Background: Prostate cancer (PCa) is the most diagnosed cancer in men and the second leading cause of male-cancer related deaths in the U.S. Dramatic ethnic disparities have been observed in PCa patients, as African-American (AA) men are 60% more likely to be diagnosed with PCa and have a 2.4 fold higher mortality rate compared to European American (EA) men. Increasing evidence suggests that, after accounting for epidemiological factors, a remaining component of this disparity is due to intrinsic genetic and biological factors. Interestingly, recent exon array data from our lab suggest that differential expression of splicing factors (SFs) and differential alternative splicing may be occurring in AA PCa. We hypothesize that differential alternative splicing involving exon 14 of the FGFR3 gene is generating a shorter, more oncogenic variant in AA PCa. Differential splicing of FGFR3 and increased expression of SFs in AA patients may be mechanisms contributing to AA PCa health disparities. Purpose: In this study, we investigate the role of differential expression of splicing factors and exon skipping in the receptor tyrosine kinase family on prostate cancer health disparities. Results: Exon array data suggested FGFR3 as a candidate for differential alternative splicing. Exon profiling and RT-PCR validated differential expression (exon skipping) of exon 14 of FGFR3 in AA patient samples and cell lines. Cloning confirmed the presence of the FGFR3-L variant (containing exon 14) and the FGFR3-S variant (without exon 14) from an EA and AA PCa cell line, respectively. Enrichment of FGFR3-S resulted in increased cell proliferation in an AA cell line. Additionally, our exon array data predicted increased expression of seven SFs in AA patients. RT-PCR and IHC analysis validated increased expression in AA specimens. Knockdown of a subset of these SFs resulted in decreased invasion and FGFR3 splice switching in an AA cell line. Conclusions: We have identified an oncogene of interest, FGFR3, which undergoes exon skipping that is specific to AA PCa. In cell lines, this shorter isoform of FGFR3 leads to an increased oncogenic phenotype based on proliferation assays. We have shown that AA PCa patient specimens have increased expression of specific SFs compared to EA specimens and knockdown of a subset of SFs reduces AA PCa cell invasion and causes splice switching of FGFR3. Thus, differential expression of SFs and exon skipping in FGFR3 may be one mechanism contributing to the increased aggressiveness of PCa in AA patients
