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Background Pancreatic cancer is associated with an extremely poor prognosis, so new biomarkers that can detect the initial stages are urgently needed. The significance of serum microRNA (miR) levels in pancreatic neoplasm such as pancreatic cancer and intraductal papillary mucinous neoplasm (IPMN) diagnosis remains unclear. We herein evaluated the usefulness of miRs enclosed in serum exosomes (ExmiRs) as diagnostic markers. Methods The ExmiRs from patients with pancreatic cancer ( n  = 32) or IPMN ( n  = 29), and patients without neoplasms (controls; n  = 22) were enriched using ExoQuick-TC™. The expression of ExmiRs was evaluated using a next-generation sequencing analysis, and the selected three miRs through this analysis were confirmed by a quantitative real-time polymerase chain reaction. Results The expression of ExmiR-191, ExmiR-21 and ExmiR-451a was significantly up-regulated in patients with pancreatic cancer and IPMN compared to the controls ( p  < 0.05). A receiver operating characteristic curve analysis showed that the area under the curve and the diagnostic accuracy of ExmiRs were 5–20% superior to those of three serum bulky circulating miRs (e.g.; ExmiR-21: AUC 0.826, accuracy 80.8%. Circulating miR-21: AUC 0.653, accuracy 62.3%). In addition, high ExmiR-451a was associated with mural nodules in IPMN ( p  = 0.010), and high ExmiR-21 was identified as a candidate prognostic factor for the overall survival ( p  = 0.011, HR 4.071, median OS of high-ExmiR-21: 344 days, median OS of low-ExmiR-21: 846 days) and chemo-resistant markers ( p  = 0.022). Conclusions The level of three ExmiRs can thus serve as early diagnostic and progression markers of pancreatic cancer and IPMN, and considered more useful markers than the circulating miRs (limited to these three miRs).

Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease characterized by continuous inflammation and the production of autoantibodies. Exosomes, acting as a critical tool for communication between cells, are involved in the pathogenesis of SLE, particularly in inflammation and immune imbalance. In this study, we aimed to extract and confirm the pro-inflammatory effect of serum exosomes in SLE. Then, we attempted to find differentially expressed exosomal microRNAs in the serum of healthy subjects and SLE patients via miRNA microarray analysis and validated the target exosomal microRNA, exosomal miR-451a, which expression level decreased in serum of SLE patients by RT-qPCR. Furtherly, we analyzed the correlation between exosomal miR-451a and disease activity, kidney damage and typing, and traditional medicine therapy. Finally, we investigated the intercellular communication role of exosomal miR-451a in SLE by co-culture assay in vitro . Taken together, our study demonstrated that downregulated serum exosomal miR-451a expression correlated with SLE disease activity and renal damage as well as its intercellular communication role in SLE which provided potential therapeutic strategies.

Background The downregulation of microRNA (miR)-451a has been reported in bladder cancer (BCa) tissues. Herein, we elucidated the role of miR-451a in BCa with the involvement of DNA methyltransferase 3B (DNMT3B). Methods We first screened the differentially expressed miRNAs from the serum of 12 BCa patients and 10 healthy controls in the BCa database GSE113486. Subsequently, we detected miR-451a expression and CpG island methylation of the promoter in BCa cells T24 and 5637 with DNMT3B knockdown. The downstream mRNAs of miR-451a were predicted by bioinformatics and KEGG enrichment analysis. Afterwards, the expression patterns of DNMT3B, miR-451a and erythropoietin-producing hepatocellular receptor tyrosine kinase class A2 (EPHA2) were altered in BCa cells to test the ability of cell proliferation, apoptosis, migration as well as invasion. Finally, the effect of miR-451a and DNMT3B was evaluated in vivo. Results miR-451a was significantly reduced in serum of BCa patients and cell lines. Moreover, the expression of DNMT3B in BCa cells was significantly increased, thus promoting methylation of the miR-451a promoter, resulting in miR-451a inhibition. Additionally, we found that miR-451a targeted and negatively regulated EPHA2, while EPHA2 could activate the PI3K/AKT signaling, driving BCa cell growth and metastasis. Conclusions Our study proposed and demonstrated that miR-451a downregulation mediated by DNMT3B is critical for proliferation, migration, and invasion of BCa, which may be beneficial for developing more effective therapies against BCa.

The IL-6R/JAK2/STAT3 pathway mediated by interleukin-6 (IL-6) plays an important role in the occurrence and development of multiple myeloma (MM), which is associated with decreased microRNA-451a. However, the biological function of microRNA-451a in MM remains unclear. The bone marrow (BM) of patients with MM was sampled, and the plasma cells were enriched. BM miR-451a, IL-6 and IL-6R levels and Ki-67 expression intensity were evaluated using reverse transcription-quantitative PCR, ELISA and flow cytometry, respectively. U266 cell proliferation, viability and apoptosis were measured using BrdU, CCK-8 and Annexin V/propidium iodide assays, respectively. Total and phospo-(p-)JAK2 and p-STAT3 levels were measured by western blotting. Dual-luciferase reporter assays were performed to validate the predicted target binding sites. miR-451a expression was low in patients with MM and was associated with the Revised International Staging System (R-ISS) stage. IL-6 concentrations were significantly higher in patients with MM than in normal controls and were inversely associated with miR-451a levels (r=−0.96, P<0.0001). IL-6R levels were positively correlated with the R-ISS stage. miR-451a was downregulated, and IL-6R was upregulated in myeloma cell lines. Treatment with an miR-451a mimic inhibited viability and induced apoptosis in U266 cells. p-JAK2 and p-STAT3 levels were significantly lower in mimic-treated U266 cells than in control cells. Thus, miR-451a was shown to regulate myeloma cell proliferation and apoptosis via the IL-6R/JAK2/STAT3 pathway and may be used to predict patient prognosis.

The natural course of multiple myeloma (MM) varies greatly between patients. The Revised MM International Staging System (R-ISS) identifies high-risk patients, but it is unsuitable for assessing minimal residual disease (MRD). Furthermore, the focal location of myeloma cells and clonal evolution often produce false negative results in flow cytometry. Extracellular microRNA (miRNA/miR) expression levels are stable in bodily fluids, and are retrievable and measurable from fresh or archived serum or plasma samples. Therefore, the present study aimed to investigate the clinical utility of circulating miRNA levels in patients with MM, particularly miR-451a, which is commonly downregulated in MM, and whether it could predict the prognosis and relapse of patients with MM. In total, 66 patients with MM, stratified using the R-ISS criteria, were recruited, while 10 healthy subjects (transplantation donors) were enrolled as controls. Reverse transcription-quantitative PCR was used to evaluate miR-451a expression in bone marrow (BM) and in the circulation. IL-6 levels were measured using ELISA, while western blotting was conducted to analyze the protein expression levels of the IL-6 receptor (IL-6R). During follow-up, MRD was assessed via multiparameter flow cytometry (MFC). miR-451a was identified to target IL-6R using a dual-luciferase reporter assay. Circulating miR-451a levels were low in patients with MM, and was found to be 0.39 times that of the control group (U=4.00; P<0.001). Among the 66 patients with MM, the median level of miR-451a was 0.73 and 0.41 times that of the control group in R-ISS stage I MM (15 patients) and R-ISS stage II stage (17 patients), respectively; patients with R-ISS stage III MM (34 patients) had the lowest level, at 0.24 times the value of the control group. Circulating miR-451a levels had a strong positive correlation with miR-451a levels in BM, but negatively correlated with IL-6 and IL-6R levels. After two courses of consolidation chemotherapy, 19 patients achieved complete remission, 10 of whom presented steady circulating miR-451a levels during follow-up; the other nine patients had an abrupt decrease in circulating miR-451a levels. The turning points in the trend appeared 4-8 weeks before positive results were obtained via MFC, and 4-16 weeks before clinical relapse. Moreover, miR-451a overexpression notably downregulated the expression of the IL-6R mRNA and protein. Collectively, circulating miR-451a levels potentially represent a novel biomarker to monitor MRD and predict relapse.

Hypertension or angiotensin II (Ang II) induces cardiac inflammation and fibrosis, thus contributing to cardiac remodeling. MicroRNAs (miRNAs) are considered crucial regulators of cardiac homeostasis and remodeling in response to various types of stress. It has been reported that miR-451a is involved in regulating ischemic heart injury. However, its role in Ang II-induced cardiac fibrosis remains unknown. Cardiac remodeling was induced in mice by infusion of low-dose Ang II (490 ng/kg/min) with a minipump for 2 weeks. Echocardiography and histological examinations were performed to evaluate cardiac function and pathological changes. We observed that miR-451a expression was the most significantly downregulated in the hearts of Ang II-infused mice and in both primary cardiac myocytes and fibroblasts. Overexpression of miR-451a in mice significantly attenuated Ang II–induced cardiac fibrosis and inflammation. Conversely, knockdown of miR-451a in mice aggravated this effect. Bioinformatics analysis and a luciferase reporter assay revealed that TBX1 was a direct target of miR-451a. Mechanistically, miR-451a directly targeted TBX1 expression, which inhibited TGF-β1 production in both cardiac myocytes and fibroblasts, inactivating of TGF-β1/SMAD2/3 signaling, inhibiting myofibroblast differentiation and proinflammatory cytokine expression, and leading to attenuation of cardiac fibrosis and inflammation. In conclusion, these results indicate that miR-451a acts as a novel regulator of Ang II–induced cardiac fibrosis and inflammation by directly targeting TBX1, and may be a promising therapeutic target for treating hypertensive cardiac diseases.

The role of microRNAs (miRNAs/miRs) in governing the progression of cutaneous squamous cell carcinoma (cSCC) has been the focus of recent studies. However, the functional role of miR-451a in cSCC growth remains poorly understood. Therefore, the present study aimed to determine the expression levels of miR-451a in cSCC cell lines and the involvement of miR-451a in cSCC progression. The results revealed that the expression levels of miR-451a were downregulated in cSCC tissues and cell lines, and that this subsequently upregulated 3-phosphoinositide-dependent protein kinase-1 (PDPK1) expression levels. PDPK1 was validated as a direct target of miR-451a in cSCC using bioinformatics software Starbase, dual-luciferase reporter gene assays and western blotting. Additionally, CCK-8, EdU and Transwell assays, as well as flow cytometry and Hoechst 3325 staining, were performed to assess the malignant aggressiveness of cSCC cells. Overexpression of miR-451a was demonstrated to impair the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT), and promoted apoptosis in cSCC cells by interacting with PDPK1, possibly by direct targeting. Furthermore, the western blotting results indicated that miR-451a overexpression may block the PI3K/AKT signaling pathway by interacting with PDPK1. In conclusion, the findings of the present study suggested that miR-451a may prevent the proliferation, migration, invasion and EMT of cSCC cells through the PDPK1-mediated PI3K/AKT signaling pathway, which may offer potential therapeutic targets for the treatment of cSCC.

Background To find new diagnostic markers for idiopathic membranous nephropathy (IMN) and also conduct preliminary explorations into the possible pathogenesis of IMN by comparing the expression of microRNA‐451a (miR‐451a), miR‐106a, miR‐19b, miR‐17, and phosphatase and tensin homolog (PTEN) protein in the serum of patients with IMN and healthy controls. Methods The expression levels of miR‐451a, miR‐106a, miR‐19b, and miR‐17 in the serum of patients in the IMN group (n = 55, age: 50.2 ± 12.1 years) and the control group (n = 58, age 47.4 ± 13.1 years) were measured by quantitative real‐time polymerase chain reaction (qRT‐PCR), and the concentration of serum PTEN protein was determined by enzyme‐linked immunosorbent assay (ELISA). Results Compared with the control group, the expression of miR‐106a, miR‐19b, and miR‐17 was decreased significantly in the IMN group, whereas PTEN protein concentration was increased significantly in the IMN group. The areas under the receiver operating characteristic curve (AUC) of serum miR‐106a, miR‐19b, miR‐17, and PTEN were 0.66 (95% confidence interval [CI], 0.56–0.76), 0.81 (95% CI, 0.73–0.89), 0.69 (95% CI, 0.59–0.79), and 0.86 (95% CI, 0.79–0.93), respectively. The level of serum PTEN protein was negatively correlated with the expression of miR‐106a and miR‐19b. PTEN concentration was positively correlated with serum urea (Urea), creatinine (Crea), cystatin C (Cysc), 24 h urine total protein (24 h‐UP) and negatively correlated with albumin (Alb) and estimated glomerular filtration rate (eGFR). Conclusions MiR‐106a, miR‐19b, miR‐17, and PTEN are involved in the pathogenesis of IMN and may become new biomarkers for the diagnosis of IMN. The concentration of serum PTEN protein was significantly increased in IMN as compared with controls. Compared with miR‐106a, miR‐19b, and miR‐17, the diagnostic performance of PTEN was the highest in IMN. Serum PTEN was positively correlated with Urea, Crea, Cysc, and 24h‐UP, and negatively correlated with Alb and eGFR. Serum PTEN was involved in the pathogenesis of IMN, and may become a new biomarker for the diagnosis of IMN.

The present study aimed to investigate whether microRNA (miR)-451a plays a role in polycystic ovary syndrome by regulating the biological function of ovarian granulosa cells and investigate the underlying molecular mechanism. In the present study, reverse transcription-quantitative PCR (RT-qPCR) analysis detected markedly low expression of miR-451a in KGN cells. TargetScan predicted that cyclic AMP-dependent transcription factor ATF-2 (ATF2) was a potential target gene of miR-451a, which was confirmed by a Dual-Luciferase reporter gene assay. Moreover, western blotting and RT-qPCR experiments indicated that ATF2 was significantly overexpressed in KGN cells. In addition, western blotting and RT-qPCR experiments were utilized to assess cell transfection efficiency, and it was found that miR-451a mimic significantly increased miR-451a expression in KGN cells. Subsequently, MTT assay was performed to detect cell proliferation and flow cytometry was utilized to detect cell apoptosis. Western blot and RT-qPCR assays were utilized to assess the protein and mRNA expression of ATF2 and cyclin D1. The results confirmed that miR-451a mimic significantly decreased ATF2 protein and mRNA expression in KGN cells, and this decrease was reversed by ATF2-plasmid co-transfection. Moreover, miR-451a mimic inhibited cell proliferation, enhanced cell apoptosis, reduced cyclin D1 expression, increased caspase-3 activity and cleaved caspase-3 protein levels, while it reduced pro-caspase 3 protein levels in KGN cells, and these effects were significantly reversed by ATF2-plasmid. The present preliminary results demonstrated that miR-451a regulated the proliferation and apoptosis of ovarian granulosa cells by targeting ATF2. Thus, the miR-451a/ATF2 axis may be a new potential target for the treatment of polycystic ovary syndrome.

To investigate differentially expressed genes regulated by microRNA-451a in colorectal cancer. We detected expression of microRNA-451a in colorectal cancer samples and normal pericarcinous tissues from 68 colorectal cancer patients and the correlation between microRNA-451a and clinical features of these patients. Then, the expression of microRNA-451a in HCT116, SW620, HT29, SW480, and DLD cells was also measured. The suppression subtractive hybridization method was used with two HCT116 cell lines with overexpressing or underexpressing microRNA-451a, respectively. The most highly increased genes were screened. Their functions were predicted by gene ontology analysis. The expression ratio of microRNA-451a in colorectal cancer to pericarcinous tissues was 0.37. Expression of microRNA-451a was decreased in HCT116, SW620, HT29, SW480, and DLD cells. In our suppression subtractive hybridization library, expression of seven genes was the most highly increased when underexpressing microRNA-451a. They were BCAP31, EEF1A1, CDC20, WDR6, TUFM, RPL13, and RPL7A. Expression of DKK1, PSME1, NDUFA3, and GNB2 was most highly increased when overexpressing microRNA-451a. Gene ontology analysis showed that the main functions of these genes were associated with translational elongation, protein localization to the endoplasmic reticulum, translation, poly(A) RNA binding, negative regulations of Wnt signaling pathway, and so on. MicroRNA-451a was demonstrated to be downregulated in colorectal cancer patient tissues whose target genes were analyzed and functions were predicted by suppression subtractive hybridization.