Expression Of miR-21 Research Articles

MiRNAs in Neurological Manifestation in Patients Co-Infected with SARS-CoV-2 and Herpesvírus 6 (HHV-6).

Human herpesviruses (HHVs) can establish latency and be reactivated, also are neurotropic viruses that can trigger neurological disorders. HHV-6 is a herpesvirus that is associated with neurological disorders. Studies have reported the detection of HHV-6 in patients with COVID-19 and neurological manifestations. However, specific diagnoses of the neurological disorders caused by these viruses tend to be invasive or difficult to interpret. This study aimed to establish a relationship between miRNA and neurological manifestations in patients co-infected with COVID-19 and HHV-6 and evaluate miRNAs as potential biomarkers. Serum samples from COVID-19 patients in the three cohorts were analyzed. miRNA analysis by real-time polymerase chain reaction (qPCR) revealed miRNAs associated with neuroinflammation were highly expressed in patients with neurological disorders and HHV-6 detection. When compared with the group of patients without detection of HHVs DNA and without neurological alterations, the group with detection of HHV-6 DNA and neurological alteration, displayed significant differences in the expression of mir-21, mir-146a, miR-155 and miR-let-7b (p < 0.01). Our results reinforce the involvement of miRNAs in neurological disorders and provide insights into their use as biomarkers for neurological disorders triggered by HHV-6. Furthermore, understanding the expression of miRNAs may contribute to therapeutic strategies.

Identification of miR-106b-5p, miR-601, and miR-760 Expression and Their Clinical Values in Non-Small Cell Lung Cancer (NSCLC) Patients' Serum

Aimto explore the relative quantitative determination of the serum level of three miRNAs (miR-601, 760, and 106b-5p) and determine their expression pattern in non-small cell lung cancer (NSCLC) patients in comparison to controls. Also, to reveal each miRNA's diagnostic and prognostic impact on NSCLC patients. Materials and methodsSerum miR-106b-5p, 601, and 760 expression profiles were estimated by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) for 70 NSCLC patients, age-matched with 30 control subjects. The receiver operating characteristic (ROC) curve analysis estimated their diagnostic and prognostic potentials. ResultsIn comparison to the control, the miR-106b-5p expression pattern was upregulated (1.836 ± 0.254, p = 0.0012) while both miR-601 and miR-760 expression patterns were considerably downregulated (−0.586 ± 0.1906, p < 0.0001) and (−1.633 ± 0.152, p < 0.0001), respectively with predominant down-expression for miR-760 among cases. MiR-760 showed the highest diagnostic potential (AUC = 0.943 and 0.864 respectively), whereas miR-601 has a higher prognostic power (AUC = 0.771 and 0.682, respectively) for differentiating early stages (I/II) NSCLC patients from control subjects. Moreover, miR-760 presented the highest prognostic potential for differentiating NSCLC stages. ConclusionBoth serum miR-760 and miR-601 may be used as potential biomarkers of NSCLC in Egyptian patients with a stronger staging and diagnostic potential for miR-760.

Targeting microRNA-145-mediated progressive phenotypes of early bladder cancer in a molecularly defined in vivo model

A progressive subclass of early-stage non-muscle-invasive bladder cancer (NMIBC) frequently recurs and progress into invasive carcinoma, thus decreasing the overall survival rate of NMIBC. However, therapeutic development for progressive NMIBC has been challenging due to the lack of molecularly validated invivo models and agents targeting its genetic vulnerability. We herein molecularly characterized an interventional model of progressive NMIBC and revealed the principal functions and therapeutic potential of microRNA-145 (miR-145) in early bladder tumorigenesis. N-butyl-N-(4-hydroxybutyl)nitrosamine-induced premalignant lesions (BiPLs) in rats exhibited downregulated expression of miR-145 as well as highly similar mutation/expression profiles to those of the human progressive NMIBC subclass with the worst prognosis. The expression patterns of miR-145 inversely correlated with those of BC-related oncogenes in BiPLs. We also demonstrated that miR-145 dominantly regulated interferon pathways and c-Myc expression, which play a crucial role in the pathogenesis of progressive NMIBC. Furthermore, we demonstrated that miR-145 replacement with a novel miR-145-based intravesical agent (miR-145S1) significantly inhibited the progression of BiPLs invivo. These results provide insights into the essential role of miR-145 as the earliest-acting oncogenic driver of bladder tumorigenesis as well as a validated interventional model and novel miR-145-based nucleic acid therapeutic agent for progressive NMIBC.

Inhibition of miR-543 alleviates cardiac fibroblast-to-myofibroblast transformation and collagen expression in insulin resistance via targeting PTEN

BackgroundMyocardial interstitial fibrosis is an important manifestation of diabetic heart disease, and insulin resistance is one of the mechanisms of myocardial interstitial fibrosis. Some studies have found that miR-543 is associated with insulin resistance, but whether it plays a role in diabetic myocardial interstitial fibrosis remains unclear. This study aimed to investigate the role of miR-543 in diabetic myocardial interstitial fibrosis. MethodsThe combination of high glucose and high insulin was used to establish an insulin-resistant myocardial fibroblast model. The expression levels of miR-543, α-SMA, collagen Ⅰ, collagen Ⅲ and PTEN were detected. Cell proliferation and migration were detected. Luciferase reporter gene assay was used to verify the targeting relationship between miR-543 and PTEN. ResultsThe expression of miR-543 was up-regulated in myocardial fibroblasts with insulin resistance, which was consistent with the results of bioinformatics analysis. The proliferation and migration levels of myocardial fibroblasts in insulin-resistant states were increased, and the expression levels of α-SMA, collagen Ⅰ and collagen Ⅲ were also increased. Inhibition of miR-543 expression could reverse the above changes. Target gene prediction and dual luciferase reporter assay demonstrated that miR-543 could bind to the 3′UTR region of PTEN. Moreover, the effect of miR-543 on insulin-resistant myocardial fibroblasts is mediated by targeting PTEN. ConclusionsInhibition of miR‐543 can reduce myocardial fibroblast-myofibroblast transformation and collagen expression in insulin-resistant states by targeting PTEN.

MiR-153 Targets Autophagy and Apoptosis Caspase Family to Explore the Molecular Mechanism of Polystyrene Nanoparticles Intervening in Thoracoabdominal Aortic Aneurysm

This study investigates whether miR-153 regulates the expression of autophagy and apoptosis-related gene Caspase3, and analyzes the role of polystyrene nanoparticles in thoracoabdominal aortic aneurysm cells. Surgically resected thoracoabdominal aortic aneurysm tissue samples were included as the observation group and the control group included 2 cm tissues from the side of thoracoabdominal aortic aneurysm. The mRNA levels of miR-153 and Caspase3 were assessed by reverse transcription polymerase chain reaction (RT-PCR) and cell proliferation, apoptosis, invasion, and migration were evaluated. Tissue microarray and RT-PCR showed that miR-153 was expressed in tissues and it displayed a targeted relationship with Caspase3. Transwell results showed that transfection of miR-153-targeted Caspase3 nanoparticles significantly reduced the infiltration of thoracic and aortic aneurysm. After si-RNA interfered with the expression of miR-153, the proliferation rate of thoracoabdominal aortic aneurysms in the miR-153-targeted Caspase3-directed nanoparticle group was significantly reduced. On the contrary, when miR-153 was overexpressed, the apoptosis was significantly reduced. Transfection of si-miR-153-targeting Caspase3 nanoparticles significantly reduced the invasion and metastasis ability of thoracoabdominal aortic aneurysm cells and the migration ability was increased after reversing miR-153 expression. The decreased expression of miR-153 is related to the increased expression of Caspase3 and enhanced invasion and metastasis of thoracoabdominal aortic aneurysms. Overexpression of miR-153 can inhibit the expression of Caspase3 and targeted nanoparticles can effectively enhance cell activities.

Circulating and Endometrial Profiles of miR-145, miR-155-5p, miR-224, MPP-5, and PECAM-1 Expression in Patients with Repeated Implantation Failure: A Case Control Study.

An association between microRNAs (miRNAs) and adhesion proteins expression with repeated implantation failure (RIF) has been recently reported; however, these findings are controversial. This study aims to evaluate the endometrial and circulating expressions of miR-145, miR-155-5p, and miR-224 in addition to the endometrial expressions of membrane protein palmitoylated-5 (MPP-5) and endothelial cell adhesion molecule-1 (PECAM-1) in patients with RIF compared to control subjects. This case-control study was carried out between June 2021-July 2022. Subjects included 17 patients with RIF and 17 control subjects, who had previous spontaneous term pregnancy with a live birth, who referred to the Medical Centre of Arash Hospital, Tehran, Iran. Endometrial tissue samples were obtained via hysteroscopy and Pipelle catheter in the RIF and control subjects, respectively. Plasma samples were collected after ovulation in all subjects. The expression levels of MPP5, PECAM-1, miR-224, miR-145, and miR-155-5p were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). The student's t test, chi-square, Mann-Whitney U, and analysis of covariance (ANCOVA) were used for data analyses. RIF patients had less endometrial miR-155-5p expression, and higher endometrial and circulating expressions of miR-145 and miR-224 compared to control subjects. Endometrial PECAM-1 and MPP5 expression significantly decreased in patients with RIF compared to the control group. There was a positive correlation between circulating miR-224 and endometrial miR-155-5p, and between circulating miR-155-5p and endometrial PECAM-1 expression levels in patients with RIF. The present study suggests that circulating miR-224, endometrial miR-145, and PECAM-1 can be reliable, novel biomarkers for diagnosis of RIF.

Biological and therapeutic viewpoints towards role of miR-218 in human cancers: Revisiting molecular interactions and future clinical translations

Understanding the exact pathogenesis of cancer is difficult due to heterogenous nature of tumor cells and multiple factors that cause its initiation and development. Treatment of cancer is mainly based on surgical resection, chemotherapy, radiotherapy and their combination, while gene therapy has been emerged as a new kind of therapy for cancer. Post-transcriptional regulation of genes has been of interest in recent years and among various types of epigenetic factors that can modulate gene expression, short non-coding RNAs known as microRNAs (miRNAs) have obtained much attention. The stability of mRNA decreases by miRNAs to repress gene expression. miRNAs can regulate tumor malignancy and biological behavior of cancer cells and understanding their function in tumorigenesis can pave the way towards developing new therapeutics in future. One of the new emerging miRNAs in cancer therapy is miR-218 that increasing evidence highlights its anti-cancer activity, while a few studies demonstrate its oncogenic function. The miR-218 transfection is promising in reducing progression of tumor cells. miR-218 shows interactions with molecular mechanisms including apoptosis, autophagy, glycolysis and EMT, and the interaction is different. miR-218 induces apoptosis, while it suppresses glycolysis, cytoprotective autophagy and EMT. Low expression of miR-218 can result in development of chemoresistance and radio-resistance in tumor cells and direct targeting of miR-218 as a key player is promising in cancer therapy. LncRNAs and circRNAs are nonprotein coding transcripts that can regulate miR-218 expression in human cancers. Moreover, low expression level of miR-218 can be observed in human cancers such as brain, gastrointestinal and urological cancers that mediate poor prognosis and low survival rate.

1705-P: Expression of Selected MicroRNAs in Adipose Tissue-Derived Mesenchymal Stem Cells and Metabolic Syndrome

Adipose tissue mesenchymal stem cells (AdMSC) secrete microRNAs (miR). Although miR are involved in pathogenesis of metabolic syndrome, the role of those secreted by AdMSC remains elusive. We aimed to assess expression of selected miR by AdMSC in relation to basic metabolism parameters in nondiabetic adults. For this preliminary study 10 obese, 8 overweight and 5 normal weight subjects with no inflammatory or cancerous disease were enrolled, including 19 female and 6 prediabetic ones. AdMSC were harvested from abdominal subcutaneous fat and cultured in standard conditions. Expressions of four miR reported in metabolic disturbances were estimated with RT-qPCR. Total and visceral fat were assessed with bioimpedance. Expression of miR-21, miR-122, or miR-192 did not correlate with any clinical parameter. On the other hand, expression of miR-155 [2-ΔCt] was lowest in obese subjects (3.69±2.67 vs. 7.07±4.42 in overweight and 10.25±7.05 ×10-3 in normal weight ones, P =0.04, K-W ANOVA). It correlated inversely with BMI, total fat mass, visceral adiposity, and serum CRP, whereas positively (marginally significantly) with serum HDL-cholesterol (table 1). Expression of miR-155 in AdMSC appears blunted in visceral obesity, which correlates with HDL-dyslipidemia and microinflammation. This calls for further study of AdMSC miR secretome in the pathogenesis of metabolic syndrome with focus on miR-155. Disclosure G. Wystrychowski: Other Relationship; Polfa Tarchomin. K. Simka-Lampa: None. A. Witkowska: None. E. Sobecko: None. A. Skubis-Sikora: None. B. Sikora: None. E. Wojtyna: None. K. Gwizdek: None. A. Golda: Other Relationship; Servier Laboratories. M. Wróbel: Other Relationship; Novo Nordisk, Lilly, Boehringer Ingelheim Inc. C. Kruszniewska-Rajs: None. J. Gola: None. Funding Medical University of Silesia, Katowice, Poland

MiR-155 and miR-92 levels in ALL, post-transplant aGVHD, and CMV: possible new treatment options

BackgroundAcute lymphoblastic leukemia (ALL) is a malignancy that leads to altered blast cell proliferation, survival, and maturation and eventually to the lethal accumulation of leukemic cells. Recently, dysregulated expression of various micro-RNAs (miRNAs) has been reported in hematologic malignancies, especially ALL. Cytomegalovirus infection can induce ALL in otherwise healthy individuals, so a more detailed evaluation of its role in ALL-endemic areas like Iran is required.MethodsIn this cross-sectional study, 70 newly diagnosed adults with ALL were recruited. The expression level of microRNA-155(miR-155) and microRNA-92(miR-92) was evaluated by real-time SYBR Green PCR. The correlations between the miRNAs mentioned above and the severity of disease, CMV infection, and acute graft vs. host disease after hematopoietic stem cell transplantation (HSCT) were assessed. B cell and T cell ALL distinction in the level of miRNAs was provided.ResultsAfter the statistical analysis, our results indicated a marked increase in the expression of miR-155 and miR-92 in ALL patients vs. healthy controls (*P = 0.002–*P = 0.03, respectively). Also, it was shown that the expression of miR-155 and miR-92 was higher in T cell ALL compared to B cell ALL (P = 0.01–P = 0.004, respectively), CMV seropositivity, and aGVHD.ConclusionOur study suggests that the plasma signature of microRNA expression may act as a powerful marker for diagnosis and prognosis, providing knowledge outside cytogenetics. Elevation of miR-155 in plasma can be a beneficial therapeutic target for ALL patients, with consideration of higher plasma levels of miR-92 and miR-155 in CMV + and post-HSCT aGVHD patients.

#3022 REDUCED TUBULAR MIR-190A-5P: A NOVEL BIOMARKER FOR STRATIFICATION OF PATIENTS WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims Circulating microRNA (miRNAs) have been proposed as potential diagnostic and prognostic biomarkers and are functionally important in disease pathogenesis. In this study, we used an unbiased measurement of circulating miRNAs in patients with type 2 diabetes to identify a miRNA differentially expressed in kidney disease before moving to a larger, unselected cohort of patients with CKD to assess its potential to predict progression in CKD. Method MiRNA next generation sequencing (NGS) studies were undertaken to measure differential expression of plasma miRNAs in a discovery cohort of 3 groups; individuals with type 2 diabetic kidney disease (T2DKD, n = 9), age and sex matched patients with type 2 diabetes mellitus and normal renal function (T2DNRF, n = 13) and patients without diabetes and with normal renal function (NDNRF, n = 11). Differentially expressed miRs were validated in a separate cohort of the same groups (each n = 10). The prognostic value of miR-190a-5p in a general CKD population was assessed using the seNSOR cohort (n = 395, excluding patients on RRT, with an eGFR of &amp;lt; = 20 ml/min/1.73 m2 or AKI at recruitment). The primary outcome of CKD progression was defined as reaching ESKD (starting RRT or maintaining an eGFR &amp;lt;15mls/min) or &amp;gt;30% reduction in renal function from eGFR at baseline. Reaching ESKD alone was used as a secondary outcome. Results MiR-190a-5p was the only miRNA differentially expressed between T2DKD and both control groups in both the discovery and validation cohorts. In the seNSOR cohort, miR-190a-5p levels correlated positively with eGFR (rho = 0.12, p = 0.04) and inversely with age (rho = -0.12, p = 0.04). MiR-190a-5p levels below the median predicted CKD progression in individuals with minimal and moderate albuminuria (ACR &amp;lt; 3mg/mmol and 3-300mg/mmol respectively) but not in those with severe albuminuria (ACR&amp;gt;300mg/mmol, see figure). In those without severe albuminuria, miR-190a-5p levels predicted CKD progression in multivariate Cox proportional hazards models (HR 0.8, 95% CI: 0.66-0.96, p = 0.015), independently of baseline eGFR, ACR, age, SBP, DBP and sex. When participants with an ACR &amp;gt; 300mg/mmol were included, miR-190a-5p was not predictive of the composite CKD progression endpoint (multivariate HR 0.86, p = 0.064) but was predictive for reaching ESKD alone (multivariate HR 0.68, 95% CI: 0.5-0.93, p = 0.015). Analysis of miR-190 expression in individual renal cell types in the reversible unilateral ureter obstruction mouse model revealed that it is enriched in proximal tubule cells and falls significantly following injury before increasing again the repair phase. Conclusion miR-190a-5p is expressed by healthy proximal renal tubular cells and serum miR-190a-5p levels correlate positively with eGFR. Low serum miR-190a-5p levels may predict progression of CKD in patients with low or moderate proteinuria independently of existing risk factors.

Exosomal miR-21-5p derived from multiple myeloma cells promote renal epithelial-mesenchymal transition through targeting TGF-β/SMAD7 signalling pathway.

The prognosis of multiple myeloma (MM) patients combined with renal insufficiency is poor. Renal fibrosis is an important pathological cause for MM patients combined with renal insufficiency. It is reported that epithelial-mesenchymal transition (EMT) of renal proximal tubular epithelial cells is an important mechanism in renal fibrosis. We speculated that EMT might play an important role in the renal insufficiency of MM with unclear mechanism. MM cells derived exosomes could affect the function of targeted cells by delivering microRNAs (miRNAs). Literature has shown that the expression of miR-21 is closely related to EMT. In this research, we found that co-culture of HK-2 cells (human renal proximal tubular epithelial cells) and exosomes derived from MM cells promoted the EMT of HK-2 cells, resulting in the down-regulation of epithelial-related marker (E-cadherin), and up-regulation of stroma-related marker (Vimentin). Meanwhile, the expression of SMAD7, one of the downstream targets in the TGF-β signalling pathway, was suppressed and the expression of TGF-β was increased. After transfecting the inhibitor of miR-21 in MM cells, the expression of miR-21 in exosomes secreted by MM cells was significantly decreased, and the co-culture of these treated exosomes and HK-2 cells inhibited the EMT of HK-2 cells. In conclusion, these findings showed that exosomal miR-21 derived from MM cells could promote renal EMT through targeting TGF-β/SMAD7 signalling pathway.

MiR-145 as a Potential Biomarker and Therapeutic Target in Patients with Non-Small Cell Lung Cancer.

Our previous study found that miR-145 was downregulated in non-small cell lung cancer (NSCLC) tissues and that it could inhibit the cell proliferation in transfected NSCLC cells. In this study, we found that miR-145 was downregulated in NSCLC plasma samples compared to healthy controls. A receiver operating characteristic curve analysis indicated that plasma miR-145 expression was correlated with NSCLC in patient samples. We further revealed that the transfection of miR-145 inhibited the proliferation, migration, and invasion of NSCLC cells. Most importantly, miR-145 significantly delayed the tumor growth in a mouse model of NSCLC. We further identified GOLM1 and RTKN as the direct targets of miR-145. A cohort of paired tumors and adjacent non-malignant lung tissues from NSCLC patients was used to confirm the downregulated expression and diagnostic value of miR-145. The results were highly consistent between our plasma and tissue cohorts, confirming the clinical value of miR-145 in different sample groups. In addition, we also validated the expressions of miR-145, GOLM1, and RTKN using the TCGA database. Our findings suggested that miR-145 is a regulator of NSCLC and it plays an important role in NSCLC progression. This microRNA and its gene targets may serve as potential biomarkers and novel molecular therapeutic targets in NSCLC patients.

CircRNA-02191 regulating unsaturated fatty acid synthesis by adsorbing miR-145 to enhance CD36 expression in bovine mammary gland

CD36 functions as a receptor for long-chain fatty acids, promoting the absorption and transport of long-chain unsaturated fatty acids. However, the regulatory influence of upstream circRNAs or miRNAs on its expression in cow mammary gland remains unclear. Herein, we performed high-throughput sequencing to screen for differentially expressed miRNAs and mRNAs in bovine mammary tissue during the late-lactation and the dry period to screen and conducted bioinformatics analysis to identify 420 miRNA/mRNA pairs, including miR-145/CD36. Experimental results indicate that miR-145 can directly target CD36 and inhibit its expression. Additionally, the circRNA-02191 sequence is predicted to contain a miR-145 binding site. As shown by dual luciferase reporter system detection, circRNA-02191 bound to miR-145 and its overexpression significantly reduced the expression of miR-145. Furthermore, the overexpression of miR-145 inhibited triglyceride accumulation, while circRNA-02191 enhanced the expression of the miR-145 target gene CD36. The above results indicate that circRNA-02191 can regulate triglyceride and fatty acid components by binding miR-145 and subsequently alleviating the inhibitory effect of miR-145 on the expression of CD36. Taken together, these findings present a novel approach to improve milk quality by analyzing the regulatory effect and mechanism regulating the circ02191/miR-145/CD36 pathway on fatty acid synthesis in the mammary gland of dairy cows.

Circular RNA Circ_0038467 promotes the maturation of miRNA-203 to increase lipopolysaccharide-induced apoptosis of chondrocytes.

Circ_0038467 and miR-203 exert important functions in lipopolysaccharide (LPS)-induced inflammation, which contributes to osteoarthritis (OA). Our preliminary deep sequencing analysis revealed altered expression of Circ_0038467 and miR-203 in OA and a close correlation between them. This study was therefore to explore crosstalk between them in OA. The expression of Circ_0038467, mature miR-203, and miR-203 precursor in OA patients and controls was determined using RT-qPCR. An overexpression assay was performed to explore the role of Circ_0038467 in regulating the expression of mature miR-203 and miR-203 precursor. Cell apoptosis was analyzed by cell apoptosis assay. Circ_0038467 was upregulated in OA and positively correlated with mature miR-203 but not that of miR-203 precursor. In chondrocytes, increased expression levels of both Circ_0038467 and miR-203 were observed after LPS treatment. In chondrocytes, overexpression of Circ_0038467 increased the expression levels of mature miR-203 but not that of miR-203 precursor. Overexpression of Circ_0038467 and miR-203 increased cell apoptosis. Then, the miR-203 inhibitor reversed the effects of overexpression of Circ_0038467 on cell apoptosis. Interestingly, Circ_0038467 was detected in both the cytoplasm and nucleus. Circ_0038467 directly interacted with the precursor miR-203. Therefore, Circ_0038467 is highly expressed in OA and it may promote the production of mature miR-203 to increase apoptosis of chondrocytes induced by LPS.

Deregulation of miR-10b and miR-21 Correlate with Cancer Stem Cells Expansion through the Apoptotic Pathway in Prostate Cancer.

MicroRNAs are small, non-coding RNA molecules that regulate important cellular processes such as tumorigenesis, cell proliferation, and apoptosis. Cancer stem cells are a subset of cells that control metastasis and cell proliferation. In this study, we focus on the roles of miR-10b, miR-21 and correlate with cancer stem cells through the apoptotic pathway in different stages of prostate cancer (PCa). In total, 45 patients, each group with Benign prostatic hyperplasia (BPH), localised PCa, and metastatic PCa, were recruited. MicroRNA and gene expression were estimated through quantitative polymerase chain reaction. Flow cytometry was used to characterise prostate cancer stem cells (PCSCs), estimate reactive oxygen species (ROS), apoptosis and chemiluminescent immunoassay was used to estimate interleukin 6 (IL-6), tumour necrosis factor (TNF-α), prostate-specific antigen (PSA), and testosterone. The fold change mean expressions of miR-21, miR-10b, Cytochrome C, and B-cell lymphoma 2 (BCL-2) were significantly upregulated in localised and metastatic PCa compared with BPH. In contrast, the mean fold change expressions of Bcl-2-associated X protein (BAX), Caspase-3, Caspase-9, and Second mitochondria-derived activator of caspase (SMAC) were lower in localised and metastatic PCa compared to BPH. The levels of IL-6, TNF-α, ROS, PSA and testosterone also showed a significant increase while apoptosis was decreased in both localized PCa and metastatic PCa as compared with BPH. In bioinformatics analyses, we found a similar pattern of miRNAs and gene expression in PCa databases. Our study also found a high expression of CD44+/CD24- and CD44+/CD133+ in localised and metastatic PCa compared with BPH. Our findings suggest miR-10b and miR-21 promote PCSCs and may target apoptotic genes involved in PCa pathogenesis; these miRNAs could be used as diagnosis biomarkers of PCa. In PCa pathogenesis and PCSCs regulation, the interaction between these two players is crucial and will help develop new PCa therapeutic targets.

Exosomal miR-218 derived from mesenchymal stem cells inhibits endothelial-to-mesenchymal transition by epigenetically modulating of BMP2 in pulmonary fibrosis.

Endothelial-to-mesenchymal transition (EndMT), the process by which endothelial cells lose their characteristics and acquire mesenchymal phenotypes, participates in the pathogenic mechanism of idiopathic pulmonary fibrosis. Recently, exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-Exos) has been introduced as a promising treatment in organ fibrosis. This study aimed to explore the effects as well as the molecular mechanism for hucMSC-Exo in pulmonary fibrosis. The intravenous administration of hucMSC-Exos alleviated bleomycin-induced pulmonary fibrosis in vivo. Moreover, hucMSC-Exos elevated miR-218 expression and restored endothelial properties weakened by TGF-β in endothelial cells. Knockdown of miR-218 partially abrogated the inhibition effect of hucMSC-Exos on EndMT. Our mechanistic study further demonstrated that MeCP2 was the direct target of miR-218. Overexpressing MeCP2 aggravated EndMT and caused increased CpG islands methylation at BMP2 promoter, which lead to BMP2 post-transcriptional gene silence. Transfection of miR-218 mimic increased BMP2 expression as well, which was downregulated by overexpression of MeCP2. Taken together, these findings indicate exosomal miR-218 derived from hucMSCs may possess anti-fibrotic properties and inhibit EndMT through MeCP2/BMP2 pathway, providing a new avenue of preventive application in pulmonary fibrosis.

Mechanisms of human umbilical cord mesenchymal stem cells-derived exosomal lncRNA GAS5 in alleviating EMT of HPMCs via Wnt/β-catenin signaling pathway.

Prolonged peritoneal dialysis (PD) can result in epithelial-to-mesenchymal transition (EMT) and peritoneal fibrosis (PF), which can cause patients to discontinue PD. It is imperative to urgently investigate effective measures to mitigate PF. This study aims to reveal mechanisms of exosomal lncRNA GAS5 derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) on EMT of human peritoneal mesothelial cells (HPMCs) under high glucose (HG) conditions. HPMCs were stimulated with 2.5% glucose. The effects on EMT of HPMCs were observed by using an hUC-MSC conditioned medium (hUC-MSC-CM) and extracted exosomes. After hUC-MSCs were transfected with GAS5 siRNA, exosomes were extracted to act on HPMCs for detecting EMT markers, PTEN, and Wnt/β-catenin pathway, lncRNA GAS5 and miR-21 expressions in HPMCs. We found that HG could induce the EMT of HPMCs. Compared with the HG group, the hUC-MSC-CM could alleviate the EMT of HPMCs induced by HG through exosomes. Exosomes in the hUC-MSC-CM entered HPMCs, by transferring lncRNA GAS5 to HPMCs, which down-regulates miR-21 and up-regulates PTEN, thus finally alleviating EMT of HPMCs. The Wnt/β-catenin pathway plays an essential role in alleviating EMT of HPMCs by exosomes in the hUC-MSC-CM. By transferring lncRNA GAS5 to HPMCs, exosomes derived from hUC-MSCs may competitively bind to miR-21 to regulate suppression on target PTEN genes and alleviate EMT of HPMCs through the Wnt/β-catenin pathway. Exosomes from the hUC-MSCs-CM could alleviate the EMT of HPMCs induced by HG via regulating lncRNA GAS5/miR-21/PTEN through the Wnt/β-catenin signaling pathway.

Pterostilbene-isothiocyanate reduces miR-21 level by impeding Dicer-mediated processing of pre-miR-21 in 5-fluorouracil and tamoxifen-resistant human breast cancer cell lines.

Converging evidences identifies that microRNA-21 (miR-21) is responsible for drug resistance in breast cancer. This study aims to evaluate the miR-21-modulatory potential of a hybrid compound, pterostilbene-isothiocyanate (PTER-ITC), in tamoxifen-resistant MCF-7 (TR/MCF-7) and 5-fluorouracil-resistant MDA-MB 231 (5-FUR/MDA-MB 231) breast cancer cell lines, established by repeated exposure to gradually increasing the concentrations of tamoxifen and 5-fluorouracil, respectively. The outcome of this study shows that PTER-ITC effectively reduced the TR/MCF-7 (IC50: 37.21µM) and 5-FUR/MDA-MB 231 (IC50: 47.00µM) cell survival by inducing apoptosis, inhibiting cell migration, colony and spheroid formations in TR/MCF-7 cells, and invasiveness of 5-FUR/MDA-MB 231 cells. Most importantly, PTER-ITC significantly reduced the miR-21 expressions in these resistant cell lines. Moreover, the downstream tumor suppressor target gene of miR-21 such as PTEN, PDCD4, TIMP3, TPM1, and Fas L were upregulated after PTER-ITC treatment, as observed from transcriptional (RT-qPCR) and translational (immunoblotting) data. In silico and miR-immunoprecipitation (miR-IP) results showed reduced Dicer binding to pre-miR-21, after PTER-ITC treatment, indicating inhibition of miR-21 biogenesis. Collectively, the significance of this study is indicated by preliminary evidence for miR-21-modulatory effects of PTER-ITC that highlights the potential of this hybrid compound as an miR-21-targeting therapeutic agent.

Different expression profiles of circulating miR-31 and miR-181a in CD4+ T cells and plasma of patients with oral lichen planus

Oral lichen planus (OLP) is a T cell-mediated inflammatory–immune disease in which CD4+ T cells may be significantly involved in the dysregulated immune response. MicroRNAs (miRNAs) critically control gene expression post-transcriptionally and regulate the immune response and inflammation. Here, we explored the expression profiles of circulating miRs (miR-19b, miR-31, and miR-181a), which can modulate CD4+ T cell activation, differentiation, and immune function. Quantitative real-time PCR showed that miR-31 and miR-181a dramatically decreased in peripheral CD4+ T cells, whereas they markedly increased in the plasma of OLP patients, especially in the erosive form. However, no significant differences were observed in the expression of miR-19b in CD4+ T cells and plasma between OLP patients and healthy controls or between different forms of OLP. Moreover, miR-31 expression positively correlated with the miR-181a expression in the CD4+ T cells and plasma of OLP patients. Furthermore, receiver operating characteristic (ROC) curve analyses indicated that miR-31 and miR-181a, rather than miR-19b, in CD4+ T cells and plasma could discriminate OLP, especially erosive OLP, from healthy controls. In conclusion, there were different expression profiles of circulating miR-31 and miR-181a in CD4+ T cells and plasma of patients with OLP, which could synergistically serve as potential biomarkers for OLP.

MicroRNA-98 inhibition accelerates the development of atherosclerosis via regulation of dysfunction of endothelial cell

ABSTRACT Background Atherosclerosis has been recognized as a chronic inflammation initiated by dysfunction of endothelial cell that contributes to the increased morbidity and mortality of severe cardiovascular events. The reported important role of microRNA-98 (miR-98) in regulation of endothelial cell behaviors prompt us to hypothesize that miR-98 could be involved in the process of atherosclerosis. Methods and Results The current research showed the miR-98 expression was gradually down-regulated in atherosclerotic mouse arteries isolated from ApoE ablation mice subjected to high fat diet. Additionally, a dramatically reduced miR-98 expression in endothelial cells administrated to oxidized low-density lipoprotein (Ox-LDL) but a slight down-regulated level was found in macrophages. Functionally, attenuated miR-98 expression promoted secretion of chemokines and adhesion molecules in human umbilical vein endothelial cells (HUVECs) induced by Ox-LDL, which subsequently increased infiltration and pro-inflammatory genes expression of macrophages, as well as the foam cell formation. Mechanistically, in vitro experiments indicated that the endothelial cell dysfunction regulated by miR-98 knockdown was partially contributed by upregulated expression of HMGB1. Furthermore, the animal experiment with ApoE−/− mice administrated with miR-98 inhibitor demonstrated that miR-98 silencing enhanced the atherosclerotic lesions in aorta and aortic sinus that were accompanied with increased adhesion molecules, chemokines, and pro-inflammatory markers expression. Conclusion MicroRNA-98 knockdown promoted endothelial cell dysfunction to affect the inflammatory state of macrophage and the development of atherosclerosis, at least partially, through direct targeting HMGB1. Collected, these data suggested that miR-98 could be a novel drug target for atherogenesis management.