Search

This project aimed to investigate the protective mechanism of sufentanil pretreatment on myocardial ischemia-reperfusion injury (IRI). An in vivo rat model of myocardial IRI and an in vitro cultured cardiomyocyte model of hypoxia-reoxygenation (H/R) were used to confirm the anti-oxidation and anti-autophagy effects of sufentanil. The interaction between miR-125a and damage-regulated autophagy regulator 2 (DRAM2) was verified by luciferase reporter assay. We showed that pretreatment with sufentanil suppressed myocardial damage caused by IRI in rats by inhibiting oxidative stress and mitochondrial autophagy. Furthermore, the cardioprotective mechanism of sufentanil was mediated by miR-125a. MiR-125a targeted DRAM2 to ameliorate cardiomyocyte autophagy and oxidative injury following H/R treatment. In conclusion, our results demonstrated that sufentanil pretreatment produced a protective effect against myocardial IRI via regulating miR-125a/DRAM2 signaling axis.

Predictive biomarkers for early diagnosis of prostate cancer are important for its treatment. The functional microRNAs in the exosomes of plasma and serum samples are of interest as stable and non-invasive biomarkers for recurrence in cancer patients. The present study aimed to clarify the value of plasma exosomal miRNA-125a-5p and miR-141-5p as biomarkers for the diagnosis of prostate cancer. The study included 19 healthy individuals and 31 prostate cancer patients. In comparison to the levels in healthy controls, exosomal miR-141-5p levels showed a slight increase in prostate cancer patients (p=0.085), and miR-125a-5p levels that showed a significant decrease in patients with prostate cancer than in healthy controls (p=0.032). As a derived parameter, the miR-125a-5p/miR-141-5p ratio was significantly higher in patients with prostate cancer than in healthy controls (p

Background Thyroid cancer is a very common endocrine cancer worldwide. How long noncoding RNA (lncRNA) regulates thyroid cancer is elusive. LncRNA MFI2-AS1 has been demonstrated to initiate colorectal cancer. Nevertheless, the role of MFI2-AS1 in thyroid cancer remains unknown. This study aims to determine the roles of MFI2-AS1 in thyroid cancer. Methods qRT-PCR was used to determine the expression of MFI2-AS1 in thyroid cancer tissues and cells. Proliferation was determined by using CCK8 and colony formation assays. Transwell assay was utilized to analyze migration and invasion. Luciferase reporter assay was performed to confirm the interaction between MFI2-AS1 and miR-125a-5p. Results MFI2-AS1 was shown to be highly expressed in thyroid cancer tissues and predicted poor prognosis. Knockdown of MFI2-AS1 inhibited proliferation, colony formation, migration and invasion of thyroid cancer cells in vitro. Bioinformatics screening identified MFI2-AS1 as the sponge for miR-125a-5p. And miR-125a-5p was further confirmed to target TRIAP1 directly. Our data further demonstrated that MFI2-AS1 promoted TRIAP1 expression via repressing miR-125a-5p. Finally, TRIAP1 was found to be upregulated in thyroid cancer tissues and its restoration reversed the effects of MFI2-AS1 depletion. Conclusion Our results elucidated a novel mechanism that MFI2-AS1 promotes thyroid cancer progression via the miR-125a-5p/TRIAP1 pathway.

Systemic lupus erythematous (SLE) is an autoimmune disease with production of various autoantibodies directed against various autoantigens. But the research on melanoma differentiation-associated gene 5 (MDA5) in SLE is still scarce. Here we try to elucidate the effect of hsa_circ_0012919 on MDA5 and its potential clinical value in SLE. CD4+ T cells from SLE patients and healthy control subjects were isolated. Expression of hsa_circ_0012919 and MDA5, and methylation level of MDA5 promoter were detected. Then expression and methylation level of MDA5 promoter was examined after transfection of hsa_circ_0012919-targeted siRNA and plasmids. Expression of hsa_circ_0012919 and MDA5 were further confirmed to be significantly higher in CD4+ T cells of SLE patients ( p

Background. Mycobacterium leprae infects skin and peripheral nerves causing a broad of clinical forms. Data have shown that the miR-125a-3p can influence immune mechanisms such as autophagy as well as to target genes leading to abnormal proliferation, metastasis, and invasion of cells. Methods. Here we used quantitative real time PCR (qPCR) to evaluate the miR-125a-3p expression pattern as a marker for leprosy phenotypes in biopsies obtained from patients with and without reactions. Data were analysed according to clinical forms and bacillary index (BI). Results. Our results show a significant increase in the miR-125a-3p expression in paucibacillary (PB) vs multibacillary (MB) (p = 0.007) and vs RR (reversal reactions) (p = 0.005), respectively; and also a higher expression in patients with erythema nodosum leprosum (ENL) vs MB without reactions (p = 0.002). In addition, there was a positive correlation between the miR-125a-3p expression and BI in patients with reactions (r=0,81; p=0,002). Conclusions. All together we underpin a role for miR-125-3p in leprosy pathogenesis, raising the hypothesis that this miR might have a distinct role in PB and ENL forms, influencing mechanisms such as apoptosis and autophagy according to the local context. A functional study should help to validate the miR-125a-3p as a potential therapeutic target for leprosy treatment.

Certain microRNAs (miRNA/miRs) serve important roles in the progression of atherosclerosis (AS); however, the exact regulatory mechanisms of miRNAs in AS remain to be fully elucidated. The present study aimed to investigate the effects of miR-125a-5p in AS and the underlying mechanisms. Oxidized low-density lipoprotein (ox-LDL) was employed to stimulate human aortic vascular smooth muscle cells (HAVSMCs) to establish a cell model of AS. Reverse transcription-quantitative PCR was used to determine the expression levels of miR-125a-5p. Cell proliferation was evaluated using a Cell Counting Kit-8 (CCK-8) and migration was detected using a Transwell assay. In addition, the levels of the VSMC-specific marker gene α-smooth muscle actin, the cell cycleregulatory proteins cyclin-dependent kinase (CDK)2, cyclin D1, cyclin E and p27, as well as the migration-associated proteins matrix metalloproteinase-2 (MMP2) and MMP9, and phosphorylated phosphoinositide 3-kinase (p-PI3K) and p-AKT were determined by western blot analysis. The results revealed that transfection of miR-125a-5p mimics inhibited the ox-LDL-induced proliferation of HSVSMCs, accompanied by decreased expression of CDK-2, cyclin D1 and cyclin E, and increased expression of p27. Furthermore, miR-125a-5p mimics attenuated the ox-LDL-induced migration of HAVSMCs in parallel with downregulation of the expression of MMP2 and MMP9. Furthermore, the effect of ox-LDL to increase p-PI3K and p-AKT levels was significantly blunted by miR-125a-5p mimics. In conclusion, the present results suggested that miR-125a-5p mimics inhibited ox-LDL-induced proliferation and migration of HAVSMCs through inhibition of PI3K/AKT signaling, providing a potential novel therapeutic strategy for AS.

Objective: Many studies have shown that long non-coding RNAs (lncRNAs) are closely related to various cancers. This study aims to explore the roles of lncRNA HOXA11-AS in the development and progression of osteosarcoma (OS). Methods: The expression levels of HOXA11-AS and miR-125a-5p in tumor tissues and the adjacent tissues were detected by RT-PCR method. The proliferation, migration and invasion of MG-63 and KHOS cells were determined. Results: It was found that HOXA11-AS expression levels in OS tissues and OS cell lines were higher than those in OS adjacent tissues and normal human osteoblast cell lines. The higher expression level of HOXA11-AS was positively correlated with more severe clinical stage, distant metastasis and poor prognosis of OS. Inhibition of HOXA11-AS expression could reduce metastasis and invasion of OS cell lines. In addition, HOXA11-AS was found to be an endogenous inhibitor of miR-125a-5p, it down regulated the expression level of miR-125a-5p, and this process could promote the expression of Rab3D, the target gene of miR-125a-5p. Conclusion: Our study elucidated the role of a new HOXA11-AS/miR-125a-5p/Rab3D regulatory pathway in promoting OS metastasis.

We, the Editor, Publisher, and Authors of Artificial Cells, Nanomedicine and Biotechnology, have retracted the following article:Qian Li, Xia He, Qiao Yu, Yuan Wu, Mingyu Du, Jing Chen, Fanyu Peng,...

The aim of the present study was to investigate whether miRNA (miRNA or miR)-125a-5p regulates angiogenesis in hepatocellular carcinoma (HCC) via VEGF-A. Reverse transcription-quantitative polymerase chain reaction was used to determine the expression of miRNA or mRNA. Western blotting was used to determine the expression of target protein in cells, while ELISA was employed to measure the secretion of target protein by cells. Dual luciferase reporter assay was performed to identify the direct interaction between miRNA and the 3’-untranslated region of its target mRNA. CCK-8 assay was carried out to evaluate the proliferation of cells. MTT assay was performed to examine the migration of cells. The results showed that decreased expression of miR-125a-5p in HHC HepG2 cells was potentially related to the increased expression of VEGF-A. The expression of miR-125a-5p regulated VEGF-A expression and secretion of HepG2 cells. miR-125a-5p could bind with the 3’-UTR seed region of VEGF-A mRNA to inhibit its expression. miR-125a-5p increased the expression and secretion of VEGF-A by HepG2 cells, which subsequently promoted the proliferation of HUVECs by increasing the phosphorylation of Akt. miR-125a-5p regulated the migration of HUVECs via the VEGF-A/VEGFR2/Akt signalling pathway, which was affected by the expression and secretion of VEGF-A by HepG2 cells. Thus, the present study demonstrates that overexpression of miR-125a-5p inhibits the growth and angiogenesis of HCC by regulating the expression of VEGF-A.

Inflamma-miRs are a group of microRNAs involved in the regulation of innate and adaptive immune responses. Increasing evidence support the contribution of dysregulated inflamma-miRs in the pathogenesis of multiple sclerosis. The aim of this study was to evaluate the expression of selected inflamma-miRs, i.e., miR-34a-5p, -125a-5p, -146a-5p, and -155, in relapsing-remitting multiple sclerosis (RRMS) and their modulation after treatment with dimethyl fumarate (DMF).Circulating levels of microRNAs involved in inflammatory response (inflamma-miRs) were compared between healthy controls (CTRs, n=21) and patients with RRMS (n=24) who started treatment with DMF.Plasma levels of miR-34a (p0.001) and miR-125a-5p (p=0.034) were higher, whereas miR-146a-5p levels were lower (p=0.041) in RRMS patients compared to CTRs. Circulating miR-125a-5p (p=0.001), miR-146a-5p (p0.001), and miR-155 (p=0.013) were reduced after 4-month treatment with DMF. Among these, baseline and 4-month follow up miR-125a-5p (p=0.028) and miR-146a-5p (p=0.042) levels were related to disability progression.Circulating inflamma-miRs could represent candidate tools to predict MS clinical course and evaluate the effectiveness of disease-modifying treatments in RRMS.

Aims: In this study, we aimed to decipher the impact of enhancer of zeste homolog 2 (EZH2) in psoriasis as well as the underlying mechanism. Methods: A mouse model of psoriasis was developed by means of imiquimod induction, with the expression of EZH2, microRNA-125a-5p (miR-125a-5p), and SFMBT1 determined. The role of EZH2, miR-125a-5p, and SFMBT1 in malignant phenotypes of HaCaT cells and the development of psoriasis in vivo was subsequently investigated through gain- and loss-of-function experiments. Chromatin immunoprecipitation assay and dual-luciferase reporter assay were conducted to explore the relationship between EZH2 or SFMBT1 and miR-125a-5p. Finally, the effects of EZH2 and miR-125a-5p on the transforming growth factor β (TGFβ)/SMAD pathway were analyzed. Results: Overexpressed SFMBT1 and EZH2 was detected while miR-125a-5p were downregulated in psoriasis tissues and human keratinocyte (HaCaT) cells. EZH2 increased the levels of IL-17A-induced cytokines and promoted the malignant phenotypes of HaCaT cells. Functionally, EZH2 reduced miR-125a-5p expression while miR-125a-5p targeted SFMBT1 to activate the TGFβ/SMAD pathway in vitro. Knockdown of EZH2 or up-regulation of miR-125a-5p inhibited cell proliferation and the levels of IL-17A-induced cytokines, but increased the expression of TGFβ1 and the extent of smad2 and smad3 phosphorylation in HaCaT cells. Notably, EZH2 contributed to the development of psoriasis in vivo by inhibiting the TGFβ/SMAD pathway via impairment of miR-125a-5p-mediated SFMBT1 inhibition. Conclusion: Taken together, the results of the current study highlight the ability of EZH2 to potentially inactivate the TGFβ/SMAD pathway via upregulation of miR-125a-5p-dependent SFMBT1during the progression of psoriatic lesions.

IntroductionPatients with primary nephrotic syndrome (PNS) were reported to exhibit the evident imbalance between the number of Th17 and Treg cells in their peripheral blood monocytes (PBMCs), which might be the immunological basis of the disease.Material and methods40 PNS patients and 42 healthy individuals were recruited in this study. FCM assay was used to observe the levels of Treg and Th17 cells.ResultsThe Treg/Th17 ratio was evidently decreased in PNS patients. The levels of MEG3 and RORγt were increased in the PNS group, while the levels of miR-17, miR-125a and FOXP3 mRNA were reduced in the PNS group. Moreover, the levels of IL-6 and IL-1β were highly increased in PNS patients. Ox-low density lipoprotein (ox-LDL) treatment significantly increased the levels of MEG3 and RORγt mRNA/protein while decreasing the levels of miR-17, miR-125a, and FOXP3 mRNA/protein in THP-1 cells, and the transfection of MEG3 siRNA partly alleviated the dysregulation in the expression of MEG3, relevant miRNAs and relevant mRNAs induced by ox-LDL. Also, the expression of miR-17 and miR-125a was evidently decreased upon the successful transfection of MEG3, but the RORγt mRNA/protein levels were promoted while the FOXP3 mRNA/protein levels were inhibited.ConclusionsOur results demonstrated that ox-LDL could promote the inflammatory response of PNS by decreasing the Treg/Th17 ratio via activating the MEG3 signaling. The activation of MEG3/miR-125a/FOXP3 axis and MEG3/miR-17/RORγt axis respectively lead to the Treg/Th17 imbalance, which resulted in up-regulated IL-6 and IL-1β levels, thus increasing the susceptibility of PNS.

Background: Accumulating evidence indicates that circular RNAs (circRNAs) play critical roles in tumorigenesis and progression of various cancers. We previously identified a novel upregulated circRNA, circBCBM1 (hsa_circ_0001944), in the context of breast cancer brain metastasis. However, the potential biological function and molecular mechanism of circBCBM1 in breast cancer brain metastasis remain largely unknown.Methods: In this reserch, we validated the expression and characterization of circBCBM1 through RT-qPCR, Sanger sequencing, RNase R assay and fluorescence in situ hybridization (FISH). Functional experiments were performed to determine the effect of circBCBM1 on growth and metastasis of 231-BR cells both in vitro and in vivo. The regulatory mechanisms among circBCBM1, miR-125a (has-miR-125a-5p), and BRD4 (bromodomain containing 4) were investigated by RNA immunoprecipitation (RIP), RNA pull-down, luciferase reporter assay and western blot. Results: Our findings demonstrated that circBCBM1 is a stable and cytoplasmic circRNA. Functionally, silencing of circBCBM1 led to decreased proliferation and migration of 231-BR cells whereas elevated circBCBM1 expression showed reverse effects in vitro. These findings were confirmed in vivo in mouse models, as knockdown of circBCBM1 significantly decreased growth and brain metastases of 231-BR cells. Mechanistically, circBCBM1 functions as an endogenous miR-125a sponge to inhibit miR-125a activity, resulting in the upregulation of BRD4 expression and subsequent upregulation of MMP9 (matrix metallopeptidase 9) through Sonic hedgehog (SHH) signaling pathway. Importantly, circBCBM1 was markedly upregulated in the breast cancer brain metastasis cells and clinical tissue and plasma samples; besides, the overexpression of circBCBM1 in primary cancerous tissues was associated with shorter brain metastasis-free survival (BMFS) of breast cancer patients.Conclusions: These findings indicate that circBCBM1 is involved in breast cancer brain metastasis via circBCBM1/miR-125a/BRD4 axis, which sheds light on the pathogenic mechanism of circBCBM1 and provides translational evidence that circBCBM1 may serve as a novel diagnostic or prognostic biomarker and potential therapeutic target for breast cancer brain metastasis.

Background Cardiovacular diseases (CVD) are the leading cause of death worldwide. Platelet play a key role in the pathophysiology of multiple CVD. LincRNAs are long non-coding RNAs transcribed from intergenic DNA segments. Some members of this class were recently associated with human disease. Linc-223 is co-transcribed together with mir-223 and was recently shown to bind to miR-125. Both miR-223 and miR-125 are highly expressed in platelets. Purpose In light of the capability of Linc-223 to bind to miR-125, we aimed to investigate whether their reciprocal expression levels might reflect the degree of platelet activity. Methods RNA was extracted using miRVANA. MiRNAs and lncRNAs were measured by means of quantitative Real Time RT-PCR. Results We found a significant reduction of Linc-223 levels (p Conclusions We identify a reciprocal modulation of Linc-223 and miR-125, its ligand upon different levels of platelet aggregations. These results are compatible with previous evidence from patients with Acute Myeloid Leukemia, that Linc-223 might bind to and sponge miR-125, inhibiting its effect. These results suggest that plasma levels of Linc-223, miR-125 and miR-223 might be used a biomarkers of platelet finction in a clinical context, for risk stratification of patients or to assess the responsiveness to antiplatelet treatments. Funding Acknowledgement Type of funding source: None

Background: Thyroid cancer is the fifth communal cancer type in females and its occurrence rate continues to rise rapidly worldwide. Latest data demonstrated mir-125 is down-regulated in various cancer types. Methods: a case-control (179 cases, 165 controls) study in order to explore the association of mir-125 rs12976445 with the risk of thyroid cancer in the Iranian population was performed. In order to investigate rs12976445 C/T polymorphisms, polymerase chain reaction restriction–fragment length polymorphism (PCR–RFLP) was done. Logistic regression analyses were done to find the association of mir-125 rs12976445 C/T polymorphisms with thyroid cancer and its stages. Results: The genotype frequencies for patients was [(CC: 81(45.2%), CT: 75(41.9%), TT: 23 (12.9%)], and for controls was [(CC: 100 (60.1%), CT: 53(32.2%), TT: 12 (6.7%)]. The T allele distribution was significantly altered between patients and controls (P=0.002) with the odds ratio of 1.68. In the co-dominant model CC genotype was set as reference and compared with CT, and TT genotypes. In the dominant model, there was a significant difference between CC vs CT genotypes (adjusted OR = 1.69, 95% CI= 1-2.8, P = 0.026), and slightly significant differences between CC vs TT genotypes (adjusted OR = 2.18, 95% CI= 1-4.7, P = 0.047). we compared CT/TT genotype to the reference genotype (CC) and found a highly significant difference (adjusted OR = 1.78, 95% CI= 1.15-2.74, P = 0. 0.009).Conclusion: as the first study, our findings suggest that miR-125a rs12976445 is a possible prognostic biomarker for thyroid cancer patients.

The aim of this study was to evaluate the expression of miR-125a-5p in patients with dyspeptic symptoms and gastric cancer, correlating them with the development of this cancer and H. pylori. Patients were divided in groups according to histopathological analysis (control, gastritis, and cancer groups). Polymerase chain reaction was performed to detect H. pylori and real-time quantitative PCR to determine miR-125a-5p expression. H. pylori was detected in 44% of the patients, with prevalence in the gastritis and cancer groups. A statistically significant decrease of miR-125a-5p expression was found in the control positive (p = 0.0183*), gastritis positive (p = 0.0380*), and cancer positive (p = 0.0288*) groups when compared with the control negative group. We suggest that decreased expression of the miRNA-125a-5p associated with the presence of the H. pylori is an important mechanism in gastric diseases and could be a possible marker for early diagnosis of gastric cancer.

Micro-RNAs are a novel class of single-strand non-coding RNAs, which play an important role in tumorigenesis. This investigation aimed to evaluate associations between the hsa-miR-27a (rs895819 T > C) and hsa-miR-125a (rs12976445 C > T) gene variations and the risk of PCa. In the present case–control investigation, we have obtained 300 peripheral blood samples, consisting of 150 subjects with PCa and 150 healthy men. The genotype frequencies of hsa-miR-27a and hsa-miR-125a gene variations evaluated using the PCR–RFLP technique. Based on our findings, the genotype frequencies did not reveal a significant association between the rs895819T and rs12976445C variations and the risk of PCa in the three heredity models (P > 0.05). Minor alleles C and T of rs895819 and rs12976445 did not show an increased risk of PCa progression (P > 0.05). Our findings indicated that the hsa-miR-27a and hsa-miR-125a gene variations are not increased PCa predisposition in the Iranian population.

Giant cell tumors of bone (GCTBs) exhibit high recurrence and aggressive bone lytic behavior; but, the mechanism of GCTB progression is largely unknown. In GCTB, we detected abundant levels of miR-125a, which were associated with tumor extension, grade, and recurrence. miR-125a stimulates stromal cell tumorigenicity and growth in vivo by promoting the expression of interleukin-17A (IL-17A) and β-catenin. In contrast, inhibition of miR-125a suppressed stromal cell tumorigenicity and growth. Then, we found that miR-125a stimulates IL-17A by targeting TET2 and Foxp3, and it stimulates β-catenin expression by targeting APC and GSK3β in stromal cells. Furthermore, we identified that IL-17A stimulates miR-125a by activating nuclear factor κB (NF-κB) signaling in stromal cells. Finally, our data show that simultaneous inhibition of IL-17A signaling and miR-125a more significantly inhibits stromal cell growth than miR-125a inhibition alone. miR-125a stimulates the progression of GCTB, and it might represent a useful candidate marker for progression. Simultaneously blocking miR-125a and IL-17A might represent a new therapeutic strategy for GCTB. Keywords: miR-125a, GCTB, recurrence, IL-17A, β-catenin signaling

Breast cancer is a major leading cause of cancer death in women in almost all countries, including developing countries. Despite the significant progress that has been made in cancer detection and ...

To study the roles and mechanisms of HuR in cancer stem cell maintenance of lung cancer. HuR expression was increased in tumor spheres of lung cancer cells. Knockdown of HuR suppressed spheroid formation and size, inhibited the expression of stemness-related marker, Oct4, Nanog and ALDH in lung cancer cells. Importantly, HuR and CDK3 expressions were increased in lung cancer tissues compared with normal adjacent tissues, and positively correlated. Mechanistically, HuR directly bound to CDK3, and increased CDK3 mRNA stability and expression. Additionally, miR-873 or miR-125a-3p attenuated the promotion of HuR on CDK3 expression and lung cancer stemness. Furthermore, HuR facilitated lung cancer stemness dependent on CDK3 expression. miR-873 or miR-125a-3p level was negatively correlated with HuR and CDK3 expression levels in lung cancer tissues. HuR facilitates lung cancer stemness via regulating miR-873/CDK3 and miR-125a-3p/CDK3 axis.

Calorie restriction (CR) is a dietary intervention known to delay aging. In order, to understand molecular mechanisms of CR, we analyzed the expression of 983 MicroRNAs (miRNAs) in the liver of female mice after 2 years of 30% CR using micro-array. 16 miRNAs demonstrated significant changes in their expression upon CR in comparison with age-matched control. mmu-miR-125a-5p (miR-125a-5p) was significantly upregulated upon CR, and in agreement with this, the expression of mRNAs for its three predicted target genes: Stat3, Casp2, and Stard13 was significantly downregulated in the liver of CR animals. The expression of precursor miRNA for miR-125a-5p was also upregulated upon CR, which suggests its regulation at the level of transcription. Upon aging miR-125a-5p expression was downregulated while the expression of its target genes was upregulated. Thus, CR prevented age-associated changes in the expression of miR-125a-5p and its targets. We propose that miR-125a-5p dependent downregulation of Stat3, Casp2, and Stard13 contributes to the calorie restriction-mediated delay of aging.

MicroRNA-125a-5p (miR-125a-5p) could participate in the pathogenesis of vascular diseases. In this study, we investigated the role of miR-125a-5p in oxidized low-density lipoprotein (ox-LDL)-induced functional changes in human brain microvessel endothelial cells (HBMEC). The reactive oxygen species (ROS) production, nitric oxide (NO) generation, senescence, apoptosis, and functions of HBMEC were analyzed. For mechanism study, the epidermal growth factor receptor (EGFR)/extracellular signal-regulated protein kinase (ERK)/p38 mitogen-activated protein kinase (p38 MAPK) pathway and phosphatidylinositol-3-kinase (PI3K)/serine/threonine kinase (Akt)/endothelial nitric oxide synthase (eNOS) pathway were analyzed. Results showed the following: 1) Expression of miR-125a-5p was reduced in ox-LDL-treated HBMEC. 2) Overexpression of miR-125a-5p protected HBMEC from ox-LDL-induced apoptosis, senescence, ROS production, and NO reduction. 3) Overexpression of miR-125a-5p increased HBMEC proliferation, migration, and tube formation, while decreasing HBMEC adhesion to leukocytes, as well as counteracting the effects of ox-LDL on those functions. 4) The levels of EGFR/ERK/p38 MAPK pathway, PI3K/Akt/eNOS pathway, cleaved caspase-3, and adherent molecular ICAM-1 and VCAM-1 were associated with the effects of ox-LDL on these HBMEC functions. In conclusion, miR-125a-5p could counteract the effects of ox-LDL on various HBMEC functions via regulating the EGFR/ERK/p38 MAPK and PI3K/Akt/eNOS pathways and cleaved caspase-3, ICAM-1, and VCAM-1 expression.

Circulating exosomes have a great impact in human health as a biomarker or as messengers in intercellular signaling. In this study we aimed to determine how miRNA profile in circulating exosomes interfere with angiogenic phenotype of endothelial cell (EC) during acute event of coronary syndrome. Exosomes were purified from serum of patients with non-ST segment elevation myocardial infarction in the acute phase (NSTEMI, n=34) during percutaneous coronary intervention. Healthy donors (n=23) were included as control. Purified exosomes were quantified and characterized by nanoparticle tracking analysis (Nanosight). Healthy EC (HUVEC) were treated for 48h with labeled exosomes (5x10 5 particles/1x10 6 cells) and tested for their angiogenic potential (migration and tube formation) and mRNA expression. Exosome miRNA profile was determined by miRNA array. Exosomes levels were markedly increased in NSTEMI (1.3x10 9 particle/ml) vs control (7.5x10 8 particle/ml; p=0.02). HUVEC treatment with healthy exosomes improve migration and tube formation compared to untreated HUVEC. Nevertheless, exosomes from NSTEMI patients, in the acute phase lack their pro-angiogenic potential (Fig A). Network analysis of exosome miRNA and HUVEC mRNA expression revealed a correlation of increased miR-199a and miR-125a expression with decrease of components involved in EC sprout and stabilization (Fig B). Circulating exosomes have an important role in the control of angiogenesis. However, in the acute phase of NSTEMI intercellular communication via exosome is modified and exert an inhibitory effect on angiogenesis. These results could contribute to the progression and outcomes of the disease.

Putative anion transporter 1 (PAT1, SLC26A6), an intestinal epithelial Cl−/[Formula: see text] exchanger, also plays a key role in oxalate homeostasis via mediating intestinal oxalate secretion. Indeed, Slc26a6-null mice showed defect in intestinal oxalate secretion and high incidence of kidney stones. Recent emergence of PAT-1 as a novel therapeutic target for nephrolithiasis warrants detailed understanding of the mechanisms of PAT-1 regulation in health and disease. Therefore, we investigated the regulation of PAT-1 expression by microRNAs (miRNA), as they have been shown to play key role in modulating expression of other ion transporters. In silico analysis of PAT-1 3′-untranslated region (UTR) revealed potential binding sites for several miRNAs, suggesting the role of miRNAs in modulating PAT1 expression. miRNAs showing highest context scores (125a-5p, 339-5p, 423-5p, 485-5p, and 501-3p) were selected as candidates for their effects on the activity of a 263-bp PAT-1 3′-untranslated region (UTR) fragment cloned into pmirGLO vector upstream of luciferase. The 3′-UTR activity was measured by dual luciferase reporter assay in Caco-2, T-84, HT-29, and SK-CO15 cells. Transient transfection of PAT-1 3′-UTR significantly decreased the relative luciferase activity compared with the empty vector suggesting binding of potential miRNA(s) to the PAT-1 3′-UTR. Among all the selected candidates, cotransfection with miRNA mimics 125a-5p and 423-5p further decreased PAT-1 3′-UTR activity. Furthermore, increasing miR-125a-5p abundance via mimic transfection in Caco-2 cells decreased both mRNA and protein levels of PAT-1. Our results demonstrate a novel regulatory mechanism of intestinal PAT-1 expression via miR-125a-5p that could be of therapeutic importance in disorders associated with decreased PAT-1 expression and function.

An Editorial Expression of Concern: to this paper has been published: https://doi.org/10.1007/s13105-021-00805-0

MicroRNAs (miRNAs) have been widely studied in various human cancers, including bladder cancer. Previous report revealed that miR-125a-5p is downregulated in urothelial carcinomas. However, the biological function and molecular mechanism of miR-125a-5p in bladder cancer has not been elucidated. Therefore, this study focused on the role of miR-125a-5p in bladder cancer. The expression levels of miR-125a-5p were firstly tested in one normal cell line and four bladder cancer cell lines with qRT-PCR. The relative lower expression of miR-125a-5p was detected in bladder cancer cells. To confirm the effects of ectopic expression of miR-125a-5p on the biological behaviors of bladder cancer cells, gain-of-function assays were carried out. According to experimental results, miR-125a-5p overexpression suppressed cell proliferation and cell cycle progression, induced cell apoptosis. Moreover, overexpression of miR-125a-5p suppressed cell migration and invasion and reversed epithelial-mesenchymal transition (EMT). Mechanism investigation indicated that FUT4 is a target mRNA of miR-125a-5p in bladder cancer. The effects of FUT4 on cell proliferation, apoptosis, migration and invasion were identified by conducting gain-of-function assays. Finally, rescue assays indicated that FUT4 can reverse the effects of miR-125a-5p on bladder cancer progression. In summary, miR-125a-5p suppresses bladder cancer progression through targeting FUT4.

CD147 contributes to increased aerobic glycolysis through which it promotes tumor growth. Accumulating evidence suggests that CD147 exerts a variety of functions in thyroid cancer (TC) progression but the molecular mechanisms and therapeutic value of CD147 remain unclear.CD147 levels in TC tissues were analyzed to assess its relationship with prognosis and disease progression. A microRNA (miRNA) microarray and bioinformatics approach were used to identify microRNA regulators of CD147 through measurement of the expression and functions of these miRNAs in TC tissues and cell lines. Precursor miRNA-transfected cells were used to assess regulation of CD147 by miRNA. The effect of miRNA on TC cells via inhibition of glycolysis through CD147 targeting was also evaluated.We found that miR-125a-5p regulates CD147 and is negatively correlated with its expression and function. Moreover, CD147 knockdown or increased miR-125a-5p expression significantly reduced the viability, migration, and invasion of TC cells. Our mechanistic studies demonstrate that, through directly repressing the expression of the CD147 protein, miR-125a-5p suppresses aerobic glycolysis and lactate production and subsequently reduces TC cell viability, migration, and invasion, thereby exerting tumor suppressor functions.The novel connection identified between miR-125a-5p and CD147 suggests a new diagnostic and prognostic role for miR-125a-5p and that CD147 inhibition may be a candidate therapeutic target in the therapy of for TC.

Recently, increasing evidence has indicated that lncRNAs may play a critical role in the progression of oral cancer (OC). However, whether lncRNA-ANRIL is involved in the tumorigenesis of OC remains undetermined. In the present study, ANRIL showed significantly higher, while miR-125a showed lower, expression in OC tissues and sera than in normal controls. MTT, colony formation, flow cytometry analysis, wound-healing, transwell and mice xenograft model assays were used to detect the proliferation, migration, and invasion of ARNIL-overexpressing HB56 cells and ARNIL-knockdown CAL27 cells. The results showed that cell proliferation, migration, and invasion were significantly increased by ARNIL overexpression and decreased by ARNIL silencing in oral cancer cells. Furthermore, we found a negative correlation between ARNIL and miR-125a, and ARNIL acts as a miRNA-sponge by directly interacting with miR-125a.

AIM To determine the association of circulating miR-125a/b expression with the risk and disease severity of Crohn’s disease (CD), and with inflammatory cytokines. METHODS Plasma samples were collected from patients with active CD (A-CD), or CD in remission (R-CD) and from healthy controls (HCs). The levels of the inflammatory cytokines interleukin-17 (IL-17), tumour necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) were measured by enzyme-linked immunosorbent assay. The expression of miR-125a/b was assessed by quantitative polymerase chain reaction (qPCR). RESULTS Twenty-nine A-CD patients, 37 R-CD patients, and 37 HCs were included in the study. Plasma miR-125a expression was decreased in A-CD patients compared with that in R-CD patients (P < 0.001) and HCs (P < 0.001). miR-125a expression levels enabled the differentiation of A-CD from R-CD patients [area under curve (AUC) = 0.854] and from HCs (AUC = 0.780), whereas miR-125b expression did not. miR-125a was negatively correlated with C-reaction protein (CRP) (P = 0.017), erythrocyte sedimentation rate (ESR) (P = 0.026), Crohn’s disease activity index (CDAI) (P = 0.003), IL-17 (P = 0.015), and TNF-α (P = 0.004) in A-CD patients. Furthermore, miR-125a was negatively associated with CRP (P = 0.038) and CDAI (P = 0.021) in R-CD patients. Regarding miR-125b, no association with CRP, CDAI, IL-17, TNF-α, or IFN-γ was found in A-CD or in R-CD patients. miR-125a levels gradually increased in A-CD patients who achieved clinical remission (P = 0.009) after 3-mo treatment, whereas they remained unchanged among patients who failed to achieve remission. No changes in miR-125b expression were detected in remission or non-remission patients after treatment. CONCLUSION Circulating miR-125a but not miR-125b is decreased in patients with active disease status and negatively correlates with disease severity and inflammatory cytokines in patients with CD.

Aberrant expression of various microRNAs (miRNA) has shown diagnostic and prognostic significance in non-small cell lung cancer (NSCLC). qRT-PCR analysis confirmed altered expression of miR-125a-5p, let-7e, miR-30a, miR-30e and miR-30e-3p in 70 paired tissue and serum samples from NSCLC patients. The reduced expression of miR-125a-5p, let-7e and miR-30e was strongly associated with NSCLC dedifferentiation. The lost expression of miR-125a-5p and let-7e was associated with shorter overall survival and let-7e was an independent prognostic factor for NSCLC patients. These five miRNA expressions should be further evaluated as biomarkers for the early detection and prognosis of NSCLC patients.

Circulating miRNAs have been shown to serve as diagnostic/prognostic biomarkers in cancers and other diseases. However, the role of plasma miRNAs in Late-onset hypogonadism (LOH) diagnosis is still unknown. Using Illumina HiSeq2000 sequencing at discovery phase, and then two-step validated by reverse transcriptase polymerase chain reaction (RT-PCR) assays in verification phases. We verified that the expression levels of miR-125a-5p, miR-361-5p and miR-133a-3p were significantly altered in LOH group compared to the control group. The area under the receiver operating characteristic (ROC) curve (AUC) is 0.682, 0.698 and 0.765, respectively. The combination of three miRNAs showed a larger AUC (0.835) that was more efficient for the diagnosis of LOH. Among three miRNAs, miR-133a-3p had the best diagnostic value for LOH with 68.2% sensitivity and 77.3% specificity. Regression analyses show that miR-133a-3p level was negatively associated with the ageing males’ symptoms (AMS) scale. However, miR-361-5p level was positively associated with serum testosterone concentrations. In summary, plasma miRNAs are differentially expressed between LOH and healthy controls. We validated three miRNAs that could act as novel biomarkers for diagnosis of LOH. These miRNAs may be involved in the development of LOH. However, further large and functional studies are warranted to confirm our findings.

Fetal cardiopulmonary development is a strictly regulated process that may be perturbed by intrauterine stress, but it is unknown whether such stress affects gestation-related changes in heart or l...

To investigate the correlation of miR-125a/b expression with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) patients and inflammatory cytokines. Eighty-seven AECOPD patients, 93 stable chronic obstructive pulmonary disease (COPD) patients and 100 health volunteers (HCs) were recruited. Plasma samples were collected from AECOPD patients at the day 1, day 7, day 14, and day 28 of admission and from stable COPD patients as well as HCs. Total RNA was extracted from plasma, and miR-125a/b relative expressions were determined by quantitative real time-polymerase chain reaction. MiR-125b had a great capacity for distinguishing AECOPD from stable COPD (AUC = 0.926, 95% CI: 0.884–0.967) and HCs (AUC = 0.923, 95% CI: 0.880–0.966), while miR-125a did not. There were associations between miR-125b expression with TNF-α, IL-8, and LTB-4 in AECOPD patients (P = .012, P = .032, and P = .047, respectively), while no correlation of miR-125a with inflammatory cytokines was found. MiR-125b expression gradually decreased at day 7, day 14, and day 28 compared with day 1 (all P

Decline of transcription factor FoxN1, which predominantly regulates thymic epithelial cell (TEC) differentiation and homeostasis lifelong, is demonstrated to be casually related to age-related thymic involution. Whereas, a global role of microRNAs (miRNAs) has also been demonstrated to control and maintain TEC-constituting thymic microenvironment and to be changed in expression profile in the aged thymus. Therefore, it is urgently necessary to build knowledge regarding whether and which miRNAs regulate FoxN1 gene in the aged thymus. We primarily compared changes in miRNA expression profile between young and aged murine TECs with Mus musculus miRBase-V20 arrays (containing 1892 unique probes), and clearly identified and validated that at least one miRNA, miR-125a-5p, was increased in aged thymus. Applying miR-125a-5p mimics was able to inhibit FoxN1 3'UTR luciferase activity in a 293T cell line and to suppress FoxN1 expression in murine TEC Z210 cells. Since a single miRNA can play a fine-tuning role to regulate expression of multiple genes and a single gene can be regulated by multiple miRNAs, our result adds a single miRNA, miR-125a-5p, into the panel of FoxN1-regulating miRNAs associated with thymic aging.

4055Background: HER2 (ERBB2) amplification in gastric cancer ranges from 6-23%, accordingly Trastuzumab has been incorporated into the treatment arsenal of HER2-enriched gastric cancer. We had prev...

Xian Qin,1 Yajun Wan,1 Saiying Wang,2 Min Xue1 1Department of Obstetrics and Gynecology, 2Department of Anesthesiology, Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China Background: In this study, we intended to understand the regulatory mechanisms of microRNA-125a-5p (miR-125a-5p) in human cervical carcinoma.Methods: The gene expressions of miR-125a-5p in seven cervical carcinoma cell lines and 12 human cervical carcinoma samples were evaluated by quantitative real-time reverse transcription polymerase chain reaction. Ca-Ski and HeLa cells were transduced with lentivirus carrying miR-125a-5p mimics, and the effects of lentivirus-induced miR-125a-5p upregulation on cervical carcinoma proliferation and migration were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and transwell assays, respectively. In additional, HeLa cells were inoculated into null mice to evaluate the effect of miR-125a-5p upregulation on in vivo cervical carcinoma growth. The direct regulation of miR-125a-5p on its target gene, ABL proto-oncogene 2 (ABL2), in cervical carcinoma was evaluated by quantitative real-time reverse transcription polymerase chain reaction, Western blotting and luciferase reporter assays, respectively. ABL2 was then downregulated by small interfering RNA to examine its effect on cervical carcinoma proliferation and migration.Results: miR-125a-5p was downregulated in both cervical carcinoma cell lines and humancervical carcinomas. In Ca-Ski and HeLa cells, lentivirus-mediated miR-125a-5p upregulation inhibited cancer proliferation and migration in vitro and cervical carcinoma transplantation invivo. ABL2 was shown to be directly targeted by miR-125a-5p. In cervical carcinoma, ABL2 gene and protein levels were both downregulated by miR-125a-5p. Small interfering RNA-mediated ABL2 downregulation also had tumor-suppressive effects on cervical carcinoma proliferation and migration.Conclusion: The molecular pathway of miR-125a-5p/ABL2 plays an important role in human cervical carcinoma. Targeting miR-125a-5p/ABL2 pathway may provide a new treatment strategy for patients with cervical carcinoma. Keywords: cervical carcinoma, miR-125a-5p, ABL2, cancer proliferation, cancer migration