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Background: This study explores the immunohistochemical expression of protein C inhibitor (PCI) in patients with prostatic adenocarcinoma (PCa) and benign prostatic hyperplasia (BPH). Methods and Results: Our study involved 56 prostate samples morphologically diagnosed as PCa and 30 BPH samples. An immunohistochemical analysis of the PCI expression was performed. Our analysis encompassed variables including age, serum prostate-specific antigen (PSA), local and distant metastasis, PCI staining, and morphological features such as Gleason Score and Grade Group. In addition to descriptive statistics, Spearman's rank correlation test was performed. All patients with BPH had no staining or low staining for PCI. 60% of PCa patients had moderate or strong staining intensity for PCI. There was no correlation between PCI expression and clinicopathological parameters, including PCI expression and PSA, Gleason Score, and Grade Group. A negative correlation was observed between age at diagnosis and PCI expression. Conclusion: Our study did not find a statistically significant correlation between PCI and PCa. However, we report that in 60% of our PCa cases, there is a moderate and high-intensity expression for PCI.

Protein C inhibitor (PCI) maintains hemostasis by inhibiting both procoagulant and anticoagulant serine proteases, and plays important roles in coagulation, fibrinolysis, reproduction, and anti-angiogenesis. The reactive site loop of PCI traps and irreversibly inhibits the proteases like APC (activating protein C), thrombin (FIIa) and factor Xa (FXa). Previous studies on antithrombin (ATIII) had identified Tyr253 and Glu255 as functional exosites that interact and aid in the inhibition of factor IXa and FXa. Presence of exosite in PCI is not known, however a sequence comparison with the PCI from different vertebrate species and ATIII identified Glu239 to be absolutely conserved. PCI residues analogous to ATIII exosite residues were mutated to R238A and E239A. Purified variant PCI in the presence of heparin (10 μg/ml) showed a 2–4 fold decrease in the rate of inhibition of the proteases. However, the stoichiometry of inhibition of FIIa, APC, and FXa by native PCI, R238A and E239A variants were found to be close to 1.0, which also indicated the formation of stable complexes based on SDS-PAGE and western blot analysis with thrombin and APC. Our findings revealed the possible presence of an exosite in PCI that influences the protease inhibition rates. [ABSTRACT FROM AUTHOR]