the SRC inhibitor dasatinib, the specific FAK inhibitor PF-573228, and FAK siRNA. Notably, dasatinib and PF573228 could also efficiently block the invasion of cancer stem cell subpopulations. Downstream of SRC/FAK signaling, we found that FUS-CHOP expression increases the levels of the RHO/ROCK downstream effector phospho-MLC2 (T18/S19) and that this activation was prevented by dasatinib or PF573228. Moreover, the ROCK inhibitor RKI-1447 was able to completely abolish invasion in FUS-CHOP-expressing cells. These data uncover the involvement of SRC/FAK/RHO/ROCK signaling axis in FUS-CHOP-mediated invasion, thus providing a rationale for testing inhibitors of this pathway as potential novel antimetastatic agents for MRCLS treatment.
Databáze: OpenAIRE
Externí odkaz: