TY - JOUR
T1 - FGFR-4 Arg388 enhances prostate cancer progression via extracellular signal-related kinase and serum response factor signaling
AU - Yu, Wendong
AU - Feng, Shu
AU - Dakhova, Olga
AU - Creighton, Chad J.
AU - Cai, Yi
AU - Wang, Jianghua
AU - Li, Rile
AU - Frolov, Anna
AU - Ayala, Gustavo
AU - Ittmann, Michael
PY - 2011/7/1
Y1 - 2011/7/1
N2 - Purpose: Increased expression of FGFR-4 and its ligands have been linked to lethal prostate cancer (PCa). Furthermore, a germ line polymorphism in the FGFR-4 gene, resulting in arginine at codon 388 (Arg388) instead of glycine (Gly388), is associated with aggressive disease. The FGFR-4 Arg388 variant results in increased receptor stability, sustained receptor activation, and increased motility and invasion compared with Gly 388. However, the impact of sustained signaling on cellular signal transduction pathways is unknown. Experimental Design: Expression microarray analysis of immortalized prostatic epithelial cells lines expressing FGFR-4 Arg388 or Gly388 was used to establish a gene signature associated with FGFR-4 Arg388 expression. Transient transfection of reporters and inhibitors was used to establish the pathways activated by FGFR-4 Arg388 expression. The impact of pathway knockdown in vitro and in an orthotopic model was assessed using inhibitors and/or short hairpin RNA (shRNA). Results: Expression of the FGFR-4 Arg388 protein leads to increased activity of the extracellular signal-related kinase (ERK) pathway, increased activity of serum response factor (SRF) and AP1, and transcription of multiple genes that are correlated with aggressive clinical behavior in PCa. Increased expression of SRF is associated with biochemical recurrence in men undergoing radical prostatectomy. Consistent with these observations, knockdown of FGFR-4 Arg388 in PCa cells decreases proliferation and invasion in vitro and primary tumor growth and metastasis in vivo. Conclusions: These studies define a signal transduction pathway downstream of FGFR-4 Arg 388 that acts via ERK and SRF to promote PCa progression.
AB - Purpose: Increased expression of FGFR-4 and its ligands have been linked to lethal prostate cancer (PCa). Furthermore, a germ line polymorphism in the FGFR-4 gene, resulting in arginine at codon 388 (Arg388) instead of glycine (Gly388), is associated with aggressive disease. The FGFR-4 Arg388 variant results in increased receptor stability, sustained receptor activation, and increased motility and invasion compared with Gly 388. However, the impact of sustained signaling on cellular signal transduction pathways is unknown. Experimental Design: Expression microarray analysis of immortalized prostatic epithelial cells lines expressing FGFR-4 Arg388 or Gly388 was used to establish a gene signature associated with FGFR-4 Arg388 expression. Transient transfection of reporters and inhibitors was used to establish the pathways activated by FGFR-4 Arg388 expression. The impact of pathway knockdown in vitro and in an orthotopic model was assessed using inhibitors and/or short hairpin RNA (shRNA). Results: Expression of the FGFR-4 Arg388 protein leads to increased activity of the extracellular signal-related kinase (ERK) pathway, increased activity of serum response factor (SRF) and AP1, and transcription of multiple genes that are correlated with aggressive clinical behavior in PCa. Increased expression of SRF is associated with biochemical recurrence in men undergoing radical prostatectomy. Consistent with these observations, knockdown of FGFR-4 Arg388 in PCa cells decreases proliferation and invasion in vitro and primary tumor growth and metastasis in vivo. Conclusions: These studies define a signal transduction pathway downstream of FGFR-4 Arg 388 that acts via ERK and SRF to promote PCa progression.
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U2 - 10.1158/1078-0432.CCR-10-2858
DO - 10.1158/1078-0432.CCR-10-2858
M3 - Article
C2 - 21622724
AN - SCOPUS:79960297620
SN - 1078-0432
VL - 17
SP - 4355
EP - 4366
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 13
ER -