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Alternative splicing of fibroblast growth factor receptors in human prostate cancer
B Kwabi-Addo1, F Ropiquet, D Giri
1Department of Pathology, Baylor College of Medicine, Houston Department of Veterans Affairs Medical Center, 2002 Holcombe Blvd., Houston, TX 77030, USA.
Background:
Fibroblast growth factors (FGFs) are known to play an important role in the growth of normal prostatic epithelial cells and may promote proliferation of neoplastic prostatic epithelial cells via autocrine or paracrine mechanisms. The affinity of FGFs for FGF receptors 1-3 is critically dependent on an alternative splicing event involving the coding region for the carboxy terminal portion of the third extracellular immunoglobulin-like domain that leads to two different isoforms of each receptor (IIIb and IIIc). We therefore sought to determine whether changes in alternative splicing of FGF receptors occur in human prostate cancer.
Methods:
RNAs from normal prostate and clinically localized or metastatic prostate cancers were analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) followed by digestion of products with restriction enzymes specific for each FGF receptor isoform and quantitation of the relative amounts of each isoform after electrophoresis. For FGFR-2, this was correlated with immunohistochemistry to determine the localization of the protein product.
Results:
FGFR-1 is expressed exclusively as the IIIc isoform in prostate cancer while FGFR-3 is expressed predominantly as the IIIb isoform, similar to the expression pattern in normal prostatic epithelial cells. In contrast, there was variable expression of the FGFR-2 IIIb and IIIc isoforms. In the majority of cases the FGFR-2 IIIb isoform was the predominant or exclusive isoform expressed, similar to normal epithelial cells, but in a subset of cases the IIIc isoform was increased, indicating a change in alternative splicing of FGFR-2 in some cases.
Conclusions:
In most cases of prostate cancer there are no changes in alternative splicing of FGF receptors, but in a subgroup there is increased expression of the FGFR-2 IIIc isoform. Given that the affinity of FGFs is highly dependent on the isoform of FGF receptor expressed, this information is critical in understanding the effects of FGFs on prostate cancer cells in vivo.