Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
Department of Pathology, School of Medicine, University of Pittsburgh, S405A-BST, 200 Lothrop Street, Pittsburgh, PA, 15261, USA.
Sci Rep. 2022 Jan 7;12(1):206. doi: 10.1038/s41598-021-04358-6.
Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease characterized by progressive inflammation and fibrosis of the bile ducts. We have previously demonstrated the importance of Wnt/β-catenin signaling in mouse models of PSC. In this study, we wished to determine the clinical relevance of β-catenin localization in patient samples. In livers explanted from patients diagnosed with PSC, the majority (12/16; 75%) lacked β-catenin protein expression. Biopsies from patients post-transplant were classified as recurrent or non-recurrent based on pathology reports and then scored for β-catenin activation as a function of immunohistochemical localization. Despite lack of statistical significance, patients with recurrent primary disease (n = 11) had a greater percentage of samples with nuclear, transcriptionally active β-catenin (average 58.8%) than those with no recurrence (n = 10; 40.53%), while non-recurrence is correlated with β-catenin staining at the cell surface (average 52.63% for non-recurrent vs. 27.34% for recurrent), as determined by three different methods of analysis. β-catenin score and years-to-endpoint are both strongly associated with recurrence status (p = 0.017 and p = 0.00063, respectively). Finally, there was significant association between higher β-catenin score and increased alkaline phosphatase, a marker of biliary injury and disease progression. Thus, β-catenin expression and activation changes during the progression of PSC, and its localization may be a useful prognostic tool for predicting recurrence of this disease.
原发性硬化性胆管炎 (PSC) 是一种罕见的慢性胆汁淤积性肝病，其特征为胆管进行性炎症和纤维化。我们之前已经证明了 Wnt/β-连环蛋白信号通路在 PSC 小鼠模型中的重要性。在这项研究中，我们希望确定β-连环蛋白定位在患者样本中的临床相关性。在从诊断为 PSC 的患者中移植的肝脏中，大多数（12/16；75%）缺乏β-连环蛋白蛋白表达。根据病理报告，将移植后的患者活检分为复发或非复发，并根据免疫组织化学定位对β-连环蛋白激活进行评分。尽管没有统计学意义，但原发性疾病复发的患者（n=11）具有核转录活性β-连环蛋白（平均 58.8%）的样本比例大于无复发的患者（n=10；40.53%），而非复发与β-连环蛋白在细胞表面的染色相关（非复发的平均为 52.63%，复发的为 27.34%），这是通过三种不同的分析方法确定的。β-连环蛋白评分和到达终点的时间都与复发状态密切相关（p=0.017 和 p=0.00063）。最后，β-连环蛋白评分与碱性磷酸酶的升高有显著相关性，碱性磷酸酶是胆汁淤积和疾病进展的标志物。因此，β-连环蛋白的表达和激活在 PSC 的进展过程中发生变化，其定位可能是预测这种疾病复发的有用预后工具。
