Inhibition of miR-7 promotes angiogenesis in human umbilical vein endothelial cells by upregulating VEGF via KLF4

Li, Yi-Ze; Wen, Lu; Xu, Wei; Wang, Qianrong; Xu, Lina; Zhang, Hongmei; Li, Wenchao

doi:10.3892/or.2016.4912

Cited by 26 publications

(19 citation statements)

References 33 publications

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“…Many of these transcriptional regulators are involved in the control of vegfa expression in higher vertebrates 35–39 . Amongst those, foxo3 (Forkhead box o3) , a transcriptional repressor of vegfa in cancer cells 25,26 , and klf4 (Krüppel-like factor 4) , a transcriptional activator of vegfa in endothelial cells and a regulator of metastatic processes 27,28 , are known to exert their functions through direct binding to the VegfA promoter 25,27 . In Xenopus somites, their expression is respectively repressed and activated by Etv6 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To allow vegfa expression, Etv6 directly represses foxo3 , a known transcriptional repressor of VegfA in cancer cells 25,26 , thus participating in a double negative gate. Unexpectedly, Etv6 also directly activates expression of klf4 , a known activator of VegfA in endothelial cells and a regulator of metastatic processes 27,28 . Consistent with a feed-forward loop mechanism, Etv6 also binds the vegfa promoter through a Klf4-dependent mechanism.…”

Section: Introductionmentioning

confidence: 99%

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Etv6 activates vegfa expression through positive and negative transcriptional regulatory networks in Xenopus embryos

Rispoli

Patient

et al. 2019

Nat Commun

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VEGFA signaling controls physiological and pathological angiogenesis and hematopoiesis. Although many context-dependent signaling pathways downstream of VEGFA have been uncovered, vegfa transcriptional regulation in vivo remains unclear. Here, we show that the ETS transcription factor, Etv6, positively regulates vegfa expression during Xenopus blood stem cell development through multiple transcriptional inputs. In agreement with its established repressive functions, Etv6 directly inhibits expression of the repressor foxo3 , to prevent Foxo3 from binding to and repressing the vegfa promoter. Etv6 also directly activates expression of the activator klf4 ; reflecting a genome-wide paucity in ETS-binding motifs in Etv6 genomic targets, Klf4 then recruits Etv6 to the vegfa promoter to activate its expression. These two mechanisms (double negative gate and feed-forward loop) are classic features of gene regulatory networks specifying cell fates. Thus, Etv6’s dual function, as a transcriptional repressor and activator, controls a major signaling pathway involved in endothelial and blood development in vivo.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Etv6 activates vegfa expression through positive and negative transcriptional regulatory networks in Xenopus embryos

Rispoli

Patient

et al. 2019

Nat Commun

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“…Chang et al reported that miR-7 inhibited the tumorigenesis and stemness of prostate cancer via repressing KLF4/PI3K/Akt/p21 pathway [ 41 ]. On the other hand, inhibition of miR-7 was shown to promote angiogenesis in human umbilical vein endothelial cells by up-regulating VEGF via KLF4 [ 22 ]. Consistent with these observations, our data suggested that inhibitory effect on KLF4 expression of miR-7 was significantly mitigated by TINCR in breast cancer via competitive mechanism.…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of ceRNA TINCR by SP1 contributes to tumorigenesis in breast cancer

Liu

et al. 2018

BMC Cancer

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BackgroundAssembling evidences suggested that aberrant expression of tissue differentiation-inducing non-protein coding RNA (TINCR) intimately associated with variety of human cancer. However, the expression pattern and involvement of TINCR in breast cancer has not been fully investigated. Here we set out to analyze expression of TINCR in breast cancer and elucidate its mechanistic involvement in tumor incidence and progression.MethodsThe expression of TINCR was determined by q-PCR. SP1 binding sites were analyzed by ChIP-qPCR. The relative transcription activity was measured with luciferase reporter assay. Cell viability was measured with CCK-8 method. Clonogenic capacity was evaluated by soft agar assay. Cell apoptosis was analyzed by Annexin V/7-AAD staining. The migration and invasion were determined by trans-well assay and wound healing. The tumor growth in vivo was evaluated in xenograft mice model. Protein expression was quantified by immunoblotting.ResultsTINCR was aberrantly up-regulated by SP1, which in turn stimulated cell proliferation, anchorage-independent growth and suppressed cell apoptosis in breast cancer. TINCR silencing significantly suppressed migration and invasion in vitro and xenograft tumor growth in vivo. Mechanistically, TINCR modulated KLF4 expression via competing with miR-7, which consequently contributed to its oncogenic potential. MiR-7 inhibition severely compromised TINCR silencing-elicited tumor repressive effects.ConclusionOur data uncovered a crucial role of TINCR-miR-7-KLF4 axis in human breast cancer.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4255-3) contains supplementary material, which is available to authorized users.

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“…If extrapolated to the in-vivo situation, increased placental miR-10 in IUGR placentas may reflect increased E-cadherin ensuring maturation of cell adhesions towards premature trophoblastic terminal differentiation rather than proliferation, underlying the small sized placentas. On the other hand, KLF4 , a nuclear transcription factor, has been shown to play a number of regulatory roles, including in immune activation, cell growth, and in particular, angiogenesis [66–68]. Inhibition of miR-10b led to up-regulation of KLF4 in vitro suggesting that KLF4 suppression as a result of up-regulation of miR-10b in human IUGR placentas in-vivo.…”

Section: Discussionmentioning

confidence: 99%

Differential microRNA expression in human placentas of term intra-uterine growth restriction that regulates target genes mediating angiogenesis and amino acid transport

et al. 2017

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Placental insufficiency leading to intrauterine growth restriction (IUGR) demonstrates perturbed gene expression affecting placental angiogenesis and nutrient transfer from mother to fetus. To understand the post-transcriptional mechanisms underlying such placental gene expression changes, our objective was to identify key non-coding microRNAs that express biological function. To this end, we initially undertook microarrays targeting microRNAs in a small sub-set of placentas of appropriate (AGA) versus small for gestational age (SGA) weight infants, and observed up-regulation of 97 miRs and down-regulation of 44 miRs in SGA versus AGA. In a larger cohort of samples (AGA, n = 21; SGA, n = 11; IUGR subset, n = 5), we validated by qRT-PCR differential expression of three specific microRNAs (miR-10b, -363 and -149) that target genes mediating angiogenesis and nutrient transfer. Validation yielded an increase in miR-10b and -363 expression of ~2.5-fold (p<0.02 each) in SGA versus AGA, and of ~3-fold (p<0.005) in IUGR versus AGA, with no significant change despite a trending increase in miR-149. To further establish a cause-and-effect paradigm, employing human HTR8 trophoblast cells, we assessed the effect of nutrient deprivation on miR expression and inhibition of endogenous miRs on target gene expression. In-vitro nutrient deprivation (~50%) increased the expression of miR-10b and miR-149 by 1.5-fold (p<0.02) while decreasing miR-363 (p<0.0001). Inhibition of endogenous miRs employing antisense sequences against miR-10b, -363 and -149 revealed an increase respectively in the expression of the target genes KLF-4 (transcription factor which regulates angiogenesis), SNAT1 and 2 (sodium coupled neutral amino acid transporters) and LAT2 (leucine amino acid transporter), which translated into a similar change in the corresponding proteins. Finally to establish functional significance we performed dual-luciferase reporter assays with 3’-insertion of miR-10b alone and observed a ~10% reduction in the 5’-luciferase activity versus the control. Lastly, we further validated by microarray and employing MirWalk software that the pathways and target genes identified by differentially expressed miRs in SGA/IUGR compared to AGA are consistent in a larger cohort. We have established the biological significance of various miRs that target common transcripts mediating pathways of importance, which are perturbed in the human IUGR placenta.

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Inhibition of miR-7 promotes angiogenesis in human umbilical vein endothelial cells by upregulating VEGF via KLF4

Cited by 26 publications

References 33 publications

Etv6 activates vegfa expression through positive and negative transcriptional regulatory networks in Xenopus embryos

Etv6 activates vegfa expression through positive and negative transcriptional regulatory networks in Xenopus embryos

Up-regulation of ceRNA TINCR by SP1 contributes to tumorigenesis in breast cancer

Differential microRNA expression in human placentas of term intra-uterine growth restriction that regulates target genes mediating angiogenesis and amino acid transport

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