Vasohibin 2 is transcriptionally activated and promotes angiogenesis in hepatocellular carcinoma
Vasohibin 2 is transcriptionally activated and promotes angiogenesis in hepatocellular carcinoma
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Vasohibin 2 被转录激活并促进肝细胞癌中的血管生成
DOI：
10.1038/onc.2012.177
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发表时间：
2013-03-28
期刊：
影响因子：
8
通讯作者：
Kondo, Y.
中科院分区：
文献类型：
--
作者：
Xue, X.;Gao, W.;Kondo, Y.
肝细胞癌（HCC）的恶性行为通常依赖于血管生成，包括生长和转移。Vasohibin 2 （VASH2）先前被确定为血管生成因子，但其在肿瘤发生中的作用尚不清楚。通过定量PCR和western blot分析，我们发现VASH2在HCC细胞和组织中过表达。利用染色质免疫沉淀法，我们检测到VASH2启动子上的组蛋白修饰，H3K4三甲基化和H3乙酰化增加，H3K27三甲基化减少，这表明表观遗传机制是导致HCC中VASH2转录失调的原因。通过siRNA敲低VASH2通过延缓细胞周期进程和增加细胞凋亡来抑制肝癌细胞系的增殖。重要的是，我们发现VASH2在培养上清中分泌，其分泌伴侣小血管hibin-binding protein （SVBP）的共表达进一步增强了VASH2的分泌。表达VASH2的HepG2细胞上清液能促进人脐静脉内皮细胞的增殖、迁移和成管，而敲低VASH2可明显抑制这些作用。在裸鼠模型的体内研究中，我们发现外源性VASH2对肿瘤生长、微血管密度和血红蛋白浓度有显著影响。进一步分析表明，vash2介导的成纤维细胞生长因子-2、血管内皮生长因子和vasohibin 1转录的增加可能是这些作用的机制。综上所述，这些数据表明，由于组蛋白修饰，VASH2在HCC细胞中异常表达，并且VASH2通过svbp介导的旁分泌机制参与HCC血管生成。这些结果表明VASH2在HCC血管生成和恶性转化中具有新的重要作用。
Hepatocellular carcinoma (HCC) typically relies on angiogenesis for its malignant behavior, including growth and metastasis. Vasohibin 2 (VASH2) was previously identified as an angiogenic factor, but its role in tumorigenesis is unknown. Using quantitative PCR and western blot analyses, we found that VASH2 is overexpressed in HCC cells and tissues. Using chromatin immunoprecipitation, we detected histone modifications at the putative VASH2 promoter, with increased H3K4 trimethylation and H3 acetylation and decreased H3K27 trimethylation, suggesting that epigenetic mechanisms are responsible for the deregulated VASH2 transcription in HCC. Knockdown of VASH2 via siRNA inhibited the proliferation of the hepatoma cell lines by delaying cell cycle progression and increasing apoptosis. Importantly, we found VASH2 secreted in the culture supernatant, and co-expression of its secretory chaperone small vasohibin-binding protein (SVBP) further enhanced VASH2 secretion. The supernatant from HepG2 cells expressing VASH2 enhanced the proliferation, migration and tube formation of human umbilical vein endothelial cells, and knockdown of VASH2 significantly inhibited these effects. In an in vivo study using a nude mouse model, we found that exogenous VASH2 significantly contributed to tumor growth, microvessel density and hemoglobin concentration in the tumors. Further analyses showed that the VASH2-mediated increase in the transcription of fibroblast growth factor-2, vascular endothelial growth factor and vasohibin 1 may be the mechanism underlying these effects. Taken together, these data indicate that VASH2 is abnormally expressed in HCC cells as a result of histone modifications and that VASH2 contributes to the angiogenesis in HCC via an SVBP-mediated paracrine mechanism. These results indicate a novel and important role for VASH2 in HCC angiogenesis and malignant transformation.