title: The endogenous zinc finger transcription factor, ZNF24, modulates the angiogenic potential of human microvascular endothelial cells.
abstract: We have previously identified a zinc finger transcription factor, ZNF24 (zinc finger protein 24), as a novel inhibitor of tumor angiogenesis and have demonstrated that ZNF24 exerts this effect by repressing the transcription of VEGF in breast cancer cells. Here we focused on the role of ZNF24 in modulating the angiogenic potential of the endothelial compartment. Knockdown of ZNF24 by siRNA in human primary microvascular endothelial cells (ECs) led to significantly decreased cell migration and invasion compared with control siRNA. ZNF24 knockdown consistently led to significantly impaired VEGF receptor 2 (VEGFR2) signaling and decreased levels of matrix metalloproteinase-2 (MMP-2), with no effect on levels of major regulators of MMP-2 activity such as the tissue inhibitors of metalloproteinases and MMP-14. Moreover, silencing ZNF24 in these cells led to significantly decreased EC proliferation. Quantitative PCR array analyses identified multiple cell cycle regulators as potential ZNF24 downstream targets which may be responsible for the decreased proliferation in ECs. In vivo, knockdown of ZNF24 specifically in microvascular ECs led to significantly decreased formation of functional vascular networks. Taken together, these results demonstrate that ZNF24 plays an essential role in modulating the angiogenic potential of microvascular ECs by regulating the proliferation, migration, and invasion of these cells.
authors.affiliation: *Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, USA; and Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Jia
authors.affiliation: *Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, USA; and Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Huang
authors.affiliation: *Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, USA; and Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Bischoff
authors.affiliation: *Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Boston, Massachusetts, USA; and Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA marsha.moses@childrens.harvard.edu.
authors.forename: Marsha A
authors.initials: MA
authors.lastname: Moses
mesh_terms: D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C457300:ZNF24 protein, human; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
keywords: VEGF repression; angiogenesis; transcriptional regulation