Martini Andrea, Prasai Kritika, Zemla Tyler J, Ahmed Fowsiyo Y, Elnagar Mamoun B, Giama Nasra H, Guzzardo Vincenza, Biasiolo Alessandra, Fassan Matteo, Yin Jun, Pontisso Patrizia, Roberts Lewis R
Department of Medicine, University of Padua, via Giustiniani 2, 35128 Padua, Italy.
Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, 200 First Street SW, Rochester, MN 55905, USA.
Cancers (Basel). 2024 Jan 3;16(1):225. doi: 10.3390/cancers16010225.
Cholangiocarcinoma (CCA), the second most common primary liver tumor, is associated with a dismal outcome, and useful prognostic markers are not currently available in clinical practice. SerpinB3, a serine protease inhibitor, was recently found to play a relevant role in malignant transformation in different cancers. The aim of the present study was to determine the expression of SerpinB3/4 in tissue and serum samples of patients with CCA in relation to clinical outcomes. SerpinB3/4 was assessed in the tissue microarrays (TMAs) of 123 surgically resected CCAs. ELISA assays were carried out in 188 patients with CCA to detect the free and IgM-linked forms of SerpinB3/4. Overall survival was analyzed in relation to SerpinB3/4 expression, and Cox models were used to identify the variables associated with survival. High levels of SerpinB3/4 (TMA score 2+/3+) were detected in 15 tumors (12.2%), characterized by a more advanced TNM stage (III/IV: 64.3% vs. 31.3%; = 0.031) and lower overall patient survival, independently of CCA subclass (intrahepatic CCA: median 1.1 (0.8-Not Estimable, NE) vs. 2.4 (1.8-3.4) years; = 0.0007; extrahepatic CCA: median 0.8 (0.2-NE) vs. 2.2 (1.5-5.4) years; = 0.011). Vascular invasion ( = 0.027) and SerpinB3/4 scores ( = 0.0016) were independently associated with mortality in multivariate analysis. Patients who had detectable free or IgM-linked SerpinB3/4 in their serum showed poorer survival (1 vs. 2.4 years, = 0.015, for free SerpinB3/4, and 1 vs. 2.6 years, = 0.0026, for SerpinB3/4-IgM). In conclusion, high levels of SerpinB3/4 in tissue and serum in CCA are associated with poor outcomes after surgery, regardless of tumor subclass.
胆管癌（CCA）是第二常见的原发性肝癌，其预后较差，目前临床实践中尚无有效的预后标志物。丝氨酸蛋白酶抑制剂SerpinB3最近被发现与不同癌症的恶性转化有关。本研究的目的是确定CCA患者组织和血清样本中SerpinB3/4的表达与临床结局的关系。在123例手术切除的CCA组织微阵列（TMA）中评估SerpinB3/4。对188例CCA患者进行酶联免疫吸附测定（ELISA），以检测SerpinB3/4的游离形式和与IgM结合的形式。分析SerpinB3/4表达与总生存期的关系，并使用Cox模型确定与生存相关的变量。在15个肿瘤（12.2%）中检测到高水平的SerpinB3/4（TMA评分2+/3+），其特征为TNM分期更晚（III/IV期：64.3%对31.3%；P = 0.031），患者总生存期更低，且与CCA亚类无关（肝内CCA：中位生存期1.1（0.8-未评估，NE）对2.4（1.8-3.4）年；P = 0.0007；肝外CCA：中位生存期0.8（0.2-NE）对2.2（1.5-5.4）年；P = 0.011）。多因素分析显示，血管侵犯（P = 0.027）和SerpinB3/4评分（P = 0.0016）与死亡率独立相关。血清中可检测到游离或与IgM结合的SerpinB3/4的患者生存期较差（游离SerpinB3/4：1年对2.4年，P = 0.015；SerpinB3/4-IgM：1年对2.6年，P = 0.0026）。总之，无论肿瘤亚类如何，CCA组织和血清中高水平的SerpinB3/4与手术后的不良结局相关。
