Fibroblast growth factor homologous factors (FHFs) belong to the fibroblast growth factor (FGF) superfamily, which plays an important role in prostate cancer (PCa). Mining of public database suggests that FGF13 (FHF2) mRNA expression is altered in over 30% of PCa cases. This study examined the FGF13 expression pattern in human PCa specimens and evaluated its potential as a biomarker for patient outcome after radical prostatectomy (RP). Immunohistochemistry (IHC) showed that FGF13 was detectable in the majority of human PCa samples, and FGF13 IHC scores were higher in high-grade prostatic intraepithelial neoplasia, in primary PCa and in metastatic PCa than in benign prostatic tissue. There was a significant association between high cytoplasmic FGF13 staining and a risk of biochemical recurrence (BCR) after RP. This was also evident in the intermediate to high-risk patient groups. In contrast, positive nuclear FGF13 staining along with low cytoplasmic FGF13 group showed a decreased BCR risk. Multivariate regression analysis indicated that high cytoplasmic FGF13 staining was associated with BCR and that this could serve as an independent prognostic marker in PCa. Several PCa cell lines showed increased FGF13 expression at the mRNA and protein levels compared to the immortalized prostate epithelial cell line PNT1a. Analysis of co-labeled cells suggested a possible interaction of FGF13 with a-tubulin and the voltage-gated sodium channel proteins (Na V s/VGSCs). Our data indicate that, for PCa patients after RP, FGF13 serves as a potential novel prognostic marker that improves prediction of BCR-free survival, in particular if combined with other clinical parameters.Prostate cancer (PCa) is one of the most commonly diagnosed cancers in men, especially in developed countries. Globally, PCa is estimated to account for 15% of all cancers diagnosed in men and 6.6% of total male cancer mortality. 1

Fibroblast growth factor homologous factors (FHF1-4) belong to the FGF family involved in prostate cancer. Based on the cBioPortal database (MSKCC, Cancer Cell 2010), FGF13 (FHF2), one of the FHF subfamily members, shows altered mRNA expression in prostate cancer. In this study we aimed to analyze FGF13 expression and functions in prostate cancer. We collected prostate cancer specimens from 234 patients who underwent radical prostatectomy in Turku University Hospital. Frozen tissue was used for qRT-PCR to measure FGF13 mRNA in 76 samples in which glandular or cancer area covered at least 50% of the specimen (non-cancer, n = 31; cancer, n = 45). Tissue microarrays (TMA) containing cancer (n = 152) and adjacent non-cancer (n = 203) samples were examined for FGF13 protein by immunohistochemical staining. Total FGF13 staining score of each TMA core was calculated using HistoScore system. Chi-square test, Kaplan-Meier and Cox proportional hazards regression model were used to analyze the association between FGF13 staining and clinicopathological parameters. Immunofluorescence was used to detect FGF13 localization in prostate cancer cells in vitro. The level of FGF13 mRNA was significantly higher in cancer tissues than in non-cancer tissues (p = 0.0028). FGF13 mRNA levels did not show significant association with the Gleason score, pathologic stage, pre-operation PSA value or PSA failure time. In the TMA study, cancer cells showed weak, moderate or strong cytoplasmic staining for FGF13 in over 99% of the samples whereas luminal epithelial cells were positive in only 53% of the adjacent non-cancer samples. Correspondingly, the cytoplasmic staining of FGF13 presented higher scores in cancer than in non-cancer areas (p<0.001). Moreover, nuclear staining of FGF13 was also observed, and it was more frequent in cancer samples compared to non-cancer samples (59% and 12%, respectively). Especially, basal cells showed positive immunoreactivity sporadically in non-cancer tissues. Only very weak or negative immunostaining of FGF13 was found in stromal cells but interestingly, prominent expression of FGF13 was observed in mononuclear cells. In terms of time to biochemical recurrence after prostatectomy, patients with high FGF13 cytoplasmic staining had a shorter PSA failure free time compared to patients who had lower cytoplasmic FGF13 expression (p = 0.009). Multivariate analysis revealed that high cytoplasmic FGF13 staining (HR = 3.76, 95%CI [1.5-9.3], p = 0.004) was significantly associated with a shorter PSA failure time. Immunofluorescence staining in PC3M cells showed that FGF13 was located to the cytoplasm and nuclei. Overall, our study demonstrates, for the first time, expression and location of FGF13 protein in prostate cancer and suggests that FGF13 could have prognostic value in primary prostate cancer. Citation Format: Lan Yu, Miikka Tuomala, Mervi Toriseva, Teresa Elo, Johanna Tuomela, Heikki Seikkula, Martti Nurmi, Peter Boström, Tuomas Mirtti, Kalle Alanen, Markku Kallajoki, Pirkko Härkönen. High expression of fibroblast growth factor 13 (FGF13) in prostate cancer is associated with a shortened time to biochemical recurrence after radical prostatectomy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3454. doi:10.1158/1538-7445.AM2015-3454

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