Neuropilin-1 is upregulated in hepatocellular carcinoma and contributes to tumour growth and vascular remodelling
Neuropilin-1 is upregulated in hepatocellular carcinoma and contributes to tumour growth and vascular remodelling
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DOI：
10.1016/j.jhep.2011.01.033
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发表时间：
2011-10-01
影响因子：
25.7
通讯作者：
Merkulova-Rainon, Tatyana
中科院分区：
文献类型：
--
作者：
Berge, Mathieu;Allanic, David;Merkulova-Rainon, Tatyana
背景和目标：神经纤毛蛋白-1（NRP 1）是脑信号蛋白和肝素结合促血管生成细胞因子的跨膜共受体，主要是血管内皮生长因子家族的成员。最近的研究表明，NRP 1在血管生成和许多癌症的恶性进展中起重要作用。NRP 1在肝细胞癌（HCC）发生发展中的作用尚不完全清楚。方法：我们利用人组织芯片和小鼠HCC转基因模型建立了NRP 1在HCC中表达的时空模式。为了评估靶向NRP 1治疗HCC的潜力，我们用NRP 1结合重组蛋白和VEGF-A（165）/NRP 1相互作用的竞争性抑制剂肽N治疗HCC小鼠。结果：我们证明NRP 1在人类健康活检组织和HCC样品的肝内皮细胞中表达，但在正常肝细胞中不表达。我们发现NRP 1在人肿瘤肝细胞中的表达增加与原发性HCC显著相关。使用RT-PCR，免疫印迹和免疫荧光分析，我们表明，NRP 1在转基因肝癌小鼠的肝脏表达增加与疾病的进展，在血管和肿瘤隔室。阻断NRP 1的功能与肽N导致抑制血管重塑和肿瘤肝生长在HCC mice.Conclusions：我们的研究结果表明NRP 1在HCC的生长和血管重塑中的特定作用，并强调治疗靶向NRP 1治疗HCC的可能性。(C)2011年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Neuropilin-1 (NRP1) is a transmembrane co-receptor for semaphorins and heparin-binding pro-angiogenic cytokines, principally members of the vascular endothelial growth factor family. Recent studies revealed an important role of NRP1 in angiogenesis and malignant progression of many cancers. The role of NRP1 in the development of hepatocellular carcinoma (HCC) is not completely understood.Methods: We used human tissue microarrays and a mouse transgenic model of HCC to establish the spatio-temporal patterns of NRP1 expression in HCC. To evaluate the therapeutic potential of targeting NRP1 in HCC, we treated HCC mice with peptide N, an NRP1 binding recombinant protein and competitive inhibitor of the VEGF-A(165)/NRP1 interaction.Results: We demonstrate that NRP1 is expressed in hepatic endothelial cells of both human healthy biopsies and in HCC samples, but not in normal hepatocytes. We found that increased NRP1 expression in human tumour hepatocytes is significantly associated with primary HCC. Using RT-PCR, Western blot and immunofluorescence analysis we show that NRP1 expression in the liver of transgenic HCC mice is increased with disease progression, in both vascular and tumour compartments. Blocking NRP1 function with peptide N leads to the inhibition of vascular remodelling and tumour liver growth in HCC mice.Conclusions: Our results indicate a specific role of NRP1 in HCC growth and vascular remodelling and highlight the possibility of therapeutically targeting NRP1 for the treatment of HCC. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.