Iodine-Deficiency-Induced Long Lasting Angiogenic Reaction in Thyroid Cancers Occurs Via a Vascular Endothelial Growth Factor–Hypoxia Inducible Factor-1–Dependent, But Not a Reactive Oxygen Species–Dependent, Pathway

Thyroid ◽  
2012 ◽  
Vol 22 (7) ◽  
pp. 699-708 ◽  
Author(s):  
Anne-Catherine Gérard ◽  
Kevin Humblet ◽  
Cindy Wilvers ◽  
Sylvie Poncin ◽  
Hanane Derradji ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Iodine Deficiency ◽  
Hypoxia Inducible Factor ◽  
Vascular Endothelial ◽  
Oxygen Species ◽  
Hypoxia Inducible Factor 1 ◽  
Endothelial Growth Factor ◽  
Dependent Pathway

Apatinib Inhibits Angiogenesis in Intrahepatic Cholangiocarcinoma by Regulating the Vascular Endothelial Growth Factor Receptor-2/Signal Transducer and Activator of Transcription Factor 3/Hypoxia Inducible Factor 1 Subunit Alpha Signaling Axis

Pharmacology ◽  
2021 ◽  
pp. 1-11
Author(s):  
Man-Ping Huang ◽  
Shan-Zhi Gu ◽  
Bin Huang ◽  
Guo-Wen Li ◽  
Zheng-Ping Xiong ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Transcription Factor ◽  
Growth Factor ◽  
Intrahepatic Cholangiocarcinoma ◽  
Hypoxia Inducible Factor ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Signal Transducer ◽  
Hypoxia Inducible Factor 1 ◽  
Endothelial Growth Factor

<b><i>Introduction:</i></b> Intrahepatic cholangiocarcinoma (ICC), which is difficult to diagnose and is usually fatal due to its late clinical presentation and a lack of effective treatment, has risen over the past decades but without much improvement in prognosis. <b><i>Objective:</i></b> The study aimed to investigate the role of apatinib that targets vascular endothelial growth factor receptor-2 (VEGFR2) in ICC. <b><i>Methods:</i></b> MTT assays, cell scratch assays, and tube formation assays were used to assess the effect of apatinib on human ICC cell line (HuCCT-1) and RBE cells proliferation, migration, and angiogenic capacity, respectively. Expression of vascular endothelial growth factor (VEGF), VEGFR2, signal transducer and activator of transcription factor 3 (STAT3), pSTAT3, and hypoxia inducible factor 1 subunit alpha (HIF-1α) pathway proteins was assessed using Western blotting and mRNA expression analysis in HuCCT-1 was performed using RT-qPCR assays. The pcDNA 3.1(-)-VEGFR2 and pcDNA 3.1(-)-HIF-1α were transfected into HuCCT-1 and RBE cells using Lipofectamine 2,000 to obtain overexpressed HuCCT-1 and RBE cells. <b><i>Results:</i></b> We found that apatinib-inhibited proliferation, migration, and angiogenesis of HuCCT-1 and RBE cells in vitro in a dose-dependent manner. We also proved that apatinib effectively inhibits angiogenesis in tumor cells by blocking the expression of VEGF and VEGFR2 in these cells. In addition, we demonstrated that apatinib regulates the expression of STAT3 phosphorylation by inhibiting VEGFR2. Finally, we showed that apatinib regulates ICC angiogenesis and HIF-1α/VEGF expression via STAT3. <b><i>Conclusions:</i></b> Based on the above findings, we conclude that apatinib inhibits HuCCT-1 and RBE cell proliferation, migration, and tumor angiogenesis by inhibiting the VEGFR2/STAT3/HIF-1α axis signaling pathway. Apatinib can be a promising drug for ICC-targeted molecular therapy.

Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide

Blood ◽  
2000 ◽  
Vol 95 (1) ◽  
pp. 189-197 ◽  
Author(s):  
Hideo Kimura ◽  
Alessandro Weisz ◽  
Yukiko Kurashima ◽  
Kouichi Hashimoto ◽  
Tsutomu Ogura ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Hypoxia Inducible Factor ◽  
Vascular Endothelial ◽  
Hypoxia Response Element ◽  
Response Element ◽  
Hypoxia Response ◽  
Hypoxia Inducible Factor 1 ◽  
Endothelial Growth Factor

Abstract Nitric oxide (NO) regulates production of vascular endothelial growth factor (VEGF) by normal and transformed cells. We demonstrate that NO donors may up-regulate the activity of the human VEGF promoter in normoxic human glioblastoma and hepatoma cells independent of a cyclic guanosine monophosphate–mediated pathway. Deletion and mutation analysis of the VEGF promoter indicates that the NO-responsive cis-elements are the hypoxia-inducible factor-1 (HIF-1) binding site and an adjacent ancillary sequence that is located immediately downstream within the hypoxia-response element (HRE). This work demonstrates that the HRE of this promoter is the primary target of NO. In addition, VEGF gene regulation by NO, as well as by hypoxia, is potentiated by the AP-1 element of the gene. Our study also reveals that NO and hypoxia induce an increase in HIF-1 binding activity and HIF-1 protein levels, both in the nucleus and the whole cell. These results suggest that there are common features of the NO and hypoxic pathways of VEGF induction, while in part, NO mediates gene transcription by a mechanism distinct from hypoxia. This is demonstrated by a difference in sensitivity to guanylate cyclase inhibitors and a different pattern of HIF-1 binding. These results show that there is a primary role for NO in the control of VEGF synthesis and in cell adaptations to hypoxia. (Blood. 2000;95:189-197)

scholarly journals Retinoic Acid Is a Cofactor for Translational Regulation of Vascular Endothelial Growth Factor in Human Endometrial Stromal Cells

2010 ◽  
Vol 24 (1) ◽  
pp. 148-160 ◽  
Author(s):  
Neil Sidell ◽  
Yue Feng ◽  
Lijuan Hao ◽  
Juanjuan Wu ◽  
Jie Yu ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Vascular Endothelial Growth Factor ◽  
Retinoic Acid ◽  
Growth Factor ◽  
Stromal Cells ◽  
Vascular Endothelial ◽  
Oxygen Species ◽  
Transcriptional Activators ◽  
Endometrial Stromal Cells ◽  
Endothelial Growth Factor

Abstract Vascular endothelial growth factor (VEGF) and endometrial angiogenesis play a critical role in successful embryonic implantation. Despite many studies of the effects of estrogen and progesterone on VEGF expression, its focal regulation at the site of implantation is unknown. Retinoic acid (RA) has been reported to regulate VEGF in a variety of cell types. Because localized RA synthesis occurs within the periimplantation endometrium, we tested the possibility that RA regulates VEGF production in endometrial stromal cells. Using primary and telomerase-immortalized human endometrial stromal cells, we determined that RA alone did not alter constitutive levels of VEGF production, but markedly amplified secretion when the cells were cotreated with activators of VEGF gene transcription (12-O-tetradecanoyl phorbol-13-acetate, TPA; TGF-β; and IL-1β). Whereas TPA or TGF-β alone stimulated VEGF promoter activity and up-regulated mRNA levels, significant protein secretion was detected only after RA was added to the culture systems. Analysis of retinoids in secretory phase endometrial biopsies indicated that endogenous RA accumulated at concentrations sufficient to induce VEGF secretion. Polyribosome profile analysis showed that the addition of RA to transcriptional activators of VEGF shifted the translational suppressed VEGF mRNA transcripts into larger polyribosome complexes engaged in active translation. Although the precise mechanism(s) of the RA effect remains to be defined, it appears to be mediated by reactive oxygen species; the antioxidant N-acetylcysteine inhibited RA+TPA-stimulated secretion of VEGF by more than 80%. Together, our results demonstrate that in human endometrial stromal cells, RA can combine with transcriptional activators of VEGF to augment VEGF secretion through a translational mechanism of action mediated by reactive oxygen species. These findings suggest a link between the spatiotemporal changes of retinoid synthesis in the periimplantation stroma and the capacity to quickly up-regulate focal VEGF secretion needed to induce early angiogenic events of pregnancy.

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