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Abstract：
Metabolic syndrome (MetS) is a common condition closely associated with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH). Recent meta-analyses show that MetS can be prodromal to intrahepatic cholangiocarcinoma (iCCA) development, a liver tumor with features of biliary differentiation characterized by dense extracellular matrix (ECM) deposition. Since ECM remodeling is a key event in the vascular complications of MetS, we aimed at evaluating whether MetS patients with iCCA present qualitative and quantitative changes in the ECM able to incite biliary tumorigenesis. In 22 iCCAs with MetS undergoing surgical resection, we found a significantly increased deposition of osteopontin (OPN), tenascin C (TnC), and periostin (POSTN) compared to the matched peritumoral areas. Moreover, OPN deposition in MetS iCCAs was also significantly increased when compared to iCCA samples without MetS (non-MetS iCCAs, n = 44). OPN, TnC, and POSTN significantly stimulated cell motility and the cancer-stem-cell-like phenotype in HuCCT-1 (human iCCA cell line). In MetS iCCAs, fibrosis distribution and components differed quantitatively and qualitatively from non-MetS iCCAs. We therefore propose overexpression of OPN as a distinctive trait of MetS iCCA. Since OPN stimulates malignant properties of iCCA cells, it may provide an interesting predictive biomarker and a putative therapeutic target in MetS patients with iCCA.
摘要：
代谢综合征(MetS)是与非酒精性脂肪性肝病/非酒精性脂肪性肝炎(NAFLD/NASH)密切相关的常见病。最近的荟萃分析表明，MetS可以前驱到肝内胆管癌（iCCA）的发展，具有胆管分化特征的肝肿瘤，其特征是致密的细胞外基质（ECM）沉积。由于ECM重塑是MetS血管并发症的关键事件，我们旨在评估iCCA的MetS患者是否存在能够激发胆道肿瘤发生的ECM的定性和定量变化。在接受MetS手术切除的22个iCCA中，我们发现骨桥蛋白（OPN）的沉积显着增加，生腱C(TnC),和骨膜素（POSTN）与匹配的肿瘤周围区域相比。此外，与没有MetS的iCCA样品相比，MetSiCCA中的OPN沉积也显着增加（非MetSiCCA，n=44）。OPN,TnC,和POSTN显著刺激HuCCT-1(人iCCA细胞系)中的细胞运动和癌症干细胞样表型。在MetSiCA中，纤维化分布和成分在数量和质量上与非MetSiCCAs不同。因此，我们提出OPN的过表达作为MetSiCCA的独特性状。由于OPN刺激iCCA细胞的恶性特性，它可能为患有iCCA的MetS患者提供一个有趣的预测生物标志物和一个推定的治疗靶点.
