Neuropilin-2 mediates lymphangiogenesis of colorectal carcinoma via a VEGFC/VEGFR3 independent signaling
Neuropilin-2 mediates lymphangiogenesis of colorectal carcinoma via a VEGFC/VEGFR3 independent signaling
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Neuropilin-2 通过 VEGFC/VEGFR3 独立信号传导介导结直肠癌的淋巴管生成。
DOI：
10.1016/j.canlet.2014.12.046
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发表时间：
2015-03-28
期刊：
影响因子：
9.7
通讯作者：
Liang, Hou-Jie
中科院分区：
文献类型：
--
作者：
Ou, Juan-Juan;Wei, Xing;Liang, Hou-Jie
淋巴管生成在结直肠癌的淋巴转移中起重要作用，但结直肠癌淋巴管生成的潜在机制在很大程度上仍不清楚。我们先前已经证明Semaphorin-3F(SEMA3F)与结直肠癌转移密切相关，而SEMA3F的受体--Neuropilin-2(NRP2)最初被描述为参与神经发育的轴突导向化学脉冲剂，已被认为通过作为VEGFR3的专有辅助受体协同增强VEGF-C的活性来促进淋巴管生成。我们目前的研究表明，在结直肠癌中，肿瘤相关淋巴管内皮细胞(LECs)的NRP2表达水平与肿瘤淋巴管密度显著相关。在体外，晶状体上皮细胞中NRP2的激活通过调节细胞骨架极性的重排，极大地促进了其迁移、发芽和小管形成能力。体内模型进一步表明，在SEMA3F基因敲除的CRC细胞产生的异种移植瘤中，NRP2在肿瘤相关的LEC中被大量激活，导致肿瘤淋巴管生成显著增加。进一步的证据表明，结直肠癌细胞通过整合素α9β1/FAK/Erk通路非依赖的VEGF-C/VEGFR3信号通路，诱导LECs中NRP2的激活，从而促进肿瘤淋巴管的生成。我们的研究首次揭示了NRP2介导的淋巴管生成的新的分子机制，提示NRP2可能成为预防癌淋巴转移的潜在治疗靶点。(C)2014爱思唯尔爱尔兰有限公司。保留所有权利。
Lymphangiogenesis critically contributes to the lymphatic metastasis of colorectal carcinomas (CRCs), but the underlying mechanism of CRC lymphangiogenesis remains largely elusive. We have previously demonstrated that Semaphorin-3F (SEMA3F) is critically involved in CRC metastasis, and the receptor of SEMA3F, neuropilin-2 (NRP2), originally described as an axon guiding chemorepulsant implicated in nerve development, has been suggested in promoting lymphangiogenesis via acting as an obligate co-receptor of VEGFR3 cooperatively enhancing the activity of VEGF-C. Our present study revealed that in colorectal carcinomas, NRP2 expression levels of tumor-associated lymphatic endothelial cells (LECs) are significantly correlated with the density of tumor lymphatic vessels. In vitro, activation of NRP2 in LECs substantially facilitates their migration, sprouting, and tubulogenesis capacity via regulating the rearrangement of cytoskeleton polarity. In vivo model further showed that in the xenografts generated from SEMA3F knockdown CRC cells, NRP2 is substantially activated in tumor-associated LECs, resulting in a significantly increased tumor lymphangiogenesis. Further evidence demonstrated that CRC cell induces the activation of NRP2 in LECs to promote tumor lymphangiogenesis via integrin alpha 9 beta 1/FAK/Erk pathway independent VEGF-C/VEGFR3 signaling. Our study for the first time revealed the novel molecular mechanism of NRP2-mediated-lymphangiogenesis in CRCs, suggesting NRP2 as a potential therapeutic target in preventing lymphatic metastasis of CRCs. (C) 2014 Elsevier Ireland Ltd. All rights reserved.