-
Tytuł:
-
Orphan nuclear receptor TR3/Nur77 biologics inhibit tumor growth by targeting angiogenesis and tumor cells.
-
Autorzy:
-
Chen C; Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Surgery of Breast and Thyroid, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, PR China.
Li Y; Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, PR China.
Hou S; Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China.
Bourbon PM; Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Qin L; Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Zhao K; Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Ye T; Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Department of Obstetrics & Gynecology, Renji Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200127, PR China.
Zhao D; Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Zeng H; Center for Vascular Biology Research and Division of Gastroenterology, Departments of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. Electronic address: .
-
Źródło:
-
Microvascular research [Microvasc Res] 2020 Mar; Vol. 128, pp. 103934. Date of Electronic Publication: 2019 Oct 23.
-
Typ publikacji:
-
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
-
Język:
-
English
-
Imprint Name(s):
-
Original Publication: New York, Academic Press.
-
MeSH Terms:
-
Neovascularization, Pathologic*
Neovascularization, Physiologic*
RNAi Therapeutics*
Neoplasms/*therapy
Nuclear Receptor Subfamily 4, Group A, Member 1/*metabolism
RNA, Small Interfering/*genetics
Animals ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Female ; Gene Expression Regulation, Neoplastic ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Nude ; Neoplasm Metastasis ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Nuclear Receptor Subfamily 4, Group A, Member 1/deficiency ; Nuclear Receptor Subfamily 4, Group A, Member 1/genetics ; RNA, Small Interfering/metabolism ; Tumor Burden ; Tumor Microenvironment ; Vascular Endothelial Growth Factor A/genetics ; Vascular Endothelial Growth Factor A/metabolism ; Xenograft Model Antitumor Assays
-
Grant Information:
-
R01 CA133235 United States CA NCI NIH HHS; R03 CA191463 United States CA NCI NIH HHS; R01 DK095873 United States DK NIDDK NIH HHS; R21 DK080970 United States DK NIDDK NIH HHS
-
Contributed Indexing:
-
Keywords: Angiogenesis; Minigenes; TR3/Nur77; Tumor; shRNA
-
Substance Nomenclature:
-
0 (NR4A1 protein, human)
0 (Nr4a1 protein, mouse)
0 (Nuclear Receptor Subfamily 4, Group A, Member 1)
0 (RNA, Small Interfering)
0 (Vascular Endothelial Growth Factor A)
0 (vascular endothelial growth factor A, mouse)
-
Entry Date(s):
-
Date Created: 20191027 Date Completed: 20200728 Latest Revision: 20200728
-
Update Code:
-
20240104
-
DOI:
-
10.1016/j.mvr.2019.103934
-
PMID:
-
31654655
-
Pathological angiogenesis is a hallmark of many diseases. Previously, we reported that orphan nuclear receptor TR3/Nur77 was a critical mediator of angiogenesis to regulate tumor growth, sepsis and skin wound healing. However, none of the TR3/Nur77 targeting molecule has been in clinical trial so far. Here, we designed and generated novel TR3 shRNAs and two minigenes that had therapeutic potential for cancer treatment. In addition to extend our previous findings that tumor growth was inhibited in Nur77 knockout mice, we found that metastasis of colorectal tumor was completely inhibited in Nur77-/- mice. Tumor masses were increased ~70% and decreased ~40% in our transgenic EC-Nur77-S mice and EC-Nur77-DN mice, in which the full-length cDNA and the dominant negative mutant of TR3/Nur77 were inducibly and specifically expressed in mouse endothelium, respectively. TR3 was highly expressed in the vasculature and tumor cells of human melanoma and colorectal cancer tissues, but not in normal tissues. The novel TR3 shRNAs and two minigenes almost completely inhibited the proliferation and migration of HUVECs and human melanoma A375sm cells. Angiogenesis induced by adenoviruses expressing VEGF and melanoma growth in mice were greatly and significantly inhibited by systemically administration of adenoviruses expressing TR3 shRNAs and two minigenes. Tumor angiogenesis and the expressions of genes associated with angiogenesis were greatly regulated in tumor tissues treated with TR3 shRNAs and minigenes. Taken together, these studies demonstrated that TR3/Nur77 was a specific therapeutic target for several human cancers by targeting both tumor cells and tumor microenvironment. These TR3/Nur77 biologics inhibit angiogenesis and tumor growth, and have translational potential.
(Copyright © 2019. Published by Elsevier Inc.)
