Metformin inhibits HaCaT cell viability via the miR-21/PTEN/Akt signaling pathway

Deng, Yue; Ma, Wenxue

doi:10.3892/mmr.2017.8364

Cited by 8 publications

(8 citation statements)

References 25 publications

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“…PTEN plays complex roles in multiple cellular processes including proliferation, survival, apoptosis, cell cycle regulation, adhesion, and migration [21,44]. 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].…”

Section: Discussionsupporting

confidence: 91%

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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Section: Discussionsupporting

confidence: 91%

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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“…Furthermore, it was also reported that the expression of PTEN was significantly higher in skeletal muscle cells with glucose-induced insulin resistance than that in normal skeletal muscle cells, and metformin significantly reduced insulin resistance by decreasing the expression levels of PTEN in these cells (54). In human keratinocyte cell lines, metformin was found to inhibit cell growth in a dose-dependent manner by inhibiting the miR-21/PTEN/AKT pathway (55). The present study showed that the increased expression levels of PTEN in PA-treated EPcs were reversed by treatment with metformin or by the overexpression of miR-130a induced by miR-130a mimics.…”

Section: Discussionmentioning

confidence: 96%

Molecular interplay between microRNA-130a and PTEN in palmitic acid-mediated impaired function of endothelial progenitor cells: Effects of metformin

Wang

Lin

et al. 2019

Int J Mol Med

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Metformin serves an important role in improving the functions of endothelial progenitor cells (EPcs). MicroRNAs (miRNAs), small non-coding RNAs, have been investigated as significant regulators of EPC vascular functions. The present study investigated the molecular crosstalk between metformin and miRNA-130a (miR-130a) in the functions of EPcs exposed to palmitic acid (PA). Isolated EPcs were treated with metformin, PA, and metformin + PA, respectively. cell counting Kit-8, Transwell and Matrigel assays were performed to detect the proliferation, migration and tube formation ability of EPcs following different treatments. The expression of miR-130a, phosphatase and tensin homolog (PTEN) and phosphorylated-AKT was analyzed by reverse transcription-quantitative polymerase chain reaction and western blotting. The specific mechanism underlying the function of metformin in EPcs was further elucidated by transfecting miR-130a mimics and inhibitor to overexpress and inhibit the expression of miR-130a in EPcs, respectively. EPcs exhibited impaired functions of proliferation (P<0.01 compared with the control), migration (P<0.01 compared with the control) and tube formation (P<0.01 compared with the control) following treatment with PA, and the expression levels of miR-130a and PTEN were decreased and increased, respectively. However, the presence of metformin, or the overexpression of miR-130a using miR-130a mimic alleviated the impairment of angiogenesis and proliferation, decreased the expression of PTEN and activated the phosphoinositide-3 kinase/AKT pathway in EPcs exposed to PA. By contrast, downregulating the expression of miR-130a with a miR-130a inhibitor reversed the metformin-mediated protection. These results demonstrate the beneficial effect of miR-130a/PTEN on EPc functions, which can be regulated by metformin. The effects of metformin on improving PA-induced EPc dysfunction are mediated by miR-130a and PTEN, which may assist in the prevention and/or treatment of diabetic vascular disease.

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“…After transfection of miR-21 mimics, metformin could reduce the expression levels of miR-21 and change the expression of downstream signaling proteins. The inhibitory effect of metformin on miR-21 has been veri ed in various tumors and endothelium [32][33][34][35][36].…”

Section: Discussionmentioning

confidence: 99%

Metformin Inhibits the Phenotypic Transformation of Aortic Vascular Smooth Muscle Cells Induced by Hyperglycemia Through Regulation of the Mir-21-mediated PTEN/pAKT/Egr-1 Pathway

Zheng¹,

Liu²,

Sun³

et al. 2021

Preprint

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Background The phenotypic transformation of arterial vascular smooth muscle cells (VSMC) is one of the key mechanisms in the formation of atherosclerotic plaque. It is unclear whether metformin can inhibit the phenotypic transformation of VSMC. In this study, we observed the effect of metformin on the phenotypic transformation of VSMC in vivo and in vitro and its mechanism.Methods Patients who underwent simple coronary artery bypass grafting (CABG) were divided into non-diabetic(non-DM) group and diabetes (DM) group according to whether diabetes was combined. The miR-21 and VSMC contractile marker protein, smooth muscle contractile protein (αSMA) and synthetic marker protein osteopontin (OPN) were isolated from the internal mammary artery.30 male, clean, and 6 week old wild type C57/BL6J mice were randomly divided into 3 groups:the control group (NC), the diabetes mellitus group (DM) and the metformin intervention group(DM+MET).Diabetic mice model was established by high-fat diet combined with low-dose streptozotocin. Metformin was given by gavage for 8 weeks.The aortic tissue from aortic root to renal artery was retained, miR-21 was determined by real-time PCR, and SMC and OPN were determined by Western Blotting (WB). In vitro, human aortic smooth muscle cells (HA-SMC) were divided into three groups: control group, HG group and HG+ group. The content of miR-21/PTEN/pAKT/Egr-1 protein was determined by WB, the migration ability was determined by MTT and scratch method.Results 1.In vivo, the expression of miR-21 and OPN in the aortic VSMC of DM petients and diabetic mice increased and the intima media thickness increased. Metformin treatment reduced the expression of miR-21 and OPN in the aorta and decreased the thickness of intima media. 2.In vitro, glucose concentration dependently upregulates the expression of miR-21 and osteopontin in HA-SMC.Conclusion Metformin can inhibit the phenotype transformation of VSMC induced by HG, which may inhibit the migration of VSMC through miR-21/PTEN/pAkt/Egr-1.

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Metformin inhibits HaCaT cell viability via the miR-21/PTEN/Akt signaling pathway

Cited by 8 publications

References 25 publications

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

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

Molecular interplay between microRNA-130a and PTEN in palmitic acid-mediated impaired function of endothelial progenitor cells: Effects of metformin

Metformin Inhibits the Phenotypic Transformation of Aortic Vascular Smooth Muscle Cells Induced by Hyperglycemia Through Regulation of the Mir-21-mediated PTEN/pAKT/Egr-1 Pathway

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