Data_Sheet_1_YY1 Promotes Endothelial Cell-Dependent Tumor Angiogenesis in Hepatocellular Carcinoma by Transcriptionally Activating VEGFA.pdf

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.

肝细胞癌（HCC）是一种典型的血管过度丰富的实体瘤，其生长依赖于新生血管的形成。血管内皮生长因子（VEGF）是新生血管形成中最有效的促血管生成因子。多功能性的阴阳1（YY1）参与调节HCC的肿瘤恶性程度。然而，YY1与HCC中内皮细胞依赖性肿瘤血管生成之间的关系尚不明确。在本研究中，我们观察到YY1与HCC组织中微血管密度（MVD）和不良预后呈正相关。我们进一步发现，YY1通过结合HCC中的启动子来促进VEGFA的转录活性。由HCC细胞分泌的VEGFA通过激活VEGFR2的磷酸化，在体外促进血管内皮细胞的管形成、细胞迁移和侵袭，并在体内促进肿瘤生长和血管生成。此外，YY1的上调增强了贝伐珠单抗在HCC细胞中的抗药性。这些结果表明，YY1通过诱导VEGFA的转录在HCC血管生成和贝伐珠单抗耐药性中发挥关键作用，YY1可能代表HCC进展过程中抗血管生成治疗的潜在分子靶点。