Reactive oxygen species regulate ERBB2 and ERBB3 expression via miR‐199a/125b and DNA methylation

Overexpression of ERBB2 or ERBB3 is associated with cancer development and poor prognosis. In this study, we show that reactive oxygen species (ROS) induce both ERBB2 and ERBB3 expression in vitro and in vivo. We also identify that miR‐199a and miR‐125b target ERBB2 and/or ERBB3 in ovarian cancer cells, and demonstrate that ROS inhibit miR‐199a and miR‐125b expression through increasing the promoter methylation of the miR‐199a and miR‐125b genes by DNA methyltransferase 1. These findings reveal that ERBB2 and ERBB3 expression is regulated by ROS via miR‐199a and miR‐125b downregulation and DNA hypermethylation.     

Aryl hydrocarbon‐estrogen alpha receptor‐dependent expression of miR‐206, miR‐27b,and miR‐133a suppress cell proliferation and migration in MCF‐7 cells

The underlying functions of miR‐206, miR‐133a, miR‐27b, and miR‐21, and their link to the estrogen receptor alpha (ERα) and aryl hydrocarbon receptor (AhR) signaling pathways remain largely unexplored. In this study, we detect the expression of miR‐206, miR‐133a, miR‐27b, and miR‐21 in MCF‐7 through quantificational real‐time polymerase chain reaction assay along with the activation/inhibition of ERα and AhR receptors. Aside from this, cell proliferation and migration as well as AhR‐dependent CYP1A1 enzyme activity were measured. Here, we found that the forced increased expression of miR‐206, miR‐133a, and miR‐27b were closely associated with the suppression of MCF‐7 cell proliferation and migration. The anti‐proliferative‐metastatic effect of miR‐206, miR‐133a, and miR‐27b was probably mediated by targeting the ERα and AhR signaling pathways. Considered together, our study indicated that the overexpression of miR‐206, miR‐133a, and miR‐27b might be potential biomarkers for prognosis and therapeutic strategies in breast cancer.     

Upregulation of miR‐874‐3p and miR‐874‐5p inhibits epithelial ovarian cancer malignancy via SIK2

Based on miR‐874 expression levels in the GSE47841 microarray, we hypothesized that the mature products of miR‐874, miR‐874‐3p, or miR‐874‐5p, would inhibit epithelial ovarian cancer (EOC) cell proliferation, metastasis, and chemoresistance. We first examined miR‐874‐3p and miR‐874‐5p expression levels in primary EOC tumor tissue samples and found that they were significantly decreased. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide (MTT) cell proliferation and transwell assays revealed that miR‐874‐3p and miR‐874‐5p significantly inhibit EOC cell proliferation, migration, and invasion. Then, using MTT and soft agar assays of paclitaxel‐treated Caov3 and SKOV3 cells transfected with miR‐874‐3p and miR‐874‐5p, we found that miR‐874‐3p and miR‐874‐5p enhance EOC cell chemosensitivity. We then confirmed that serine/threonine‐protein kinase 2 (SIK2) was a target gene of miR‐874‐3p and miR‐874‐5p. Overall, the results of this study indicate that SIK2 expression can serve as a prognostic biomarker for EOC and that miR‐874‐3p and miR‐874‐5p have the potential to enhance clinical treatment of EOC.     

miR‐19b controls cardiac fibroblast proliferation and migration

Cardiac fibrosis is a fundamental constituent of a variety of cardiac dysfunction, making it a leading cause of death worldwide. However, no effective treatment for cardiac fibrosis is available. Therefore, novel therapeutics for cardiac fibrosis are highly needed. Recently, miR‐19b has been found to be able to protect hydrogen peroxide (H₂O₂)‐induced apoptosis and improve cell survival in H9C2 cardiomyocytes, while down‐regulation of miR‐19b had opposite effects, indicating that increasing miR‐19b may be a new therapeutic strategy for attenuating cellular apoptosis during myocardial ischaemia–reperfusion injury. However, considering the fact that microRNAs might exert a cell‐specific role, it is highly interesting to determine the role of miR‐19b in cardiac fibroblasts. Here, we found that miR‐19b was able to promote cardiac fibroblast proliferation and migration. However, miR‐19b mimics and inhibitors did not modulate the expression level of collagen I. Pten was identified as a target gene of miR‐19b, which was responsible for the effect of miR‐19b in controlling cardiac fibroblast proliferation and migration. Our data suggest that the role of miR‐19b is cell specific, and systemic miR‐19b targeting in cardiac remodelling might be problematic. Therefore, it is highly needed and also urgent to investigate the role of miR‐19b in cardiac remodelling in vivo.     

MicroRNA‐135a alleviates oxygen‐glucose deprivation and reoxygenation‐induced injury in neurons through regulation of GSK‐3β/Nrf2 signaling

MicroRNAs (miRNAs) have been suggested as pivotal regulators in the pathological process of cerebral ischemia and reperfusion injury. In this study, we aimed to investigate the role of miR‐135a in regulating neuronal survival in cerebral ischemia and reperfusion injury using an in vitro cellular model induced by oxygen‐glucose deprivation and reoxygenation (OGD/R). Our results showed that miR‐135a expression was significantly decreased in neurons with OGD/R treatment. Overexpression of miR‐135a significantly alleviated OGD/R‐induced cell injury and oxidative stress, whereas inhibition of miR‐135a showed the opposite effects. Glycogen synthase kinase‐3β (GSK‐3β) was identified as a potential target gene of miR‐135a. miR‐135a was found to inhibit GSK‐3β expression, but promote the expression of nuclear factor erythroid 2‐related factor 2 (Nrf2) and downstream signaling. However, overexpression of GSK‐3β significantly reversed miR‐135a‐induced neuroprotective effect. Overall, our results suggest that miR‐135a protects neurons against OGD/R‐induced injury through downregulation of GSK‐3β and upregulation of Nrf2 signaling.     

Novel inhibitory function of miR‐125b in melanogenesis

MicroRNAs are known to be the important regulators of skin physiology and considered as new therapeutic targets to treat skin diseases. In this study, miR‐125b was identified as a potent regulator of steady‐state melanogenesis. We found that the expression of miR‐125b was inversely related to pigment levels. A miR‐125b mimic decreased the expression of pigmentation‐related gene and melanin content, implying that miR‐125b functions to decrease pigmentation. Moreover, we observed that the reduction in miR‐125b expression in pigmented cells was at least partially due to the hypermethylation of the MIR125B‐1 promoter, and miR‐125b expression was regulated by intracellular cAMP levels.     

Exosomes from mesenchymal stem cells expressing miR‐125b inhibit neointimal hyperplasia via myosin IE

Intercellular communication between mesenchymal stem cells (MSCs) and their target cells in the perivascular environment is modulated by exosomes derived from MSCs. However, the potential role of exosome‐mediated microRNA transfer in neointimal hyperplasia remains to be investigated. To evaluate the effects of MSC‐derived exosomes (MSC‐Exo) on neointimal hyperplasia, their effects upon vascular smooth muscle cell (VSMC) growth in vitro and neointimal hyperplasia in vivo were assessed in a model of balloon‐induced vascular injury. Our results showed that MSC‐Exo were internalised by VSMCs and inhibited proliferation and migration in vitro. Further analysis revealed that miR‐125b was enriched in MSC‐Exo, and repressed the expression of myosin 1E (Myo1e) by targeting its 3? untranslated region. Additionally, MSC‐Exo and exosomally transferred miR‐125b repressed Myo1e expression and suppressed VSMC proliferation and migration and neointimal hyperplasia in vivo. In summary, our findings revealed that MSC‐Exo can transfer miR‐125b to VSMCs and inhibit VSMC proliferation and migration in vitro and neointimal hyperplasia in vivo by repressing Myo1e, indicating that miR‐125b may be a therapeutic target in the treatment of vascular diseases.     

The expression of miR‐125b in Nrf2‐silenced A549 cells exposed to hyperoxia and its relationship with apoptosis

Bronchopulmonary dysplasia (BPD) is a chronic lung disease that affects the quality of life of infants. At present, premature exposure to hyperoxia for extended periods of time is believed to affect the development of lung tissue and vascularity, resulting in BPD. The oxidative stress caused by hyperoxia exposure is an important risk factor for BPD in premature infants. Nuclear factor E2‐related factor 2 (Nrf2) is an important regulator of antioxidant mechanisms. As a microRNA, microRNA‐125b (miR‐125b) plays an important role in cell proliferation, differentiation and apoptosis. Although the Nrf2/ARE pathway has been extensively studied, little is known about the regulatory role of microRNAs in Nrf2 expression. In this study, the expression levels of Nrf2 and miR‐125b in the lung tissues of premature Sprague Dawley (SD) rats and A549 cells exposed to hyperoxia were detected by quantitative real‐time polymerase chain reaction (qRT‐PCR), and the apoptosis of A549 cells was detected by flow cytometry. The results showed that Nrf2 and miRNA‐125b in the lung tissues of premature rats increased significantly upon exposure to hyperoxia and played a protective role. Nrf2 was suppressed by small interfering RNA (siRNA) in A549 cells, miR‐125b was similarly inhibited, and apoptosis was significantly increased. These results suggest that miR‐125b helps protect against BPD as a downstream target of Nrf2.     

miR‐29a modulates tumor necrosis factor‐α‐induced osteogenic inhibition by targeting Wnt antagonists

We previously found that miR‐29a was significantly downregulated in Ankylosing spondylitis (AS) patients, a chronic inflammatory disease associated with bone metabolic disorder, however, the underlying mechanism remains unclear. In this study, we demonstrated that miR‐29a regulates tumor necrosis factor‐α (TNF‐α) mediated bone loss mainly by targeting DKK1 and GSK3β, thus activating the Wnt/β‐catenin pathway. Our findings may provide new insight into the pathogenesis of the bone metabolism disorder in inflammation environment and provide promising therapeutic target.