Expression of Neutral Endopeptidase, Endothelin-1, and Nuclear Factor Kappa B in Prostate Cancer: Interrelations and Associations with Prostate-Specific Antigen Recurrence after Radical Prostatectomy
Objective. To study the impact of the neutral endopeptidase (NEP)/neuropeptides (NPs) axis and nuclear factor kappa B (NFκB) as predictors of prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP). Patients and Methods. 70 patients with early-stage PC were treated with RP and their tumor samples were evaluated for expression of NEP, endothelin-1 (ET-1) and NFκB (p65). Time to PSA recurrence was correlated with the examined parameters and combined with preoperative PSA level, Gleason score, pathological TNM (pT) stage, and surgical margin (SM) assessment. Results and Limitations. Membranous expression of NEP ( ), cytoplasmic ET-1 ( ), and cytoplasmic NFκB ( ) were correlated with time to PSA relapse. NEP was associated with ET-1 ( ) and NFκB ( ). ET-1 was also correlated with NFκB ( ). NEP expression ( ), pT stage ( ), and SMs ( ) were independent predictors of time to PSA recurrence. Conclusions. There seems to be a clinical model of NEP/NPs and NFκB pathways interconnection, with their constituents following inverse patterns of expression in accordance with their biological roles and molecular interrelations. 1. Introduction Neuropeptides (NPs) constitute a family of potent vasoconstrictor peptides with mitogenic properties relevant to carcinogenesis. Endothelin-1 (ET-1) is a major representative, consistently implicated in prostate cancer (PC) progression through induction of proliferation of PC cells in vitro, while in vivo, increased ET-1 levels were detected in plasma and tissue specimens from patients with castrate-resistant PC [1–3]. The enzyme responsible for cleavage and inactivation of ET-1 and other bioactive NPs is neutral endopeptidase (NEP or CD10). NEP is a cell surface peptidase normally expressed by various tissues, including prostate [4, 5] but its loss of expression has been correlated with tumor progression to castration resistance by allowing NPs growth-promoting effects [6]. Nuclear factor kappa B (NFκB) is a transcription factor known for its prosurvival and antiapoptotic roles in various types of neoplasia. The most studied form of NFκB is the heterodimer formed by the p50 and RelA (p65) proteins. Emerging preclinical evidence implicates NFκB in growth, survival, angiogenesis, and metastatic progression of PC cells [7, 8]. Constitutive activation of NFκB has been detected in castrate-resistant PC xenografts and in PC tissues [9]. Since the continuously increasing list of prognostic biomarkers candidate for clinical use in PC and given the central role played by the NEP/NPs and NFκB pathways in PC progression,
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