The FOXF2 pathway in the human prostate stroma.
BACKGROUND
Forkhead box 2 (FOXF2) is a member of the large family of forkhead transcription factors and its expression pattern suggests a role in prostate cancer development. FOXF2 expression is stroma-specific and higher expressed in the prostate transition zone than the prostate peripheral zone. Moreover, expression of FOXF2 is decreased in prostate cancer.


METHODS
To identify the genes and pathways regulated by FOXF2, we compared microarray expression profiles of primary prostate stromal cells (PrSC) treated with control or small interfering RNA (siRNA) directed against FOXF2.


RESULTS
From our microarray analyses, we selected 190 differentially expressed genes, of which 104 genes were higher expressed in PrSC cells treated with FOXF2 siRNA and 86 were higher expressed in PrSC cells treated with negative control siRNA. Eight of the strongest differentially expressed genes were validated by RT-PCR. Genes down-regulated by FOXF2 included MT1E, MT1F, PDGFA, ITGB1, and PSG7 and genes up-regulated by FOXF2 included WASF2, BAMBI, and CXCL12. Ingenuity pathway analysis showed several pathways significantly regulated by FOXF2, including PPAR signaling, PDGF signaling, and extracellular matrix (ECM) signaling. GSEA analysis revealed that FOXF2 up-regulated genes were down-regulated in the same PrSC cells treated with transforming growth factor 3 (TGFbeta3).


CONCLUSIONS
The distinct expression pattern of FOXF2 in the prostate, its effect on expression of ECM signaling, and its opposing role in the TGFbeta3 pathway, suggests a role for FOXF2 in prostate homeostasis and stroma-epithelial interactions.
van der Heul-Nieuwenhuijsen
Leonie
L
Department of Urology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands.
Dits
Natasja
N
Van Ijcken
Wilfred
W
de Lange
Don
D
Jenster
Guido
G
D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011467:Prostate / Q000166:cytology / Q000502:physiology*; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism; D053782:Transforming Growth Factor beta3 / Q000494:pharmacology
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C486413:FOXF2 protein, human; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D053782:Transforming Growth Factor beta3