PO.CL01.15 · 临床研究
循环Hepsin在前列腺癌中的预后意义
Prognostic implications of circulating Hepsin in prostate cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言与目的：Hepsin是一种II型跨膜丝氨酸蛋白酶，已被认为与前列腺肿瘤进展和转移相关。近期研究揭示了其蛋白水解自激活和胞外结构域脱落现象，支持其作为循环血清生物标志物的潜力。我们开发了一种定量夹心ELISA以检测非膜结合（循环）Hepsin，并评估了其在良性前列腺增生（BPH）、原发性前列腺癌以及根治性腹腔镜前列腺切除术（RALP）后生化复发（BCR）中的临床相关性。
方法：采用两株针对卵巢腹水筛选的单克隆抗体建立了一种专有ELISA，以识别天然循环Hepsin。抗体进一步使用含凝血酶切割位点的重组胞外Hepsin进行验证，以模拟自激活和脱落。检测抗体通过高质量MALDI定位于Hepsin保守性较差的非催化结构域进行表征。对一项经IRB批准的前瞻性研究（2018年至今）的数据进行回顾性分析，纳入543例接受前列腺评估的患者，并按Hepsin状态分层。使用卡方检验或Fisher精确检验比较Hepsin阳性组与阴性组之间的临床病理变量（BPH、肿瘤分期、转移）。在200例RALP患者中，采用Kaplan-Meier法和Cox回归分析无BCR生存期。
结果：543例患者中有109例（20%）为Hepsin阳性。与Hepsin阴性患者相比，阳性患者的癌症发生率高于BPH（p<0.05）、分期更晚（≥pT3a）（p<0.05）以及转移率更高（p<0.05）。Kaplan-Meier分析显示，Hepsin阳性患者的无复发生存期显著缩短（log-rank p < 0.001），Cox风险比为4.2（95% CI 2.3-7.8）。值得注意的是，循环Hepsin被确定为BCR的独立预测因子（p = 0.0001）。此外，与CAPRA-S低危且同时Hepsin阴性的患者相比，在同时具有高CAPRA-S评分的患者中，Hepsin阳性带来了附加的预后价值（p = 0.0003），相较于单独CAPRA-S高危（p = 0.0007）。
结论：本研究提供了早期证据，表明Hepsin能够识别出RALP术后BCR风险显著升高及不良病理的前列腺癌患者。这些数据凸显了对前列腺癌背景下循环Hepsin水平进行非侵入性、纵向评估的新颖作用。
查看英文原文 English abstract
Introduction and Objective: Hepsin, a type II transmembrane serine protease, has been implicated in prostate tumor progression and metastasis. Recent studies have uncovered its proteolytic auto-activation and ectodomain shedding, supporting its potential as a circulating serum biomarker. We developed a quantitative sandwich ELISA to detect non-membrane-associated (circulating) Hepsin and evaluated its clinical relevance across benign prostatic hyperplasia (BPH), primary prostate cancer, and biochemical recurrence (BCR) following radical laparoscopic prostatectomy (RALP).
Methods: A proprietary ELISA was established using two monoclonal antibodies screened against ovarian ascites to identify native circulating Hepsin. Antibodies were further validated using recombinant extracellular Hepsin containing a thrombin cleavage site, mimicking auto-activation and shedding. The detection antibody was characterized via High-Mass MALDI mapping to the poorly conserved non-catalytic domain of Hepsin. Retrospective analyses were performed on data from an IRB-approved prospective study (2018-present) including 543 patients undergoing prostate evaluation, stratified by Hepsin status. Clinicopathologic variables (BPH, tumor stage, metastasis) were compared between Hepsin-positive and -negative groups using Chi-square or Fisher's Exact tests. Among 200 RALP patients, BCR-free survival was analyzed by Kaplan-Meier and Cox regression.
Results: Hepsin positivity occurred in 109 of the 543 (20%) patients. Compared to Hepsin-negative patients, positive patients showed higher cancer incidence vs BPH (p<0.05), advanced stage (≥pT3a) (p<0.05), and metastasis (p<0.05). Kaplan-Meier analysis demonstrated significantly reduced recurrence-free survival in Hepsin-positive patients (log-rank p < 0.001), with a Cox hazard ratio of 4.2 (95% CI 2.3-7.8). Notably, circulating Hepsin was determined to be an independent predictor of BCR (p = 0.0001). Furthermore, in comparison to CAPRA-S low-risk with concurrent Hepsin-negativity, Hepsin-positivity rendered an additive prognostic potential in patients with concurrent high CAPRA-S scores (p = 0.0003) compared to CAPRA-S high alone (p = 0.0007).
Conclusions: This study provides early evidence regarding Hepsin's ability to identify prostate cancer patients harboring a significantly elevated risk of BCR and adverse pathology post-RALP. These data highlight a novel role for non-invasive, longitudinal evaluation of circulating Hepsin levels in the prostate cancer setting.
利益披露 Disclosure
T. Wadley,
Navaux, Inc Employment.
A. Cole,
TruCore Pathology g., Board of Directors, non-salaried role).
PathNet Lab Employment.
Navaux, Inc. Stock.
B. P. Johnson,
Merck Employment.
Navaux, Inc. Stock.