miR‐20b modulates VEGF expression by targeting HIF‐1α and STAT3 in MCF‐7 breast cancer cells

Cascio, Sandra; D’Andrea, Aleco; Ferla, Rita; Surmacz, Eva; Gulotta, Eliana; Amodeo, Valeria; Bazan, Viviana; Gebbia, Nicola; Russo, Antonio

doi:10.1002/jcp.22126

Cited by 208 publications

(167 citation statements)

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“…HIF-1α is able to be targeted by the miR-17-92 cluster, miR-424 and miR-20b (40)(41)(42). A specific group of miRNAs have been reported to be induced in response to hypoxia, at least partially via a HIF-1-dependent mechanism (16).…”

Section: Discussionmentioning

confidence: 99%

miR-376b-5p regulates angiogenesis in cerebral ischemia

Huang

Zhang

et al. 2014

Molecular Medicine Reports

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Abstract. The profile of microRNAs (miRNAs) altered following middle cerebral artery occlusion (MCAO) and miRNAs are involved in angiogenesis following cerebral ischemia. miR-376b-5p was decreased following MCAO, however, whether miR-376b-5p is important in angiogenesis remains to be elucidated. The present study was designed to identify whether miR-376b-5p is involved in angiogenesis following cerebral ischemia and to elucidate the underlying mechanisms. A rat MCAO model was established and quantitative polymerase chain reaction was performed to analyze the mRNA expression level of miR-376b-5p for 1 to 7 days. In addition, the density of microvessels and the relative mRNA and protein levels of hypoxia-inducible factor-1 α (HIF-1α), vascular endothelial growth factor A (VEGFA) and Notch1 were measured. The miR-376b-5p mimic or the miR-376b-5p inhibitor were transfected into hypoxic human umbilical vein endothelial cells (HUVECs), and the proliferation, migration and tube formation were measured. To further examine the underlying mechanisms, shRNA was transfected into cells to knock down HIF-1α, and angiogenesis and the expression of associated molecules, including HIF-1α, VEGFA and Notch1 were compared between each group. Our results demonstrated that miR-376b-5p repressed angiogenesis in vivo and in vitro, and miR-376b-5p inhibited angiogenesis in HUVECs by targeting the HIF-1α-mediated VEGFA/Notch1 signaling pathway. These findings provide new insights into angiogenesis therapy for cerebral ischemia. IntroductionStroke is a life-threatening disease with a high incidence, high disability and high mortality rate, causing heavy economic burden to society and families. Cerebral infarction accounts for 80% of the total number of strokes (1). In the pathophysiological process of cerebral infarction, the recovery of the peripheral blood supply is an important factor for nerve cell prognosis (2). The clinical treatments for cerebral infarction, include thrombolysis, anticoagulation, blood pressure regulation and microcirculation improvement. The improvement and increase of blood supply in ischemic brain tissue, particularly in the ischemic penumbra, thereby improving energy metabolism of ischemic brain cells and saving neurons is one of the fundamental purposes and fundamental approaches for the treatment of cerebral ischemia.In recent years, a series of studies have revealed that good collateral circulation is able to reduce the infarct volume and reduce the risk of cerebral infarction recurrence (3,4). Clinical studies have provided preliminary evidence that promoting collateral circulation is able to lead to an improved clinical prognosis (5). Cerebral collateral circulation is blood flow which arrives in the ischemic area through other vessels (collateral or the newly formed vascular anastomosis) when arteries in the brain suffer severe stenosis or occlusion. Therefore, angiogenesis, as an effective method to improve the blood supply to the brain, is key for improving the prognosis of patients with stroke, and has...

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Section: Discussionmentioning

confidence: 99%

miR-376b-5p regulates angiogenesis in cerebral ischemia

Huang

Zhang

et al. 2014

Molecular Medicine Reports

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“…HIF-1a can be targeted by the miR-17-92 cluster, miR-424 and miR-20b. [11][12][13] A specific group of miRNAs have been reported to be induced in response to hypoxia, at least partially via an HIF-1-dependent mechanism. 14 However, much less is known about possible effects of HIF-1 on the expression of miRNAs, and the role that this regulation may have in AML cells.…”

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confidence: 99%

HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation

et al. 2012

Cell Death Differ

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Hypoxia-inducible factor 1 (HIF-1) is a crucial transcription factor for the cellular adaptive response to hypoxia, which contributes to multiple events in cancer biology. MicroRNAs (miRNAs) are involved in almost all cellular activities such as differentiation, proliferation, and apoptosis. In this work, we use miRNA microarrays to profile miRNA expression in acute myeloid leukemia (AML) cells with inducible HIF-1a expression, and identify 19 differentially expressed miRNAs. Our study shows that HIF-1a represses the expression of miR-17 and miR-20a by downregulating c-Myc expression. These two miRNAs alleviate hypoxia and HIF-1a-induced differentiation of AML cells. More intriguingly, miR-17 and miR-20a directly inhibit the p21 and STAT3 (signal transducer and activator of transcription 3) expression, both of which can reverse miR-17/miR-20a-mediated abrogation of HIF-1a-induced differentiation. Moreover, we show in vivo that miR-20a contributes to HIF-1a-induced differentiation of leukemic cells. Taken together, our results suggest that HIF-1a regulates the miRNA network to interfere with AML cell differentiation, representing a novel molecular mechanism for HIF-1-mediated anti-leukemic action. Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcriptional factor that consists of the oxygen-sensitive alpha subunit (HIF-1a) and the constitutively expressed beta subunit (HIF-1b), is a master regulator for the cellular adaptive response to oxygen concentration. 1 Under normoxic conditions, proline residues 402 and 564 of the HIF-1a protein are hydroxylated by specific prolyl hydroxylases (PHDs) that utilize O 2 and a-ketoglutarate as co-factors. The hydroxylated HIF-1a protein is subject to ubiquitination by the E3 ubiquitin ligase von Hippel-Lindau (VHL), which leads to its degradation. In contrast, hypoxic conditions cause the accumulation of HIF-1a protein by inhibiting its hydroxylation, and subsequent ubiquitination and degradation. 2 The stabilized HIF-1a protein translocates into the nucleus, where it forms a heterodimer with HIF-1b and modulates the expression of hundreds of genes through binding to hypoxia-responsive elements (HREs; 5 0 -RCGTG-3 0 ) on their promoters. These HIF-1-targeted genes help the cell adapt to hypoxia by influencing processes such as erythropoiesis, angiogenesis, cell metabolism, growth, apoptosis, and differentiation.Intriguingly, HIF-1a has been shown to contribute to the pathogenesis and progression of multiple kinds of diseases, including cancer. 1,3 Although a hypoxic microenvironment is regarded as a hallmark of solid tumors, and hypoxia-stabilized HIF-1a protein contributes to tumor growth, angiogenesis, and metastasis, 4 several groups, including our own, have reported that HIF-1a protein can trigger acute myeloid leukemia (AML) cells to undergo differentiation through a transcription-independent mechanism, inhibiting the progression of AML. [5][6][7][8][9] MicroRNAs (miRNAs) are a distinct class of small noncoding RNAs of around 22 nucleotides in length that posttra...

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“…miRNAs have also been shown to play a role in cancer progression through the modulation of cellular adhesion, cell matrix and signaling activities (14,15). In addition, miRNAs have been shown to regulate the expression of hypoxia-related genes and of the vascular endothelial growth factor (16,17).Emerging evidence shows that deregulation of miRNAs may be a primary driver of cancer initiation and progression. The rules of Watson and Crick base-pairing guide the binding of miRNAs to their target genes.…”

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confidence: 99%

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confidence: 99%

Regression of A549 lung cancer tumors by anti-miR-150 vector

Lv¹

2011

Oncol Rep

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Abstract. microRNAs (miRNAs) have been shown to play a role in cancer. Antisense oligonucleotides can bind directly to miRNAs and block their activity, which are generally named anti-miRNAs. To suppress A549 cell proliferation in vitro and in vivo by anti-miRNAs, an anti-miR-150 expression vector (PR-ASO-150), regulated by the H1 promoter and containing a 'TTTTT' sequence following a hairpin to stop transcription, was constructed. A549 cell proliferation in vitro or in nude mice was observed after PR-ASO-150 treatment. Our results showed that miR-150 expression was inhibited and the growth inhibition rate of A549 cells was higher in the PR-ASO-150-treated group compared with the control, which indicated that PR-ASO-150 could inhibit A549 cell proliferation by regulating miR-150 expression. Following establishment of A549 cancer cell xenografts in nude mice, PR-ASO-150 was delivered intratumorally to investigate the suppressive action to tumor proliferation by regulating miR-150 expression. The results indicate that the tumor volume and weight were lower compared to the control group. Our results further showed that p53 expression was higher after tumor tissue was treated with PR-ASO-150, indicating that up-regulation of p53 contributed to the suppression to tumor growth. Our study provides a novel strategy for cancer therapy through the development of antimiRNAs.Introduction microRNAs (miRNAs) are small non-coding RNA molecules (19-22 nucleotides) that bind to mRNA in a sequence-specific manner (1). Through complementary binding to mRNA targets, each microRNA has the distinct capability to potentially regulate the expression of hundreds of genes and thereby modulates several cellular pathways including proliferation and apoptosis (2).Importantly, miRNAs play critical roles in the development and progression of several types of cancers (3,4). Dependent upon the nature of their target gene(s), miRNAs may function as tumor suppressors by down-regulating target oncogenes (e.g. let-7 and miR-15/16) or as oncogenes by negatively controlling genes that regulate tumor cell differentiation and apoptosis (e.g. miR-155 and miR-21) (5). Indeed, several miRNAs are reported to have important roles in different types of cancer, including acute myelogenous leukemia (6,7), chronic myelogenous leukemia (CML) (8-10), lung cancer (11,12), and breast cancer (13), among others. miRNAs have also been shown to play a role in cancer progression through the modulation of cellular adhesion, cell matrix and signaling activities (14,15). In addition, miRNAs have been shown to regulate the expression of hypoxia-related genes and of the vascular endothelial growth factor (16,17).Emerging evidence shows that deregulation of miRNAs may be a primary driver of cancer initiation and progression. The rules of Watson and Crick base-pairing guide the binding of miRNAs to their target genes. In order to circumvent this interaction, anti-microRNA oligonucleotides (AMOs) have been generated to directly compete with endogenous miRNAs (18). Several modifi...

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miR‐20b modulates VEGF expression by targeting HIF‐1α and STAT3 in MCF‐7 breast cancer cells

Cited by 208 publications

References 34 publications

miR-376b-5p regulates angiogenesis in cerebral ischemia

miR-376b-5p regulates angiogenesis in cerebral ischemia

HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation

Regression of A549 lung cancer tumors by anti-miR-150 vector

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