MACC-1 Promotes Endothelium-Dependent Angiogenesis in Gastric Cancer by Activating TWIST1/VEGF-A Signal Pathway.
MACC-1 Promotes Endothelium-Dependent Angiogenesis in Gastric Cancer by Activating TWIST1/VEGF-A Signal Pathway.
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MACC-1 通过激活 TWIST1/VEGF-A 信号通路促进胃癌内皮依赖性血管生成
DOI：
10.1371/journal.pone.0157137
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Liao W
中科院分区：
文献类型：
--
作者：
Wang L;Zhou R;Zhao Y;Dong S;Zhang J;Luo Y;Huang N;Shi M;Bin J;Liao Y;Liao W
内皮依赖性血管生成被认为是癌症进展的关键步骤。我们之前报道了结肠癌转移相关的MACC1 （metastasis-associated in结肠癌-1）促进了胃癌（gastric cancer， GC）的血管生成模拟，但MACC1是否促进胃癌内皮依赖性血管生成以及TWIST1是否参与这一过程尚不清楚。在本研究中，我们通过免疫组织化学检测了159例I-III期胃癌患者的MACC1表达和微血管密度（MVD），并研究了TWIST1和血管内皮生长因子A （VEGF-A）在MACC1诱导的内皮依赖性血管生成中的作用，实验采用裸鼠胃癌异种移植和人脐静脉内皮细胞（HUVECs）与条件培养基共培养的过表达和干扰MACC1胃癌细胞。我们发现MACC1表达与胃癌患者MVD升高和肿瘤复发呈正相关。在GC异种移植模型中，MACC1升高MVD，上调VEGF-A的表达，加速肿瘤生长。此外，MACC1明显增加了TWIST1的表达，诱导HUVECs形成管状细胞，而TWIST1的减弱抑制了VEGF-A的蛋白表达，消除了MACC1对管状细胞形成的影响。我们的研究结果揭示了MACC1在胃癌内皮依赖性血管生成中的功能，并提出了潜在的预后和治疗价值。
Endothelium-dependent angiogenesis is thought to be a crucial step in cancer progression. We previously reported that metastasis-associated in colon cancer-1 (MACC1) contributed to the vasculogenic mimicry in gastric cancer (GC), but it remains unknown whether MACC1 promotes endothelium-dependent angiogenesis of GC and whether TWIST1 is involved in this process. In the present study, we detected MACC1 expression and microvessel density (MVD) by immunohistochemistry in 159 patients with stage I-III GC, and investigated the role of TWIST1 and vascular endothelial growth factor A (VEGF-A) in MACC1-induced endothelium-dependent angiogenesis using nude mice with GC xenografts, and human umbilical vein endothelial cells (HUVECs) that were co-cultured with conditioned media from overexpression and interference MACC1 GC cells. We found that MACC1 expression was positively correlated with an increased MVD and tumor recurrence in GC patients. In GC xenograft models, MACC1 elevated MVD and upregulated the expression of VEGF-A as well as accelerated tumor growth. In addition, MACC1 obviously increased the expression of TWIST1 and induced tube-like formation of HUVECs, whereas attenuation of TWIST1 suppressed the protein expression of VEGF-A and repealed the effect of MACC1 on tube formation. Our findings shed light on the function of MACC1 in endothelium-dependent angiogenesis of GC and suggest potential prognostic and therapeutic value.