YY1 Promotes Endothelial Cell-Dependent Tumor Angiogenesis in Hepatocellular Carcinoma by Transcriptionally Activating VEGFA
YY1 Promotes Endothelial Cell-Dependent Tumor Angiogenesis in Hepatocellular Carcinoma by Transcriptionally Activating VEGFA
复制标题
YY1 通过转录激活 VEGFA 促进肝细胞癌中内皮细胞依赖性肿瘤血管生成
DOI：
10.3389/fonc.2019.01187
复制
发表时间：
2019-11-14
影响因子：
4.7
通讯作者：
Yang, Cheng
中科院分区：
文献类型：
--
作者：
Yang, Wendong;Li, Zhongwei;Yang, Cheng
肝细胞癌是一种典型的多血管实体瘤，需要新生血管才能生长。血管内皮生长因子(VEGF)是促进新生血管形成的最有效的促血管生成因子。多功能阴阳1号(YY1)参与了肝细胞癌的肿瘤恶性调控。然而，YY1与肝细胞癌内皮细胞依赖性肿瘤血管生成的关系尚不清楚。在本研究中，我们观察到YY1与肝细胞癌组织中微血管密度(MVD)和预后不良呈正相关。我们进一步发现YY1通过结合VEGFA启动子在肝细胞癌中促进VEGFA的转录活性。肝癌细胞分泌的VEGFA激活VEGFR2的磷酸化，在体外促进血管内皮细胞的管状形成、细胞迁移和侵袭，促进体内肿瘤生长和血管生成。此外，YY1上调增强了肝癌细胞对贝伐单抗的耐药性。这些结果表明，YY1通过诱导VEGFA转录在肝癌血管生成和贝伐单抗耐药中发挥重要作用，YY1可能是肝癌进展过程中抗血管生成治疗的潜在分子靶点。
Hepatocellular carcinoma (HCC) is a typical hypervascular solid tumor that requires neoangiogenesis for growth. The vascular endothelial growth factor (VEGF) is the most potent proangiogenic factor in neovascularization. The multifunctional Yin-Yang 1 (YY1) is involved in the regulation of tumor malignancy of HCC. However, the relationship between YY1 and endothelial cell-dependent tumor angiogenesis in HCC remains unclear. In this study, we observed that YY1 is positively correlated with microvessel density (MVD) and poor prognosis in HCC tissues. We further found that YY1 promotes the transcriptional activity of VEGFA by binding its promoter in HCC. The secreted VEGFA from HCC cells activates phosphorylation of VEGFR2 to promotes tube formation, cell migration, and invasion of vascular endothelial cells in vitro, and promotes tumor growth and angiogenesis in vivo. In addition, upregulation of YY1 enhanced resistance of bevacizumab in HCC cells. These results indicate that YY1 plays essential roles in HCC angiogenesis and resistance of bevacizumab by inducing VEGFA transcription and that YY1 may represent a potential molecular target for antiangiogenic therapy during HCC progression.