MiRNA-21 mediates the antiangiogenic activity of metformin through targeting PTEN and SMAD7 expression and PI3K/AKT pathway

Luo, Mao; Tan, Xiaoyong; Mu, Lin; Luo, Yumin; Li, Rong; Deng, Xin; Chen, Ni; Ren, Mulan; Li, Yongjie; Wang, Liqun; Wu, Jianbo; Wan, Qin

doi:10.1038/srep43427

Cited by 57 publications

(45 citation statements)

References 42 publications

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“…Metabolic risk factors are known to have injurious effects on the endothelium directly through the circulation, and MetS is associated with endothelial cell dysfunction, increased endothelial injury, and reduced ability for repair (Jialal et al ). Interestingly, miR‐21 has been shown to stimulate endothelial cell migration (Luo et al ), likely via its actions on a number of targets. In order to determine the potential impacts of MetS and CRF on endothelial repair capacity via circulating factors, we tested the effects of subjects’ serum on endothelial cell migration.…”

Section: Discussionmentioning

confidence: 99%

Circulating microRNAs and endothelial cell migration rate are associated with metabolic syndrome and fitness level in postmenopausal African American women

et al. 2019

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Postmenopausal African American women are at elevated risk for metabolic syndrome (MetS), which predisposes them to cardiovascular disease and other chronic diseases. Circulating microRNAs (ci‐miR) are potential mediators of cardiometabolic diseases also impacted by cardiorespiratory fitness (CRF) level. Using real‐time quantitative PCR, we compared the expression of vascular‐related ci‐miRs (miR‐21‐5p, miR‐92a‐3p, miR‐126‐5p, miR‐146a‐5p, miR‐150‐5p, miR‐221‐3p) in sedentary, overweight/obese, postmenopausal African American women based on 1) presence ( n = 31) or absence ( n = 42) of MetS and 2) CRF level (VO 2peak ) (Very Low < 18.0 mL·kg −1 ·min −1 [ n = 31], Low = 18.0–22.0 mL·kg −1 ·min −1 [ n = 24], or Moderate >22.0 mL·kg −1 ·min −1 [ n = 18]). Endothelial migration rate in response to subjects’ serum was assessed to determine the effect of circulating blood‐borne factors on endothelial repair. Ci‐miR‐21‐5p was the only ci‐miR that differed between women with MetS compared to those without MetS (0.93 ± 0.43 vs. 1.28 ± 0.71, P = 0.03). There were borderline significant differences ( P = 0.06–0.09) in ci‐miR‐21‐5p, 126‐5p, and 221‐3p levels between the CRF groups, and these three ci‐miRs correlated with VO 2peak ( r = −0.25 to −0.28, P < 0.05). Endothelial migration rate was impaired in response to serum from women with MetS compared to those without after 16–24 h. Serum from women with Moderate CRF induced greater endothelial migration than the Very Low and Low CRF groups after 4 and 16–24 h, that was also not different from a young, healthy reference group. Ci‐miR‐21‐5p is lower in postmenopausal African American women with MetS, while ci‐miRs‐21‐5p, 126‐5p, and 221‐3p are associated with CRF. Factors which impair endothelial cell migration rate are present in serum of women with MetS, though having Moderate CRF may be protective.

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Section: Discussionmentioning

confidence: 99%

Circulating microRNAs and endothelial cell migration rate are associated with metabolic syndrome and fitness level in postmenopausal African American women

et al. 2019

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“…In our study, PTEN expression was reduced upon MTFN treatment, in line with previous studies [45,46], but this reduction was compensated following MTFN/CURC co-treatment. Cell death induction by co-treatment suggests that the co-presence of MTFN and CURC may strengthen the anti-tumor activities of PTEN via engaging several pathways and factors including miR-21 and Akt/PI3K [47]. This restriction may down-regulate or abate the insulin signaling pathway and result in insulin accumulation, insulin resistance, and hyperglycemia thereby co-promoting DM2 and BC.…”

Section: Discussionmentioning

confidence: 99%

Investigating the Inhibitory Aspects of Metformin/Curcumin Co-Treatment through Convergence of In-Silico and In-Vitro Approaches

Afzali

Nayeri

Minuchehr

et al. 2019

Preprint

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Nearly 16% of people with breast cancer (BC) have Diabetes Mellitus type 2 (DM2) and are at a higher risk of death worldwide. Their common regulatory factors and functional mechanisms can be targeted applying multi-target drugs including Metformin (MTFN) and Curcumin (CURC). In this study, we used in-silico approaches to study the potential underlying mechanisms of this co-treatment strategy on BC and DM2 in order to introduce novel therapeutic targets.The total number of 48 shared differentially expressed genes (17 up-regulated and 31 down-regulated) were identified through establishing diseases' protein-protein network and BC RNA-sequencing expression data. The integration of functional clustering and pathway analyses revealed that the most involved cellular pathways and processes are regard to cells' proliferation, death, migration, and response to external stimulus. Afterwards, the MTFN/CURC correlation and co-treatment optimization was probed through response surface methodology (RSM) based on MCF7 cell line and confirmed by MDA-MB-231. Combination index calculation by MTT viability assay proved supportive effects on both cell lines. The superior apoptotic potential of co-treatment compared to single treatments was shown on inhibition of MCF7 proliferation and induction of cell death demonstrated by cell body co-staining and flow cytometry as well as gene expression analysis via RT-PCR. Furthermore, wound-healing scratch assay showed that this co-treatment has a slightly higher effect on migration inhibition compared to single treatments.In conclusion, our study used in-silico and in-vitro approaches and introduced a potential regulatory panel between BC and DM2. We also provided a linear model and equation that show the positive relation of drugs' co-treatment. The proposed co-treatment strategy successfully controlled the biological processes under investigation. METHODS Identification and validation of overlapped DEGs between BC and DM2The STRING disease network importer of Cytoscape 3.6 was used to establish the PPI networks of BC and DM2 with ultimate number of proteins (2000 nodes) and 0.7 as the minimum interaction score. The networks were merged together to find the overlapped factors and subsequently, filtered by BC differentially expressed genes (DEGs) of The Cancer Genome Atlas (TCGA) database. TCGA database contains the RNA-sequencing (RNA-seq) expression data of 33 different types of human cancers. In this study, BC RNA-seq raw data of 224 samples (112 cancerous tissues and 112 adjacent normal ones) was downloaded and normalized using TCGAbiolinks package of R v3.5.2 software. To identify the (DEGs) the criteria of FDR < 0.05 and |logFC| > 1 were applied. Functional Annotation Clustering and Pathway AnalysisTo understand the biological meaning behind the obtained DEGs in groups, Functional Annotation Clustering tool of David 6.7 database, based on Kappa statistics and fuzzy heuristic clustering algorithms, was used to make the ontology report easier to follow [23]. Each cluster contains Gene Ont...

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“…SMAD7 and TIAM1. MiR-21 was shown to target SMAD7 in endothelial cells [39] and in colorectal cancer cells [40]. SMAD7 protects B-lymphocytes from transforming growth factor (TGF)-beta induced growth inhibition and apoptosis [41].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA High Throughput Loss-of-Function Screening Reveals an Oncogenic Role for miR-21-5p in Hodgkin Lymphoma

Yuan

Niu²,

Nolte

et al. 2018

Cell Physiol Biochem

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Background/Aims: Classical Hodgkin lymphoma (cHL) is among the most frequent lymphoma subtypes. The tumor cells originate from crippled germinal center (GC)-B cells that escaped from apoptosis. MicroRNAs (miRNAs) play important roles in B-cell maturation and aberrant expression of miRNAs contributes to the pathogenesis of cHL. Our aim was to identify oncogenic miRNAs relevant for growth of cHL using a high-throughput screening approach. Methods: A lentiviral pool of 63 miRNA inhibition constructs was used to identify miRNAs essential to cell growth in three cHL cell lines in duplicate. As a negative control we also infected cHL cell lines with a lentiviral barcoded empty vector pool consisting of 222 constructs. The abundance of individual constructs was followed over time by a next generation sequencing approach. The effect on growth was confirmed using individual GFP competition assays and on apoptosis using Annexin-V staining. Our previously published Argonaute 2 (Ago2) immunoprecipitation (IP) data were used to identify target genes relevant for cell growth / apoptosis. Luciferase assays and western blotting were performed to confirm targeting by miRNAs. Results: Four miRNA inhibition constructs, i.e. miR-449a-5p, miR-625-5p, let-7f-2-3p and miR-21-5p, showed a significant decrease in abundance in at least 4 of 6 infections. In contrast, none of the empty vector constructs showed a significant decrease in abundance in 3 or more of the 6 infections. The most abundantly expressed miRNA, i.e. miR-21-5p, showed significantly higher expression levels in cHL compared to GC-B cells. GFP competition assays confirmed the negative effect of miR-21-5p inhibition on HL cell growth. Annexin-V staining of cells infected with miR-21-5p inhibitor indicated a significant increase in apoptosis at day 7 and 9 after viral infection, consistent with the decrease in growth. Four miR-21-5p cell growth- and apoptosis-associated targets were AGO2-IP enriched in cHL cell lines and showed a significant decrease in expression in cHL cell lines in comparison to normal GC-B cells. For the two most abundantly expressed, i.e. BTG2 and PELI1, we confirmed targeting by miR-21-5p using luciferase assays and for PELI1 we also confirmed this at the protein level by western blotting. Conclusion: Using a miRNA loss-of-function high-throughput screen we identified four miRNAs with oncogenic effects in cHL and validated the results for the in cHL abundantly expressed miR-21-5p. MiR-21-5p is upregulated in cHL compared to GC-B cells and protects cHL cells from apoptosis possibly via targeting BTG2 and PELI1.

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MiRNA-21 mediates the antiangiogenic activity of metformin through targeting PTEN and SMAD7 expression and PI3K/AKT pathway

Cited by 57 publications

References 42 publications

Circulating microRNAs and endothelial cell migration rate are associated with metabolic syndrome and fitness level in postmenopausal African American women

Circulating microRNAs and endothelial cell migration rate are associated with metabolic syndrome and fitness level in postmenopausal African American women

Investigating the Inhibitory Aspects of Metformin/Curcumin Co-Treatment through Convergence of In-Silico and In-Vitro Approaches

MicroRNA High Throughput Loss-of-Function Screening Reveals an Oncogenic Role for miR-21-5p in Hodgkin Lymphoma

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