4.6 Article

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

Journal

FRONTIERS IN ONCOLOGY
Volume 9, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2019.01187

Keywords

YY1; angiogenesis; vascular endothelial growth factor A; transcription activation; hepatocellular carcinoma

Categories

Funding

  1. National Natural Science Funds of China [81572838, 81872374, 81703581, 81871972, 81902441]
  2. Tianjin Science and Technology Project [18PTSYJC00060]
  3. Chinese National Major Scientific and Technological Special Project for Significant New Drugs Development [2018ZX09736005, SQ2018ZX090201]
  4. National Key Research and Development Program of China [2018YFA0507203]
  5. Postdoctoral support scheme for innovative talents [BX20180150]
  6. China Postdoctoral Science Foundation [2018M640228]
  7. Fundamental Research Funds for the Central Universities, Nankai University

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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.

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