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

ABSTRACT: Metformin, an anti-diabetic drug commonly used for type 2 diabetes therapy, is associated with anti-angiogenic effects in conditions beyond diabetes. miR-21 has been reported to be involved in the process of angiogenesis. However, the precise regulatory mechanisms by which the metformin-induced endothelial suppression and its effects on miR-21-dependent pathways are still unclear. Bioinformatic analysis and identification of miR-21 and its targets and their effects on metformin-induced antiangiogenic activity were assessed using luciferase assays, quantitative real-time PCR, western blots, scratch assays, CCK-8 assays and tubule formation assays. In this study, miR-21 was strikingly downregulated by metformin in a time- and dose-dependent manner. miR-21 directly targeted the 3'-UTR of PTEN and SMAD7, and negatively regulated their expression. Overexpression of miR-21 abrogated the metformin-mediated inhibition of endothelial cells proliferation, migration, tubule formation and the TGF-β-induced AKT, SMAD- and ERK-dependent phosphorylations, and conversely, down-regulation of miR-21 aggravated metformin's action and revealed significant promotion effects. Our study broadens our understanding of the regulatory mechanism of miR-21 mediating metformin-induced anti-angiogenic effects, providing important implications regarding the design of novel miRNA-based therapeutic strategies against angiogenesis.

SUBMITTER: Luo M

PROVIDER: S-EPMC5322530 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Luo Mao M Tan Xiaoyong X Mu Lin L Luo Yulin Y Li Rong R Deng Xin X Chen Ni N Ren Meiping M Li Yongjie Y Wang Liqun L Wu Jianbo J Wan Qin Q

Scientific reports 20170223

Metformin, an anti-diabetic drug commonly used for type 2 diabetes therapy, is associated with anti-angiogenic effects in conditions beyond diabetes. miR-21 has been reported to be involved in the process of angiogenesis. However, the precise regulatory mechanisms by which the metformin-induced endothelial suppression and its effects on miR-21-dependent pathways are still unclear. Bioinformatic analysis and identification of miR-21 and its targets and their effects on metformin-induced antiangio ...[more]

PMID: 28230206

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Project description:The present study aimed to investigate the effects of microRNA (miR)?21 on osteoclastogenesis and its underlying molecular mechanisms. The expression levels of tartrate?resistant acid phosphatase (TRAP) and miR?21 were detected during osteoclastogenesis in receptor activator of NF??B ligand (RANKL)?induced RAW264.7 cells via reverse transcription?quantitative PCR. Bioinformatics and dual luciferase reporter assays were performed to analyze the association between miR?21 and Pten. RANKL?induced RAW264.7 cells were divided into the following groups: MiR?negative control (NC), miR?21 mimic, miR?21 inhibitor and miR?21 mimic + LY294002. The effects of miR?21 on osteoclastogenesis and bone resorption were then detected using TRAP staining and a bone resorption assay. Pten, phosphorylated?Akt and nuclear factor of activated T cell (NFATc1) expression levels were measured by western blotting to analyze the effects of miR?21 on the PI3K/Akt signaling pathway. The present study revealed that miR?21 was upregulated during osteoclastogenesis in RANKL?induced RAW264.7 cells. Furthermore, miR?21 negatively regulated Pten. Compared with the miR?negative control (NC) group, the number of osteoclasts and the percentage of bone resorption were increased in the miR?21 mimic group, whereas they were decreased in the miR?21 inhibitor group. The number of osteoclasts and the percentage of bone resorption in the miR?21 mimic + LY294002 group were lower than in the miR?21 mimic group. Compared with the miR?NC group, the protein expression levels of Pten were decreased, whereas p?Akt and NFATc1 were increased in the miR?21 mimic group. Conversely, Pten protein expression was increased, whereas p?Akt and NFATc1 were decreased in the miR?21 inhibitor group. In the miR?21 mimic + LY294002 group, Pten protein expression was higher, and p?Akt and NFATc1 were lower than in the miR?21 mimic group. In conclusion, miR?21 is upregulated during osteoclastogenesis, and may promote osteoclastogenesis and bone resorption through activating the PI3K/Akt signaling pathway via targeting Pten.

Project description:BackgroundMetformin, a traditional first-line anti-hyperglycemic agent for diabetes, recently exhibits better antitumor effect in hepatocellular carcinoma (HCC). However, its resistance and tolerance mechanism in HCC remains largely unknown. Here, we investigated whether increased matrix stiffness attenuated the intervention effects of metformin on HCC invasion and metastasis, and explored its underlying molecular mechanism.MethodsFN-coated gel substrates with 6, 10, and 16 kPa, which simulated the stiffness of normal, fibrotic, and cirrhotic liver tissues respectively, were established to evaluate matrix stiffness-mediated effects on HCC cells. Alterations in morphology, proliferation, motility, and invasive/metastatic-associated genes (PTEN, MMP2, MMP9) of HCC cells grown on different-stiffness substrates were comparatively analyzed before and after metformin intervention. Subsequently, the underlying molecular mechanism by which higher matrix stiffness attenuates antitumor effects of metformin in HCC was further elucidated.ResultsMetformin significantly inhibited proliferation, migration, and invasion of HCC cells. Compared with the controls on lower-stiffness substrate, HCC cells grown on higher-stiffness substrate exhibited an obvious resistance to intervention effects of metformin on proliferation, migration, invasion and metastasis. High stiffness stimulation significantly activated the miR-17-5p/PTEN/PI3K/Akt signaling pathway in HCC cells via integrin β1 and in turn resulted in MMP2 and MMP9 upregulation. Meanwhile, integrin β1 knockdown or PI3K inhibitor partially reversed the activation of the above signaling molecules. For HCC cells grown on the same-stiffness substrate, metformin remarkably upregulated PTEN expression and suppressed the activation of the PI3K/Akt/MMP pathway, but no effect on integrin β1 expression. Importantly, the increase in fold of PTEN expression and decrease in folds of Akt phosphorylation level and MMP2 and MMP9 expressions in the treated HCC cells with metformin on 16-kPa stiffness substrate were evidently weakened compared with those in the controls on the 6-kPa stiffness substrate.ConclusionsIncreased matrix stiffness significantly attenuates the inhibitory effect of metformin on HCC invasion and metastasis, and a common pathway of PTEN/PI3K/Akt/MMPs activated by mechanical stiffness signal and inactivated by metformin contributes to matrix stiffness-caused metformin resistance. To the best of our knowledge, this is the first report to clarify the mechanism of metformin intervention resistance from the perspective of tumor biophysical microenvironment.

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

Publications

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

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