YY1 Promotes Endothelial Cell-Dependent Tumor Angiogenesis in Hepatocellular Carcinoma by Transcriptionally Activating VEGFA.

Wendong Yang,Huihui An,Yan Zhu,Shijiao Cai,Shuang Chen,Cheng Yang,Tao Sun,Zhongwei Li,Rong Qin,Jing Meng,Xiaorui Wang,Yantao Liu,Yule Wang

doi:10.3389/fonc.2019.01187

Abstract

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.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most frequent cancer in the world and the fourth leading cause of cancer-related death [1]
Human umbilical vein endothelial cells (HUVECs) co-cultured with conditioned HCC cells or cultured with conditioned medium from HCC cells, and secreted VEGFA from HCC cells promoted tube formation, migration and invasion of HUVECs in vitro. These results showed that the exogenous overexpression of Yin-Yang 1 (YY1) in HCC cells increased the secretion of VEGFA and continued to activate the VEGFR signaling pathway in endothelial cells
Analysis of the clinical stage and pathological grade in LIHC cases of TCGA database showed that YY1 expression is a risk factor that determines the survival of HCC patients

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most frequent cancer in the world and the fourth leading cause of cancer-related death [1]. VEGFA is an important angiogenic factor secreted by both cancer cells and stromal infiltrating cells [10, 11]. It is involved in the regulation of metastasis of many solid tumors and their neovasculature [12]. VEGFA binds to two tyrosine kinase receptors of endothelial cells: VEGF receptor-1 (VEGFR1/Flt-1) and VEGFR2 (KDR). The function of VEGFR1 remains poorly defined, and VEGFR2 mediates proliferation and survival of endothelial cell [13,14,15]. The high affinity between VEGFA and VEGFRs induces the proliferation, migration, and differentiation of vascular endothelial cells. Activated endothelial cells degrade the extracellular matrix, subsequently forming tubular structures and recruiting supporting cells to form stable vessels [17, 18]

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Conclusion