FGF15/19 信号的上调促进了脂肪肝背景下的肝细胞癌。

Up-regulation of FGF15/19 signaling promotes hepatocellular carcinoma in the background of fatty liver.

机构信息

Department of Hepatology, Cancer Center, The First Hospital of Jilin University, No. 71. Xinmin Street, Changchun, 130021, Jilin, China.

Division of Surgical Oncology, Department of Surgery, School of Medicine, University of Louisville, 511 S Floyd ST MDR Bldg Rm326A, Louisville, KY, 40202, USA.

出版信息

J Exp Clin Cancer Res. 2018 Jul 4;37(1):136. doi: 10.1186/s13046-018-0781-8.

BACKGROUND

Upregulated fibroblast growth factor 19 (FGF19) expression in human hepatocellular carcinoma (HCC) specimens is associated with tumor progression and poor prognosis. Nonalcoholic steatohepatitis (NASH) patients are at high risk for malignant transformation into HCC.

METHODS

A steatohepatitis-HCC model was established in male C57L/J mice treated with N-nitrosodiethylamine (DEN) and high-fat diet (HFD). A mouse HCC cell line (Hepa1-6) and a mouse hepatocyte line (FL83B) were used to elucidate the mechanism by free fatty acids (FFA) treatment. FGF15, the mouse orthologue of FGF19, and it receptor fibroblast growth factor receptor4 (FGFR4) as well as co-receptor β-klotho were studied. FGF19 signaling was also studied in human samples of HCC with steatohepatitis.

RESULTS

HCC incidence and tumor volume were significantly increased in the DEN+HFD group compared to that in the DEN+control diet (CD) group. Increased levels of FGF15/FGFR4/β-klotho, aberrant epithelial-mesenchymal transition (EMT) and Wnt/β-catenin signaling were detected in DEN+HFD mice. Blockage of the FGF15 signal can attenuate cell migration ability and aberrant EMT and Wnt/β-catenin signaling.

CONCLUSIONS

Up-regulated FGF15/FGFR4 signaling promoted the development of HCC by activation of EMT and Wnt/β-catenin signaling in the lipid metabolic disorder microenvironment. Further investigation of FGF19/FGFR4 signaling is important for potential early diagnosis and therapeutic targeting in HCC patients.

背景

在人肝癌（HCC）标本中，成纤维细胞生长因子 19（FGF19）的表达上调与肿瘤进展和预后不良有关。非酒精性脂肪性肝炎（NASH）患者发生 HCC 恶性转化的风险较高。

方法

用 N-亚硝基二乙胺（DEN）和高脂肪饮食（HFD）处理雄性 C57L/J 小鼠建立脂肪性肝炎-肝癌模型。使用小鼠肝癌细胞系（Hepa1-6）和小鼠肝细胞系（FL83B）阐明游离脂肪酸（FFA）处理的作用机制。研究 FGF19 的鼠同源物 FGF15、成纤维细胞生长因子受体 4（FGFR4）及其共同受体β-klotho。还研究了 FGF19 信号在伴有脂肪性肝炎的 HCC 人类样本中的作用。

结果

与 DEN+对照饮食（CD）组相比，DEN+HFD 组 HCC 的发生率和肿瘤体积显著增加。在 DEN+HFD 小鼠中检测到 FGF15/FGFR4/β-klotho 水平升高、上皮-间质转化（EMT）和 Wnt/β-catenin 信号异常。阻断 FGF15 信号可以减弱细胞迁移能力和异常的 EMT 和 Wnt/β-catenin 信号。