Fibroblast growth factor and ornithine decarboxylase 5′UTRs enable preferential expression in human prostate cancer cells and in prostate tumors of PTEN−/− transgenic mice

Abstract

In this study, we have taken advantage of over-expression of eukaryotic translation initiation factor 4E (eIF4E) in prostate cancer cells to design a viral-based targeting system of prostate cancer. Three different lengths of 5 0 -untranslated regions (5 0 UTRs) derived from either fibroblast growth factor-2 (FU-FGF2-GW) or ornithine decarboxylase (FU-ODC 149 -GW and FU-ODC 274 -GW) were inserted upstream of enhanced green fluorescent protein (GFP) gene in a lentiviral backbone. Both nonmalignant control (PNT1B and BPH-1) and neoplastic (LNCaP, C4-2, DU145 and PC-3) prostate cell lines were transfected with each plasmid or virus alone, or in the presence of siRNA against eIF4E, and their expression was monitored via GFP protein levels. Two 5 0 UTRs (FU-FGF2-GW and FU-ODC-GW) were selected as being most sensitive to eIF4E status. Lentiviruses containing these sequences were injected directly into the prostates of PTEN À/À (tumor-bearing) and control mice. Immunofluorescence data and western blot analyses determined that a lentivirus containing a 5 0 UTR derived from FGF-2 is the best candidate for directing selective gene expression in the prostate tumors of PTEN À/À mice in vivo. This study demonstrates that judicious selection of a complex 5 0 UTR can enhance selective targeting of viral-based gene therapies for prostate cancer.

Fibroblast growth factor receptor signaling plays a key role in transformation induced by the TMPRSS2/ERG fusion gene and decreased PTEN

“…Our studies show increased expression of multiple FGF ligands at the mRNA level after PTEN loss. Two studies have shown increased translational efficiency of FGF ligands including FGF2 [ 42 ] and FGF10 [ 43 ] after PTEN loss. Such changes in translational efficiency have the potential to further increase FGF ligand availability after loss of PTEN.…”

“…FGF2 was particularly increased by TE expression and this FGF is a known contributor to the transformed phenotype in PCa [ 22 ]. As noted above, FGF2 translation is increased after PTEN knockdown [ 42 ] so this may lead to synergistic effects of PTEN KD and TE expression. This is accompanied by increased FGFR1, which binds FGF2, and is also strongly associated with transformation in PCa [ 22 , 24 ].…”

FGFs: crucial factors that regulate tumour initiation and progression

“…Previous studies have reported that FGFs and FGFRs are significantly overexpressed in various kinds of cancers, and it is demonstrated that FGFs are involved in the regulation of cancer cell proliferation, survival and migration . Inhibitors and antibodies directly targeting different FGF ligands have shown therapeutic promise in different tumours .…”