T. M. Bauman1, A. J. Becka1, P. D. Sehgal1, W. Huang2, W. A. Ricke1 1University Of Wisconsin School Of Medicine And Public Health,Department Of Urology,Madison, WI, USA 2University Of Wisconsin School Of Medicine And Public Health,Department Of Pathology And Laboratory Medicine,Madison, WI, USA
Introduction: Single Ig IL-1-related receptor (SIGIRR) is a negative regulator of toll-like receptor (TLR) 4 and IL-1 mediated activation of NF-κB. A tumor suppressive role of SIGIRR has previously been established in certain carcinomas, but the role and expression of SIGIRR in normal prostate, benign prostatic hyperplasia (BPH), and prostate cancer (PCa) has yet to be investigated. The purpose of this study was to characterize SIGIRR protein expression in human prostate tissues.
Methods: Nuclear and cytoplasmic SIGIRR expression were quantified in glandular prostate tissue using immunohistochemistry and multispectral imaging. Expression was compared between tumor-adjacent normal prostate (n=48 patients), BPH (n=24), high-grade prostatic intraepithelial neoplasia (HGPIN; n=25), PCa (n=73), and metastases (n=22), and SIGIRR expression was evaluated in relation to clinico-pathological features of PCa (Gleason score, pathological stage, tumor volume, surgical margin status, serum PSA). Kaplan-Meier analysis and Cox proportional hazards regression was used to investigate the association of SIGIRR expression and PSA biochemical recurrence. Patient outcomes were reanalyzed in subgroupings of low Gleason score (≤6 or 3+4) and high Gleason score (4+3 and ≥8).
Results: Compared to normal prostate, cytoplasmic SIGIRR expression was similar in BPH (p=0.37), HGPIN (p=0.20), PCa (p=0.40), and metastases (p=0.31). No significant changes in nuclear SIGIRR expression were found in BPH (p=0.07), HGPIN (p=0.37), or PCa (p=0.06), but a significant decrease in expression was found in metastasis samples (p=0.04). Decreased nuclear SIGIRR expression was observed in patients with high Gleason score (4+3 and ≥8; p=0.03), but no significant changes were found in cytoplasmic SIGIRR expression (p=0.08). Both cytoplasmic and nuclear SIGIRR expression were not related to pathologic stage, tumor volume, surgical margin status, or serum PSA (p>0.05).
Nuclear SIGIRR expression (p=0.96) and cytoplasmic SIGIRR expression (p=0.89) as continuous variables were not associated with biochemical recurrence in univariable analysis when all patients were analyzed. In sub-analysis of low Gleason score patients, high cytoplasmic SIGIRR expression was associated with increased biochemical recurrence in both univariable (p=0.01) and multivariable (HR 2.31 [95% CI 1.05-5.06] p=0.04) analysis, independent of pathologic stage, tumor volume, and margin status.
Conclusions: SIGIRR predicts biochemical recurrence in patients with low Gleason score prostate cancer, but is not associated with recurrence in high Gleason score patients. These findings highlight a potential mechanistic role of NF-κB signaling specifically in low grade PCa.
