Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome.
Department of Biosciences and Territory, University of Molise, Pesche (IS).
Eur J Histochem. 2020 Oct 19;64(4):3156. doi: 10.4081/ejh.2020.3156.
Cholangiocarcinoma (CCA) represents the second most common primary hepatic malignancy and originates from the neoplastic transformation of the biliary cells. The intrahepatic subtype includes two morpho-molecular forms: large-duct type intrahepatic CCA (iCCA) and small-duct type iCCA. Iron is fundamental for the cellular processes, contributing in tumor development and progression. The aim of this study was to evaluate iron uptake, storage, and efflux proteins in both lipopolysaccharide-inflamed small and large cholangiocytes as well as in different iCCA subtypes. Our results show that, despite an increase in interleukin-6 production by both small and large cholangiocytes, ferroportin (Fpn) was decreased only in small cholangiocytes, whereas transferrin receptor-1 (TfR1) and ferritin (Ftn) did not show any change. Differently from in vitro models, Fpn expression was increased in malignant cholangiocytes of small-duct type iCCA in comparison to large-duct type iCCA and peritumoral tissues. TfR1, Ftn and hepcidin were enhanced, even if at different extent, in both malignant cholangiocytes in comparison to the surrounding samples. Lactoferrin was higher in large-duct type iCCA in respect to small-duct type iCCA and peritumoral tissues. These findings show a different iron handling by inflamed small and large cholangiocytes, and small and large-duct type iCCA. The difference in iron homeostasis by the iCCA subtypes may have implications for the tumor management.
胆管癌（CCA）是第二大常见的原发性肝恶性肿瘤，起源于胆管细胞的肿瘤性转化。肝内型包括两种形态-分子形式：大导管型肝内 CCA（iCCA）和小胆管型 iCCA。铁对于细胞过程至关重要，有助于肿瘤的发生和发展。本研究旨在评估脂多糖诱导的小胆管和大胆管细胞以及不同 iCCA 亚型中铁的摄取、储存和外排蛋白。我们的结果表明，尽管小胆管和大胆管细胞的白细胞介素-6 产生增加，但铁蛋白（Fpn）仅在小胆管细胞中减少，而转铁蛋白受体-1（TfR1）和铁蛋白（Ftn）没有任何变化。与体外模型不同的是，与大导管型 iCCA 和肿瘤周围组织相比，小导管型 iCCA 中的恶性胆管细胞中 Fpn 表达增加。TfR1、Ftn 和hepcidin 在恶性胆管细胞中均增强，尽管程度不同。与小导管型 iCCA 和肿瘤周围组织相比，大导管型 iCCA 中的乳铁蛋白水平更高。这些发现表明，炎症小胆管和大胆管细胞以及小胆管和大导管型 iCCA 中铁的处理方式不同。iCCA 亚型中铁稳态的差异可能对肿瘤的治疗有影响。
