Nuclear receptor COUP-TFII controls pancreatic islet tumor angiogenesis by regulating vascular endothelial growth factor/vascular endothelial growth factor receptor-2 signaling.
The significance of angiogenesis in cancer biology and therapy is well established. In this study, we used the prototypical RIP-Tag model of multistage pancreatic islet tumorigenesis to show that the nuclear receptor COUP-TFII is essential to regulate the balance between pro- and anti-angiogenic molecules that influence the angiogenic switch in cancer. Conditional ablation of COUP-TFII in the tumor microenvironment severely compromised neoangiogenesis and lymphangiogenesis during pancreatic tumor progression and metastasis. We found that COUP-TFII plays a cell-autonomous role in endothelial cells to control blood vessel sprouting by regulating cell proliferation and migration. Mechanistic investigations revealed that COUP-TFII suppressed vascular endothelial growth factor (VEGF)/VEGF receptor-2 (VEGFR-2) signaling by transcriptionally repressing the expression of VEGFR-1, thereby curtailing a central angiogenic driver of vascular growth. Taken together, our results implicate COUP-TFII as a critical factor in tumor angiogenesis through regulation of VEGF/VEGFR-2 signaling, suggesting COUP-TFII as a candidate target for antiangiogenic therapy.
Qin
Jun
J
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Chen
Xinpu
X
Yu-Lee
Li-Yuan
LY
Tsai
Ming-Jer
MJ
Tsai
Sophia Y
SY
D000818:Animals; D015153:Blotting, Western; D051837:COUP Transcription Factor II / Q000037:antagonists & inhibitors / Q000502:physiology*; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004729:Endothelium, Lymphatic / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D020690:GTPase-Activating Proteins / Q000502:physiology; D006801:Humans; D007124:Immunoenzyme Techniques; D007231:Infant, Newborn; D019426:Integrases / Q000378:metabolism; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000473:pathology* / Q000517:prevention & control; D011506:Proteins / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D022661:RNA, Untranslated; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
D051837:COUP Transcription Factor II; D020690:GTPase-Activating Proteins; C110853:Gt(ROSA)26Sor non-coding RNA, mouse; C497587:Nr2f2 protein, mouse; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D022661:RNA, Untranslated; C490620:Ralbp1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; C045073:Cre recombinase; D019426:Integrases