Endothelial fatty liver binding protein 4: a new targetable mediator in hepatocellular carcinoma related to metabolic syndrome
Endothelial fatty liver binding protein 4: a new targetable mediator in hepatocellular carcinoma related to metabolic syndrome
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DOI：
10.1038/s41388-018-0597-1
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发表时间：
2019-04-18
期刊：
影响因子：
8
通讯作者：
Paradis, Valerie
中科院分区：
文献类型：
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作者：
Laouirem, Samira;Sannier, Aurelie;Paradis, Valerie
代谢综合征（MS）正在成为肝细胞癌（HCC）的主要危险因素。与 MS 相关的 HCC 发展可能发生在晚期或非晚期肝纤维化中，这表明存在特定的分子途径。在这些途径中，涉及基础炎症状态和脂肪因子的产生。本研究的目的是评估脂肪酸结合蛋白 4 (FABP4) 的作用。在这项研究中，我们证明了与慢性肝病的其他危险因素相比，来自 MS 患者的人类 HCC 样本中 FABP4 的特异性过度表达，其中 FABP4 表达仅限于瘤周内皮细胞。在体外，葡萄糖、胰岛素、VEGFA 和缺氧会上调内皮 FABP4，而二甲双胍可通过 mTOR 通路抑制来逆转这种情况。 FABP4 通过上调血管生成基因特征和参与细胞周期的通路，导致细胞增殖和迁移增加，并下调 HIF1 通路，对肝癌细胞系发挥致癌作用；当存在特定的 FABP4 抑制剂 (BMS309403) 时，效果会逆转。我们展示了微泡作为内皮细胞和肿瘤细胞之间 FABP4 载体的作用。在体内，BMS309403 显着降低异位和原位异种移植小鼠模型中的肿瘤生长。总之，本研究证明了肝内皮细胞通过 FABP4 在与 MS 相关的 HCC 中发挥新的致癌作用，并强调了二甲双胍的新抗肿瘤机制。
Metabolic syndrome (MS) is becoming the leading risk factor for hepatocellular carcinoma (HCC). HCC development related to MS may occur in advanced or non-advanced liver fibrosis, suggesting specific molecular pathways. Among these pathways, basal inflammatory state and adipokines production are involved. The aim of this study was to evaluate the role of fatty acid-binding protein 4 (FABP4). In this study, we demonstrate the specific overexpression of FABP4 in human HCC samples from patients with MS compared to other risk factors for chronic liver disease with FABP4 expression restricted to peritumoral endothelial cells. In vitro, glucose, insulin, VEGFA and hypoxia upregulated endothelial FABP4, which was reversed by metformin through mTOR pathway inhibition. FABP4 exerts oncogenic effects on hepatoma cell lines by upregulating the angiogenesis gene signature and pathways involved in the cell cycle, leading to increased cell proliferation and migration, and downregulating HIF1 pathway; effects were reversed in the presence of a specific FABP4 inhibitor (BMS309403). We showed the role of microvesicles as FABP4 vectors between endothelial and tumor cells. In vivo, BMS309403 significantly reduces tumor growth in heterotopic and orthotopic xenografted mice model. In conclusion, this study demonstrates the emerging oncogenic role of liver endothelial cells through FABP4 in HCC related to MS, and highlights new anti-neoplastic mechanism of metformin.