Knockdown of growth factor receptor bound protein 7 suppresses angiogenesis by inhibiting the secretion of vascular endothelial growth factor A in ovarian cancer cells

Bioengineered. 2021 Dec;12(2):12179-12190. doi: 10.1080/21655979.2021.2005225.

Abstract

Growth factor receptor bound protein 7 (GRB7) plays an important role in regulating the growth and metastasis of ovarian cancer. Angiogenesis is the basis for the growth, invasion, and metastasis of malignant tumors. In the current study, we aimed to determine whether GRB7 plays a role in regulating angiogenesis in ovarian cancer. Immunohistochemistry on tissue microarray showed that GRB7 and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) protein expression were positively correlated in ovarian cancer tissues. GRB7 knockdown suppressed vascular endothelial growth factor A (VEGFA) expression and reduced VEGFA secretion. The effects of GRB7-silenced SKOV-3 cells on human umbilical vein endothelial cells (HUVECs) were evaluated using a transwell cell co-culture model, which showed that knockdown of GRB7 in SKOV-3 cells suppressed HUVEC proliferation, migration, invasion, and tube formation. Moreover, knockdown of GRB7 in SKOV-3 cells downregulated the expression of proteins associated with angiogenesis, including vascular endothelial growth factor receptor-2 (VEGFR2), mitogen-activated protein kinase kinase 1 (MAP2K1/MEK1), extracellular signal-regulated kinases 1 and 2 (ERK1/2), notch receptor 1 (NOTCH1), and delta-like canonical Notch ligand 4 (DLL4) in HUVECs. In conclusion, knockdown of GRB7 in ovarian cancer cells is an attractive potential therapeutic target for the suppression of angiogenesis in ovarian cancer. GRB7 may regulate angiogenesis through VEGFA/VEGFR2 signaling and its downstream pathways.

Keywords: GRB7; HUVECS; Ovarian cancer; angiogenesis; co-culture.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Female
  • GRB7 Adaptor Protein / metabolism*
  • Gene Knockdown Techniques*
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Neovascularization, Pathologic / metabolism*
  • Ovarian Neoplasms / blood supply*
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Platelet Endothelial Cell Adhesion Molecule-1
  • Vascular Endothelial Growth Factor A
  • GRB7 Adaptor Protein

Grants and funding

This study was supported by the Guangzhou Women and Children’s Medical enter/Guangzhou Institute of Pediatrics (Grant No. YIP-2019-020 and YIP-2019-030), and the National Natural Science Foundation of China (Grant No. 81901491).