Статті в журналах: "MiR-409-3p"

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Wang, Chun, Shengxia Yin, Qin Wang, Min Jiang, Shanshan Li, Wen Zhen, Yi Duan, and Huanyu Gu. "miR-409-3p Regulated by GATA2 Promotes Cardiac Fibrosis through Targeting Gpd1." Oxidative Medicine and Cellular Longevity 2022 (October 12, 2022): 1–21. http://dx.doi.org/10.1155/2022/8922246.

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Cardiac fibrosis is a hallmark of numerous chronic cardiovascular diseases that leads to heart failure. However, there is no validated therapy for it. Dysregulation of microRNAs has been confirmed to be involved in cardiac fibrosis development. However, the regulatory network was not well explored. This study was the first to highlight the role and molecular mechanism of miR-409-3p in cardiac fibrosis. We found that miR-409-3p was consistently increased in three fibrotic models, including heart tissues of postmyocardial infarction (MI) mice and neonatal rat cardiac fibroblasts treated with angiotensin II (Ang II) or transforming growth factor-β (TGF-β). Furthermore, myocardial infarction surgery-induced cardiac fibrosis and dysfunction were attenuated by systemic delivery of miR-409-3p antagomir. Notably, transfection with miR-409-3p mimics promoted the proliferation of cardiac fibroblasts and fibroblast-to-myofibroblast differentiation, accompanied by upregulated expression of Col1a1, Col3a1, and α-SMA. On the contrary, the miR-409-3p inhibitor exhibited the opposite effect. Following this, we verified Gpd1 as a direct target of miR-409-3p. Gpd1 siRNA abolished the antifibrotic effect of miR-409-3p inhibitor in neonatal rat cardiac fibroblasts, suggesting that miR-409-3p promotes cardiac fibrosis at least partially through Gpd1. Moreover, GATA2 was identified as a cardiac fibrosis-associated upstream positive transcription factor of miR-409-3p. Finally, these findings suggest that modulating miR-409-3p could be a potential therapeutic method for cardiac fibrosis.

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Liu, Bao, Jingqi Wang, Yanhua Cui, and Hui He. "Investigation of the Disparities in Ultrasound Imaging Features of miR-323, miR-409-3p, and VEGF Expression Scales in Different Clinicopathological Features of Prostate Carcinoma and Their Correlation with Prognosis." BioMed Research International 2022 (June 18, 2022): 1–6. http://dx.doi.org/10.1155/2022/5053204.

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Prostate carcinoma (PC) is a disease of the male genitourinary system and a relatively common malignant tumor. In order to investigate the disparities in the expression of microRNA-323 (miR-323), microRNA-409-3p (miR-409-3p), and vascular endothelial growth factor (VEGF) in prostate carcinoma with different clinicopathological features and analyze their correlation with prognosis. Thirty-two sufferers with prostate carcinoma and forty-three sufferers with benign prostatic hyperplasia are included. The results show that the detection of miR-323, miR-409-3p, and VEGF scales can provide reference value for clinical guidance of prostate carcinoma prognosis.

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Dini, Pouya, Hossam El-Sheikh Ali, Mariano Carossino, Shavahn C. Loux, A. Esteller-Vico, Kirsten E. Scoggin, Peter Daels, and Barry A. Ball. "Expression Profile of the Chromosome 14 MicroRNA Cluster (C14MC) Ortholog in Equine Maternal Circulation throughout Pregnancy and Its Potential Implications." International Journal of Molecular Sciences 20, no. 24 (December 13, 2019): 6285. http://dx.doi.org/10.3390/ijms20246285.

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Equine chromosome 24 microRNA cluster (C24MC), the ortholog of human C14MC, is a pregnancy-related miRNA cluster. This cluster is believed to be implicated in embryonic, fetal, and placental development. The current study aimed to characterize the expression profile of this cluster in maternal circulation throughout equine gestation. The expression profile of miRNAs belonging to this cluster was analyzed in the serum of non-pregnant (diestrus), pregnant (25 d, 45 d, 4 mo, 6 mo, 10 mo), and postpartum mares. Among the miRNAs examined, 11 miRNAs were differentially expressed across the analyzed time-points. Four of these miRNAs (eca-miR-1247-3p, eca-miR-134-5p, eca-miR-382-5p, and eca-miR-433-3p) were found to be enriched in the serum of pregnant mares at Day 25 relative to non-pregnant mares. To further assess the accuracy of these miRNAs in differentiating pregnant (25 d) from non-pregnant mares, receiver operating characteristic (ROC) analysis was performed for each of these miRNAs, revealing that eca-miR-1247-3p and eca-miR-134-5p had the highest accuracy (AUCROC = 0.92 and 0.91, respectively; p < 0.05). Moreover, eca-miR-1247-3p, eca-miR-134-5p, eca-miR-409-3p, and eca-miR-379-5p were enriched in the serum of Day 45 pregnant mares. Among those miRNAs, eca-miR-1247-3p and eca-miR-409-3p retained the highest accuracy as shown by ROC analysis. GO analysis revealed that these miRNAs are mainly implicated in nervous system development as well as organ development. Using in situ hybridization, we localized eca-miR-409-3p in the developing embryo (25 d) and extra-embryonic membranes (25 and 45 d). In conclusion, the present study is the first to elucidate the circulating maternal profile of C24MC-associated miRNAs throughout pregnancy and to suggest that serum eca-miR-1247-3p, eca-miR-134-5p, and eca-miR-409-3p could be used as pregnancy-specific markers during early gestation (25 and 45 d). Overall, the high abundance of these embryo-derived miRNAs in the maternal circulation suggests an embryo-maternal communication during the equine early pregnancy.

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Mantilla-Escalante, Diana C., María-Carmen López de las Hazas, Judit Gil-Zamorano, Lorena del Pozo-Acebo, M. Carmen Crespo, Roberto Martín-Hernández, Andrea del Saz, et al. "Postprandial Circulating miRNAs in Response to a Dietary Fat Challenge." Nutrients 11, no. 6 (June 13, 2019): 1326. http://dx.doi.org/10.3390/nu11061326.

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Postprandial lipemia has many physiopathological effects, some of which increase the risk of cardiovascular disease. MicroRNAs (miRNAs) can be found in almost all biological fluids, but their postprandial kinetics are poorly described. We aimed to profile circulating miRNAs in response to a fat challenge. In total, 641 circulating miRNAs were assessed by real-time PCR in plasmas from mice two hours after lipid gavage. Mice with intestine-specific loss of Dicer were screened to identify potential miRNAs released by the intestine. A total of 68 miRNAs were selected for further validation. Ten circulating miRNAs were finally validated as responsive to postprandial lipemia, including miR-206-3p, miR-543-3p, miR-466c-5p, miR-27b-5p, miR-409-3p, miR-340-3p, miR-1941-3p, miR-10a-3p, miR-125a-3p, and miR-468-3p. Analysis of their possible tissues of origin/target showed an enrichment of selected miRNAs in liver, intestine, brain, or skeletal muscle. miR-206, miR-27b-5p, and miR-409-3p were validated in healthy humans. Analysis of their predicted target genes revealed their potential involvement in insulin/insulin like growth factor (insulin/IGF), angiogenesis, cholecystokinin B receptor signaling pathway (CCKR), inflammation or Wnt pathways for mice, and in platelet derived growth factor (PDGF) and CCKR signaling pathways for humans. Therefore, the current study shows that certain miRNAs are released in the circulation in response to fatty meals, proposing them as potential novel therapeutic targets of lipid metabolism.

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Kim, Yong-Chul, and Mary L. Cutler. "MicroRNA-Dependent Targeting of RSU1 and the IPP Adhesion Complex Regulates the PTEN/PI3K/AKT Signaling Pathway in Breast Cancer Cell Lines." International Journal of Molecular Sciences 21, no. 15 (July 30, 2020): 5458. http://dx.doi.org/10.3390/ijms21155458.

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(1) Background: The microRNA (miR)-directed control of gene expression is correlated with numerous physiological processes as well as the pathological features of tumors. The focus of this study is on the role of miRs in the regulation of RSU1 and proteins in the IPP (integrin linked kinase, PINCH and parvin) complex. Because the IPP adaptor proteins link β integrins to actin cytoskeleton, and the RSU1 signaling protein connects the complex to the activation of cJun, ATF2 and the transcription of PTEN, their reduction by miRs has the potential to alter both adhesion and survival signaling. (2) Methods: Multiple database analyses were used to identify miRs that target RSU1 and PINCH1. miR transfection validated the effects of miRs on RSU1, PINCH1 and downstream targets in breast cancer cell lines. (3) Results: The miRs targeting RSU1 mRNA include miR-182-5p, -409-3p, -130a-3p, -221-3p, -744-5p and -106b-5p. Data show that miR-182-5p and -409-3p reduce RSU1, PINCH1 and inhibit the ATF2 activation of PTEN expression. miR-221-3p and miR-130a-3p target RSU1 and PINCH1 and, conversely, RSU1 depletion increases miR-221-3p and miR-130a-3p. (4) Conclusions: miRs targeting RSU1 and PINCH1 in mammary epithelial or luminal breast cancer cell lines reduced RSU1 signaling to p38 MAP kinase and ATF2, inhibiting the expression of PTEN. miR-221-3p, known to target PTEN and cell cycle regulators, also targets RSU1 and PINCH1 in luminal breast cancer cell lines.

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Filardi, Tiziana, Giuseppina Catanzaro, Giuseppina Emanuela Grieco, Elena Splendiani, Sofia Trocchianesi, Carmela Santangelo, Roberto Brunelli, et al. "Identification and Validation of miR-222-3p and miR-409-3p as Plasma Biomarkers in Gestational Diabetes Mellitus Sharing Validated Target Genes Involved in Metabolic Homeostasis." International Journal of Molecular Sciences 23, no. 8 (April 12, 2022): 4276. http://dx.doi.org/10.3390/ijms23084276.

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Gestational diabetes mellitus (GDM) causes both maternal and fetal adverse outcomes. The deregulation of microRNAs (miRNAs) in GDM suggests their involvement in GDM pathogenesis and complications. Exosomes are extracellular vesicles (EVs) of endosomal origin, released via exocytosis into the extracellular compartment. Through EVs, miRNAs are delivered in distant target cells and are able to affect gene expression. In this study, miRNA expression was analyzed to find new miRNAs that could improve GDM classification and molecular characterization. MiRNA were profiled in total plasma and EVs in GDM patients and normal glucose tolerance (NGT) women. Samples were collected at third trimester of gestation from two diabetes centers. MiRNA expression was profiled in a discovery cohort using the multiplexed NanoString nCounter Human v3 miRNA. Validation analysis was performed in a second independent cohort using RT-qPCR. A set of miRNAs resulted to be differentially expressed (DE) in total plasma and EVs in GDM. Among them, total plasma miR-222-3p and miR-409-3p were validated in the independent cohort. MiR-222-3p levels correlated with fasting plasma glucose (FPG) (p < 0.001) and birth weight (p = 0.012), whereas miR-409-3p expression correlated with FPG (p < 0.001) and inversely with gestational age (p = 0.001). The major validated target genes of the deregulated miRNAs were consistently linked to type 2 diabetes and GDM pathophysiology. MiR-222-3p and miR-409-3p are two circulating biomarkers that could improve GDM classification power and act in the context of the molecular events leading to the metabolic alterations observed in GDM.

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Díaz-Beyá, Marina, Alfons Navarro, Tania Díaz, Marta Pratcorona, Maria Rozman, Mariano Monzó, and Jordi Esteve. "MicroRNAs in Intermediate Risk Cytogenetic Acute Myeloid Leukemia Add Relevant Prognostic Information to Molecular Categorization." Blood 118, no. 21 (November 18, 2011): 235. http://dx.doi.org/10.1182/blood.v118.21.235.235.

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Abstract Abstract 235 The prognosis of AML patients within the intermediate cytogenetics category is mainly determined by the mutational status of some relevant genes, such as NPM1 mutations (NPMmut), or biallelic CEBPA mutations (CEBPAmut), associated with a favorable outcome, and with the presence of FLT3 internal tandem duplication (FLT3-ITD), which correlates with an adverse prognosis. Nonetheless, additional biological features such as microRNA (miRNA) expression pattern might contribute to refine prognosis and guide therapy in this setting. The aim of the present study is to investigate whether miRNA expression is associated with molecular characteristics and clinical outcome in intermediate-risk AML patients (IR-AML). We have analyzed samples from 85 IR-AML patients (median age, 52 [range, 18–71]; 52% males) who received intensive therapy from 1994 to 2009. Forty-three patients (51%) harbored NPMmut, 37 (44%) harbored FLT3-ITD (including 23 with NPMmut), and 11 (13%) harbored CEBPAmut, including 7 with biallelic mutations. The expression of 670 mature miRNAs was analyzed by multiplex Real Time PCR using TaqMan Human MicroRNA Arrays (Applied Biosystems). All PCR reactions were performed using an ABI 7900 HT sequence detection system. miRNA expression data was analyzed by the 2−DDCt method, using RNU48 as endogenous control. Statistical analysis was performed with BRB Array Tools, SPSS version 15.0.1 and R software version 2.9.0. Supervised analysis by means of t-test based on multiplex permutations (class comparisons analysis, p<0.001) revealed a distinctive miRNA signature in patients with NPMmut, with overexpression of miR-10a, miR-10a*, miR-10b and miR-196b, and downregulation of miR-126, miR126*, miR-424, miR-424* and miR-335, as well as patients with biallelic CEBPAmut, characterized by downregulation of miR-196b and upregulation of miR-181a. Response rate in this series of patients was 84%, with 5-year survival of 43±11% and relapse incidence (RI) of 55±14%. Multivariate analysis for overall survival(OS) including NPM status, FLT3-ITD status, age, WBC, and Log Rank OS significant miRNAs (miR-632, miR-23b, miR-409-3p, let-7a*, miR-565 and miR-196b) identified age, absence of NPMmut, and FLT3-ITD as unfavorable variables together with low expression of miR-409-3p (p<0.001; HR=3.3, 95% CI: 1.7–6.4), and increased level of let-7a* (p=0.026; HR=5.1, 95% CI: 1.21–21.5) and miR-196b (p=0.056; HR=7.27, CI: 0.95–55.6). Concerning risk of relapse (RR), multivariate analysis including NPM status, age, FLT3-ITD, WBC, and Log Rank RR significant miRNAs (miR-632, miR-155*, miR-135a, miR-409-3p, miR-150, miR-23a* and miR-363) the absence of NPMmut, FLT3-ITD and increasing leukocyte count were associated with a higher RI. Remarkably, decreased miR-409-3p expression (p=0.011; HR=3.3, 95% CI: 1.3–8.2) and miR-135a (p=0.02; HR=4.2, 95% CI: 1.2–14.2), together with higher levels of miR-23a* (p<0.001; HR=6.2, 95% CI: 2.61–14.7) were independently associated with a higher relapse risk. Of note, a decreased miR-409-3p level retained its adverse prognosis value in the subgroup of patients without favorable molecular markers (i.e., wild-type NPM1 and CEBPA and/or FLT3-ITD;p=0.001) together with low miR-361-3p (p=0.013, HR= 2.4, CI: 1.2–5.1). On the contrary, let-7a* levels segregated subgroups of patients in the category of favorable genotype (i.e., mutated NPM1 without FLT3-ITD p=0.027). In this series of patients of intermediate-risk cytogenetic AML, measurement of expression levels of several miRNAs such as miR-409-3p, miR-135a, let-7a* or miR-23a* showed independent prognostic value, and contribute to predict the outcome within specific molecular subgroups. Nonetheless, confirmation of the prognostic impact of these miRNAs and investigation of possible underlying mechanisms account for this effect require future studies. Disclosures: No relevant conflicts of interest to declare.

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Malakootian, Mahshid, Parisa Naeli, Seyed Javad Mowla, and Nabil G. Seidah. "Post-Transcriptional Effects of miRNAs on PCSK7 Expression and Function: miR-125a-5p, miR-143-3p, and miR-409-3p as Negative Regulators." Metabolites 12, no. 7 (June 23, 2022): 588. http://dx.doi.org/10.3390/metabo12070588.

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The regulatory mechanism of PCSK7 gene is still unknown, although its encoded protein PC7 is the most ancient and highly conserved of all proprotein convertases and exhibits enzymatic and non-enzymatic functions in liver triglyceride regulation. Bioinformatics algorithms were used to predict regulatory microRNAs (miRNAs) of PCSK7 expression. This led to the identification of four miRNAs, namely miR-125a-5p, miR-143-3p, miR-409-3p, and miR-320a-3p, with potential binding sites on the 3′-untranslated region (3′-UTR) of human PCSK7 mRNA. The expression patterns of these miRNAs and PCSK7 mRNA were assessed in three different cell lines with quantitative polymerase chain reaction (qPCR), which revealed reciprocal expression patterns between the expression levels of the four selected miRNAs and PCSK7. Next, the interactions and effects of these miRNAs on PCSK7 expression levels were investigated via cell-based expression analysis, dual-luciferase assay, and Western blot analysis. The data revealed that PCSK7 mRNA levels decreased in cells transfected with vectors overexpressing miR-125a-5p, miR-143-3p, and miR-409-3p, but not miR-320a-3p. The dual-luciferase assay demonstrated that the above three miRNAs could directly interact with putative target sites in PCSK7 3′-UTR and regulate its expression, whereas miR-320-3p exhibited no interaction. Western blot analysis further revealed that the overexpression of miR-125a-5p in Huh7 cells inhibits the expression and ability of PC7 to cleave human transferrin receptor 1. Our results support a regulatory role of these miRNAs on PCSK7 expression and function and open the way to assess their roles in the regulation of PC7 activity in vivo in the development of hepatic steatosis.

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Zhelankin, Andrey V., Sergey V. Vasiliev, Daria A. Stonogina, Konstantin A. Babalyan, Elena I. Sharova, Yurii V. Doludin, Dmitry Y. Shchekochikhin, Eduard V. Generozov, and Anna S. Akselrod. "Elevated Plasma Levels of Circulating Extracellular miR-320a-3p in Patients with Paroxysmal Atrial Fibrillation." International Journal of Molecular Sciences 21, no. 10 (May 15, 2020): 3485. http://dx.doi.org/10.3390/ijms21103485.

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The potential of extracellular circulating microRNAs (miRNAs) as non-invasive biomarkers of atrial fibrillation (AF) has been confirmed by a number of recent studies. However, the current data for some miRNAs are controversial and inconsistent, probably due to pre-analytical and methodological differences. In this work, we attempted to fulfill the basic pre-analytical requirements provided for circulating miRNA studies for application to paroxysmal atrial fibrillation (PAF) research. We used quantitative PCR (qPCR) to determine the relative plasma levels of circulating miRNAs expressed in the heart or associated with atrial remodeling or fibrillation with reported altered plasma/serum levels in AF: miR-146a-5p, miR-150-5p, miR-19a-3p, miR-21-5p, miR-29b-3p, miR-320a-3p, miR-328-3p, miR-375-3p, and miR-409-3p. First, in a cohort of 90 adult outpatient clinic patients, we found that the plasma level of miR-320a-3p was elevated in PAF patients compared to healthy controls and hypertensive patients without AF. We further analyzed the impact of medication therapies on miRNA relative levels and found elevated miR-320a-3p levels in patients receiving angiotensin-converting-enzyme inhibitors (ACEI) therapy. Additionally, we found that miR-320a-3p, miR-21-5p, and miR-146a-5p plasma levels positively correlated with the CHA2DS2-Vasc score and were elevated in subjects with CHA2DS2-Vasc ≥ 2. Our results indicate that, amongst the analyzed miRNAs, miR-320a-3p may be considered as a potential PAF circulating plasma biomarker, leading to speculation as to whether this miRNA is a marker of platelet state change due to ACEI therapy.

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Strycharz, Justyna, Adam Wróblewski, Andrzej Zieleniak, Ewa Świderska, Tomasz Matyjas, Monika Rucińska, Lech Pomorski, et al. "Visceral Adipose Tissue of Prediabetic and Diabetic Females Shares a Set of Similarly Upregulated microRNAs Functionally Annotated to Inflammation, Oxidative Stress and Insulin Signaling." Antioxidants 10, no. 1 (January 12, 2021): 101. http://dx.doi.org/10.3390/antiox10010101.

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Hypertrophic and hypoxic visceral adipose tissue (VAT) secretes proinflammatory cytokines promoting insulin resistance (IR), prediabetes and type 2 diabetes (T2DM) microRNAs (miRNAs) are markers of metabolic disorders regulating genes critical for e.g., inflammation, glucose metabolism, and antioxidant defense, with raising diagnostic value. The aim of the current study was to evaluate whether hyperglycemia is able to affect the expression of selected miRNAs in VAT of prediabetic (IFG) and diabetic (T2DM) patients vs. normoglycemic (NG) subjects using qPCR. Statistical analyses suggested that miRNAs expression could be sex-dependent. Thus, we determined 15 miRNAs as differentially expressed (DE) among NG, T2DM, IFG females (miR-10a-5p, let-7d-5p, miR-532-5p, miR-127-3p, miR-125b-5p, let-7a-5p, let-7e-5p, miR-199a-3p, miR-365a-3p, miR-99a-5p, miR-100-5p, miR-342-3p, miR-146b-5p, miR-204-5p, miR-409-3p). Majority of significantly changed miRNAs was similarly upregulated in VAT of female T2DM and IFG patients in comparison to NG subjects, positively correlated with FPG and HbA1c, yet, uncorrelated with WHR/BMI. Enrichment analyses indicated involvement of 11 top DE miRNAs in oxidative stress, inflammation and insulin signaling. Those miRNAs expression changes could be possibly associated with low-grade chronic inflammation and oxidative stress in VAT of hyperglycemic subjects.

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Rapa, Ida, Arianna Votta, Jessica Giorcelli, Stefania Izzo, Angelica Rigutto, Jasna Metovic, Francesca Napoli, and Marco Volante. "Proposal of a Panel of Genes Identified by miRNA Profiling as Candidate Prognostic Biomarkers in Lung Carcinoids." Neuroendocrinology 111, no. 1-2 (February 11, 2020): 115–22. http://dx.doi.org/10.1159/000506401.

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Aim: To validate the prognostic role of a panel of genes previously uncovered by our group to be specific targets of miRNAs differentially expressed in lung carcinoids with aggressive pathological features. Methods: Four genes, namely, cyclic AMP response element binding protein-1 (CREBP1), activin A receptor type 2B (ACVR2B), LIM homeobox 2 (LHX2), and Krüppel-like factor 12 (KLF12), were identified in a previous study by our group using in silico analysis to be regulated by 3 miRNAs (miR-409-3p, miR-409-5p, and miR-431-5p) that were shown to be downregulated in aggressive lung carcinoids. These genes were analyzed using real-time PCR in a cohort of 102 lung carcinoids. Fifty high-grade lung carcinomas served as control group. Their expression was correlated with the expression of miR-409-3p, miR-409-5p, and miR-431-5p and with clinical pathological parameters and disease-free survival. Results: The expression of all but CREBP1 gene was significantly different between lung carcinoids and high-grade neuroendocrine carcinomas. ACVR2B and LHX2 were significantly inversely correlated with miR-409-3p and miR-409-5p. High levels of ACVR2B and LHX2 were significantly associated with atypical histotype, high tumor grade, and higher proliferation Ki-67 index (all p < 0.05). Low levels of KLF12 were significantly associated with the presence of necrosis and positive nodal status (all p < 0.05). Finally, low KLF12 expression was associated with shorter disease-free survival in lung carcinoids as a whole and in atypical carcinoids, only (all p < 0.001). Conclusions: ACVR2B, LHX2, and KFL12 are novel potential biomarkers associated with aggressive features in lung carcinoids.

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Puła, Anna, Paweł Robak, Dariusz Jarych, Damian Mikulski, Małgorzata Misiewicz, Izabela Drozdz, Wojciech Fendler, Janusz Szemraj, and Tadeusz Robak. "The Relationship between Serum miRNAs and Early Mortality in Multiple Myeloma Patients Treated with Bortezomib-Based Regimens." International Journal of Molecular Sciences 24, no. 3 (February 2, 2023): 2938. http://dx.doi.org/10.3390/ijms24032938.

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Multiple myeloma (MM) is a hematological malignancy characterized by the clonal proliferation of plasma cells in the bone marrow (BM) microenvironment. Despite the progress made in treatment, some MM patients still die within the first year of diagnosis. Numerous studies investigating microRNA (miRNA) expression patterns suggest they may be good prognostic markers. The primary aim of this study was to analyze the expression of selected miRNAs in the serum of MM patients who were later treated with bortezomib-based regimens, and to determine their potential to predict early mortality. The study was conducted in 70 prospectively recruited patients with newly diagnosed MM admitted to the Department of Hematology of the Copernicus Memorial Hospital, Lodz (Poland) between 2017 and 2021. Among them, 17 patients experienced death within 12 months of diagnosis. The expression of 31 selected miRNAs was determined using a miRCURY LNA miRNA Custom PCR Panel. The obtained clinical data included patient characteristics on diagnosis, treatment regimen, response to treatment, and follow-up. Differential expression analysis found two miRNAs to be significantly downregulated in the early mortality group: hsa-miR-328-3p (fold change—FC: 0.72, p = 0.0342) and hsa-miR-409-3p (FC: 0.49, p = 0.0357). Univariate and multivariate logistic regression analyses were performed to assess the early mortality rate. The final model consisted of hsa-miR-409-3p, hsa-miR-328-3p, age, and R-ISS 3. It yielded an area under the curve (AUC) of 0.863 (95%CI: 0.761–0.965) with 88.2% sensitivity and 77.5% specificity. Further external validation of our model is needed to confirm its clinical value.

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Chen, Mien-Cheng, Tzu-Hao Chang, Jen-Ping Chang, Hsien-Da Huang, Wan-Chun Ho, Yu-Sheng Lin, Kuo-Li Pan, Wen-Hao Liu, and Yao-Kuang Huang. "Circulating miR-148b-3p and miR-409-3p as biomarkers for heart failure in patients with mitral regurgitation." International Journal of Cardiology 222 (November 2016): 148–54. http://dx.doi.org/10.1016/j.ijcard.2016.07.179.

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Fort, Alexandre, Christelle Borel, Eugenia Migliavacca, Stylianos E. Antonarakis, Richard J. Fish, and Marguerite Neerman-Arbez. "Regulation of fibrinogen production by microRNAs." Blood 116, no. 14 (October 7, 2010): 2608–15. http://dx.doi.org/10.1182/blood-2010-02-268011.

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Abstract Elevated levels of fibrinogen are associated with increased risk of cardiovascular disease, whereas low fibrinogen can lead to a bleeding disorder. We investigated whether microRNAs (miRNAs), known to act as post-transcriptional regulators of gene expression, regulate fibrinogen production. Using transfection of a library of 470 annotated human miRNA precursor molecules in HuH7 hepatoma cells and quantitative measurements of fibrinogen production, we identified 23 miRNAs with down-regulating (up to 64% decrease) and 4 with up-regulating effects (up to 129% increase) on fibrinogen production. Among the down-regulating miRNAs, we investigated the mechanism of action of 3 hsa-miR-29 family members and hsa-miR-409-3p. Overexpression of hsa-miR-29 members led to decreased steady-state levels of all fibrinogen gene (FGA, FGB, and FGG) transcripts in HuH7 cells. Luciferase reporter gene assays demonstrated that this was independent of miRNA-fibrinogen 3′-untranslated region interactions. In contrast, overexpression of hsa-miR-409-3p specifically lowered fibrinogen Bβ mRNA levels, and this effect was dependent on a target site in the fibrinogen Bβ mRNA 3′-untranslated region. This study adds to the known mechanisms that control fibrinogen production, points toward a potential cause of variable circulating fibrinogen levels, and demonstrates that a screening approach can identify miRNAs that regulate clinically important proteins.

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Liu, Xu, Heming Ma, Ruihong Wu, Huan Wang, Hongqin Xu, Shuxuan Li, Guangyi Wang, Guoyue Lv, and Junqi Niu. "Identification of Liver Fibrosis-Related MicroRNAs in Human Primary Hepatic Stellate Cells Using High-Throughput Sequencing." Genes 13, no. 12 (November 24, 2022): 2201. http://dx.doi.org/10.3390/genes13122201.

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MicroRNAs (miRNAs) participate in hepatic stellate cell (HSC) activation, which drives liver fibrosis initiation and progression. We aimed to identify novel hepatic fibrosis targets using miRNA sequencing (miRNA-seq) of human primary HSCs. Surgically resected liver tissues were used to extract HSCs. Based on next-generation sequencing, miRNA-seq was performed on four pairs of HSCs before and after in vitro culture. Additionally, we compared our data with open access miRNA-seq data derived from fourteen cirrhotic and nine healthy liver tissues. Selected miRNAs associated with fibrosis were verified by quantitative real-time PCR. Target mRNAs of differentially expressed (DE) miRNAs were predicted to construct co-expression networks. We identified 230 DEmiRNAs (118 upregulated and 112 downregulated) upon HSC activation. Of the 17 miRNAs with the most significant differences in expression, liver disease-related miRNAs included miR-758-3p, miR-493-5p, miR-409-3p, miR-31-5p, miR-1268a, and miR-381-3p, which might play roles in hepatic fibrosis. Moreover, let-7g-5p, miR-107, miR-122-5p, miR-127-3p, miR-139-5p, miR-148a-3p, miR-194-5p, miR-215-5p, miR-26a-5p, miR-340-5p, miR-451a, and miR-99a-5p were common between our data and the publicly available sequencing data. A co-expression network comprising 1891 matched miRNA–mRNA pairs representing 138 DEmiRNAs and 1414 DEmRNAs was constructed. MiR-1268a and miR-665, possessing the richest target DEmRNAs, may be vital in HSC activation. The targeted genes were involved in collagen metabolism, extracellular matrix structural constituent, cytoskeletal protein binding, and cell adhesion. The miRNAs we identified may provide a basis and reference for the selection of diagnostic and therapeutic targets for hepatic fibrosis.

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Petrillo, Federica, Anna Iervolino, Tiziana Angrisano, Sabina Jelen, Vincenzo Costanzo, Mariavittoria D’Acierno, Lei Cheng, et al. "Dysregulation of Principal Cell miRNAs Facilitates Epigenetic Regulation of AQP2 and Results in Nephrogenic Diabetes Insipidus." Journal of the American Society of Nephrology 32, no. 6 (March 16, 2021): 1339–54. http://dx.doi.org/10.1681/asn.2020010031.

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BackgroundMicroRNAs (miRNAs), formed by cleavage of pre-microRNA by the endoribonuclease Dicer, are critical modulators of cell function by post-transcriptionally regulating gene expression.MethodsSelective ablation of Dicer in AQP2-expressing cells (DicerAQP2Cre+ mice) was used to investigate the role of miRNAs in the kidney collecting duct of mice.ResultsThe mice had severe polyuria and nephrogenic diabetes insipidus, potentially due to greatly reduced AQP2 and AQP4 levels. Although epithelial sodium channel levels were decreased in cortex and increased in inner medulla, amiloride-sensitive sodium reabsorption was equivalent in DicerAQP2Cre+ mice and controls. Small-RNA sequencing and proteomic analysis revealed 31 and 178 significantly regulated miRNAs and proteins, respectively. Integrated bioinformatic analysis of the miRNAome and proteome suggested alterations in the epigenetic machinery and various transcription factors regulating AQP2 expression in DicerAQP2Cre+ mice. The expression profile and function of three miRNAs (miR-7688-5p, miR-8114, and miR-409-3p) whose predicted targets were involved in epigenetic control (Phf2, Kdm5c, and Kdm4a) or transcriptional regulation (GATA3, GATA2, and ELF3) of AQP2 were validated. Luciferase assays could not demonstrate direct interaction of AQP2 or the three potential transcription factors with miR-7688-5p, miR-8114, and miR-409–3p. However, transfection of respective miRNA mimics reduced AQP2 expression. Chromatin immunoprecipitation assays demonstrated decreased Phf2 and significantly increased Kdm5c interactions at the Aqp2 gene promoter in DicerAQP2Cre+ mice, resulting in decreased RNA Pol II association.ConclusionsNovel evidence indicates miRNA-mediated epigenetic regulation of AQP2 expression.

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Liu, Tian, Shilong Zhong, Fang Rao, Yumei Xue, Zhoucuo Qi, and Shulin Wu. "Catheter ablation restores decreased plasma miR-409-3p and miR-432 in atrial fibrillation patients." Europace 18, no. 1 (March 16, 2015): 92–99. http://dx.doi.org/10.1093/europace/euu366.

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Diaz, Jessica L., Verl B. Siththanandan, Victoria Lu, Nicole Gonzalez-Nava, Lincoln Pasquina, Jessica L. MacDonald, Mollie B. Woodworth, et al. "An evolutionarily acquired microRNA shapes development of mammalian cortical projections." Proceedings of the National Academy of Sciences 117, no. 46 (November 2, 2020): 29113–22. http://dx.doi.org/10.1073/pnas.2006700117.

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The corticospinal tract is unique to mammals and the corpus callosum is unique to placental mammals (eutherians). The emergence of these structures is thought to underpin the evolutionary acquisition of complex motor and cognitive skills. Corticospinal motor neurons (CSMN) and callosal projection neurons (CPN) are the archetypal projection neurons of the corticospinal tract and corpus callosum, respectively. Although a number of conserved transcriptional regulators of CSMN and CPN development have been identified in vertebrates, none are unique to mammals and most are coexpressed across multiple projection neuron subtypes. Here, we discover 17 CSMN-enriched microRNAs (miRNAs), 15 of which map to a single genomic cluster that is exclusive to eutherians. One of these, miR-409-3p, promotes CSMN subtype identity in part via repression of LMO4, a key transcriptional regulator of CPN development. In vivo, miR-409-3p is sufficient to convert deep-layer CPN into CSMN. This is a demonstration of an evolutionarily acquired miRNA in eutherians that refines cortical projection neuron subtype development. Our findings implicate miRNAs in the eutherians’ increase in neuronal subtype and projection diversity, the anatomic underpinnings of their complex behavior.

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Hatzimichael, Eleftheria, Aggeliki Dasoula, Maria Igglezou, Andreas Katsenos, Ioannis Sainis, Isidore Rigoutsos, and Evangelos Briasoulis. "Expression Profiling of a Panel of Apoptosis Related Micrornas in Patients with Acute Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 4971. http://dx.doi.org/10.1182/blood.v126.23.4971.4971.

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Abstract Introduction: We evaluated the expression of a panel of apoptosis-associated microRNAs (miRNAs) in leukemic blasts isolated from AML patients and investigated their predicted targets. Patients and Methods: We used bone marrow or peripheral blood that were donated by nine AML patients (5 male, 4 female) at diagnosis. Mononuclear cells were isolated by Ficoll-Histopaque (Sigma Aldrich) density gradient centrifugation and were cryopreserved in liquid nitrogen at the Cancer Biobank Center of the University of Ioannina. MicroBeads technology (Miltenyl Biotec) was used for magnetic cell sorting of CD34+ cells of patients' samples, while mononuclear blood cells from healthy individuals were used as controls. Small RNA (< 200 b) was isolated using the NucleoSpin® miRNA kit (Macherey Nagel). Simultaneous quantification of 84 apoptosis- associated miRNAs was performed by using the miScript miRNA PCR Array Human Apoptosis (MIHS-114ZF, Qiagen) in a LightCycler® 480 instrument (Roche AG, Rotkreuz, Switzerland), and relative quantitation of expression was determined by the comparative CT method. For miRNA target prediction we used the RNA22 tool: https://cm.jefferson.edu/rna22 Results: We found 34 downregulated and 20 upregulated miRNAs compared to control. Among the downregulated miRNAs was the miR-29 family and among the upregulated was the miR-181 family, both of which have been previously implicated in AML. The top 10 downregulated miRNAs were miR-31-5p, miR-451a, miR-29b-3p, miR-409-3p, miR-144-3p, miR-9-5p, miR-192-5p, miR-542-3p, miR-134-5p, miR-29c-3p, whereas the top 10 upregulated miRNAs were miR-34a-5p, miR-181a-5p, miR-181c-5p, miR-181d-5p, miR-181b-5p, miR-222-3p, miR-125b-5p, miR-221-3p, Let-7c-5p, miR-186-3p. We used RNA22 to identify genes that are predicted to be simultaneously targeted by all of the 10 top downregulated miRNAs and also the genes that are predicted to be simultaneously targeted by all of the 10 top upregulated miRNAs. The predicted targets for all top 10 downregulated miRNAs include NSD1, MYST4 and SACS. NSD1 is an histone methyltransferase, whereas MYST4 is an histone acetyltransferase. The predicted targets of all top 10 upregulated miRNAs include 35 genes among which are zinc finger transcription factors with proapoptotic activity (ZNF704, ZNF268) and Solute Carrier (SLC) membrane transporters (SLC24A2, SLC24A4, SLC35E3) of undefined functions. When we compared miRNA expression in patients with abnormal karyotype versus patients with normal karyotype we found miR-125a-5p to be overexpressed in patients with abnormal karyotype. Overexpression of miR-125b has been previously reported in patients with myelodysplastic syndromes and APL and plays important roles in mitochondrial apoptosis. Conclusions: A variety of microRNAs are dysregylated in patients with AML. We confirm that the miR-29 family and the miR-181 family have altered expression in AML. We found miR-125a-5p to be overexpressed in patients with abnormal karyotype. Among predicted targets of the upregulated miRNAs are genes encoding proapoptotic zinc finger proteins and Solute Carrier membrane transporters, whereas among the predicted targets of the downregulated miRNAs are genes involved in chromatin remodeling, suggesting that altered function of epigenetic modifiers in AML may be due to dysregylation of miRNAs. Disclosures No relevant conflicts of interest to declare.

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BECKER-GREENE, DAKOTA R., HAO LI, WINONA WU, DENIZHAN OZDEMIR, IVANA HOLLAN, MARK W. FEINBERG, and BASAK ICLI. "269-OR: miR-409-3p Regulates Angiogenesis Brown Fat Adiposity and Insulin Resistance." Diabetes 68, Supplement 1 (June 2019): 269—OR. http://dx.doi.org/10.2337/db19-269-or.

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Zhang, Guoqiang, Zengyan Liu, Hao Xu, and Qifeng Yang. "miR-409-3p suppresses breast cancer cell growth and invasion by targeting Akt1." Biochemical and Biophysical Research Communications 469, no. 2 (January 2016): 189–95. http://dx.doi.org/10.1016/j.bbrc.2015.11.099.

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Weng, Chunhua, Haojie Dong, Guangdi Chen, Yixing Zhai, Rongpan Bai, Hu Hu, Linrong Lu, and Zhengping Xu. "miR-409-3p inhibits HT1080 cell proliferation, vascularization and metastasis by targeting angiogenin." Cancer Letters 323, no. 2 (October 2012): 171–79. http://dx.doi.org/10.1016/j.canlet.2012.04.010.

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Han, Wei, Hongli Yin, Hao Ma, Yi Wang, Desong Kong, and Zhimin Fan. "Curcumin Regulates ERCC1 Expression and Enhances Oxaliplatin Sensitivity in Resistant Colorectal Cancer Cells through Its Effects on miR-409-3p." Evidence-Based Complementary and Alternative Medicine 2020 (September 17, 2020): 1–16. http://dx.doi.org/10.1155/2020/8394574.

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Background. Oxaliplatin (L-OHP) resistance is a major obstacle to the effective treatment of colorectal cancer. The resistance mechanism(s) of colorectal tumors to L-OHP may be related to the regulation of ERCC1 by cancer-expressed miRNAs, but no in-depth studies on the miRNAs that affect drug resistance have been performed. Curcumin (Cur) can reverse the drug resistance of cancer cells, but its effects on ERCC1 expression and miRNA profiles in colorectal cancer have not been studied. Methods. To study the regulation effect of curcumin on ERCC1 expression and its effects on miRNAs, the L-OHP-resistant colorectal cancer cell line HCT116/L-OHP was established. MTT assays were used to evaluate cell proliferation. Flow cytometry was used to investigate apoptotic induction. Western blot and RT-PCR analysis were used to evaluate the expression of drug-associated ERCC1, Bcl-2, GST-π, MRP, P-gp, and survivin. Results. HCT116//L-OHP cell lines were successfully established. The combination of L-OHP and curcumin could reduce L-OHP resistance in vitro. In addition, combination therapy inhibited the expression of ERCC1, Bcl-2, GST-π, MRP, P-gp, and survivin at the mRNA and protein level. Curcumin was found to inhibit ERCC1 through its ability to modulate miR-409-3p. Conclusion. Curcumin can overcome L-OHP resistance in colorectal cancer cells through its effects on miR-409-3p mediated ERCC1 expression.

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Khalil, Susanna, Enrica Fabbri, Alessandra Santangelo, Valentino Bezzerri, Cinzia Cantù, Gianfranco Di Gennaro, Alessia Finotti, et al. "miRNA array screening reveals cooperative MGMT-regulation between miR-181d-5p and miR-409-3p in glioblastoma." Oncotarget 7, no. 19 (April 5, 2016): 28195–206. http://dx.doi.org/10.18632/oncotarget.8618.

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Lee, Jihui, and Hara Kang. "Nucleolin Regulates Pulmonary Artery Smooth Muscle Cell Proliferation under Hypoxia by Modulating miRNA Expression." Cells 12, no. 5 (March 6, 2023): 817. http://dx.doi.org/10.3390/cells12050817.

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Hypoxia induces the abnormal proliferation of vascular smooth muscle cells (VSMCs), resulting in the pathogenesis of various vascular diseases. RNA-binding proteins (RBPs) are involved in a wide range of biological processes, including cell proliferation and responses to hypoxia. In this study, we observed that the RBP nucleolin (NCL) was downregulated by histone deacetylation in response to hypoxia. We evaluated its regulatory effects on miRNA expression under hypoxic conditions in pulmonary artery smooth muscle cells (PASMCs). miRNAs associated with NCL were assessed using RNA immunoprecipitation in PASMCs and small RNA sequencing. The expression of a set of miRNAs was increased by NCL but reduced by hypoxia-induced downregulation of NCL. The downregulation of miR-24-3p and miR-409-3p promoted PASMC proliferation under hypoxic conditions. These results clearly demonstrate the significance of NCL–miRNA interactions in the regulation of hypoxia-induced PASMC proliferation and provide insight into the therapeutic value of RBPs for vascular diseases.

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Huang, Feng, Junsong Zhang, Diyuan Yang, Yuelan Zhang, Jinxiang Huang, Yaochang Yuan, Xuefeng Li, and Gen Lu. "MicroRNA Expression Profile of Whole Blood Is Altered in Adenovirus-Infected Pneumonia Children." Mediators of Inflammation 2018 (October 14, 2018): 1–11. http://dx.doi.org/10.1155/2018/2320640.

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Human adenovirus (Adv) infection is responsible for most community-acquired pneumonia in infants and children, which results in significant morbidity and mortality in children every year. MicroRNAs (miRNAs) are associated with viral replication and host immune response. Knowing the miRNA expression profile will help understand the role of miRNAs in modulating the host response to adenovirus infection and possibly improve the diagnosis of adenovirus-infected pneumonia. In our study, total RNA extracted from whole blood of adenovirus-infected pneumonia children and healthy controls were analyzed by small RNA deep sequencing. Expression profiles of whole blood microRNAs were altered and distinctly different in adenovirus-infected children. The top 3 upregulated miRNA (hsa-miR-127-3p, hsa-miR-493-5p, and hsa-miR-409-3p) were identified in adenovirus-infected children and provided a clear distinction between infected and healthy individuals. Potential host target genes were predicated and validated by qRT-PCR to study the impact of microRNAs on the host genes. Most of the target genes were involved in the MAPK signaling pathway and innate immune response. These highly upregulated microRNAs may have crucial roles in Adv pathogenesis and are potential biomarkers for adenovirus-infected pneumonia.

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Casalone, Elisabetta, Giovanni Birolo, Barbara Pardini, Alessandra Allione, Alessia Russo, Chiara Catalano, Manlio Mencoboni, et al. "Serum Extracellular Vesicle-Derived microRNAs as Potential Biomarkers for Pleural Mesothelioma in a European Prospective Study." Cancers 15, no. 1 (December 25, 2022): 125. http://dx.doi.org/10.3390/cancers15010125.

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Malignant pleural mesothelioma (MPM) is an aggressive cancer with a dismal prognosis. Early therapeutic interventions could improve patient outcomes. We aimed to identify a pattern of microRNAs (miRNAs) as potential early non-invasive markers of MPM. In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition cohort, we screened the whole miRNome in serum extracellular vesicles (EVs) of preclinical MPM cases. In a subgroup of 20 preclinical samples collected five years prior MPM diagnosis, we observed an upregulation of miR-11400 (fold change (FC) = 2.6, adjusted p-value = 0.01), miR-148a-3p (FC = 1.5, p-value = 0.001), and miR-409-3p (FC = 1.5, p-value = 0.04) relative to matched controls. The 3-miRNA panel showed a good classification capacity with an area under the receiver operating characteristic curve (AUC) of 0.81 (specificity = 0.75, sensitivity = 0.70). The diagnostic ability of the model was also evaluated in an independent retrospective cohort, yielding a higher predictive power (AUC = 0.86). A signature of EV miRNA can be detected up to five years before MPM; moreover, the identified miRNAs could provide functional insights into the molecular changes related to the late carcinogenic process, preceding MPM development.

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Wang, Yongxiang, Jianbin Zhang, Xiaochen Chen, and Liang Gao. "Circ_0001023 Promotes Proliferation and Metastasis of Gastric Cancer Cells Through miR-409-3p/PHF10 Axis." OncoTargets and Therapy Volume 13 (May 2020): 4533–44. http://dx.doi.org/10.2147/ott.s244358.

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Zhang, Quanbin, Lina Wang, Lili Cao, and Tao Wei. "Novel circular RNA circATRNL1 accelerates the osteosarcoma aerobic glycolysis through targeting miR-409-3p/LDHA." Bioengineered 12, no. 2 (November 27, 2021): 9965–75. http://dx.doi.org/10.1080/21655979.2021.1985343.

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TAN, SHIFAN, HUIJUAN SHI, MINGCHEN BA, SHENGQV LIN, HONGSHENG TANG, XIAOQI ZENG, and XIANGLIANG ZHANG. "miR-409-3p sensitizes colon cancer cells to oxaliplatin by inhibiting Beclin-1-mediated autophagy." International Journal of Molecular Medicine 37, no. 4 (February 18, 2016): 1030–38. http://dx.doi.org/10.3892/ijmm.2016.2492.

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Valera, Vladimir, Beatriz Walter, and Maria J. Merino. "Abstract 5831: Urinary exosome analysis as a marker of treatment response in bladder cancer patients." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5831. http://dx.doi.org/10.1158/1538-7445.am2022-5831.

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Abstract Introduction: Intravesical Bacillus Calmette-Guerin (BCG) is an effective immunotherapy for non-muscle invasive bladder cancer (NMIBC). However, BCG treatment failure will lead to recurrence and tumor progression. In this study, urinary exosomes content (miRNA profile) was evaluated as a possible marker of BCG treatment response in NMIBC patients. Methods: Urine samples from patients with bladder cancer were collected at the time of surgery and during patient follow up to 1 year. Urine from healthy volunteers were also included. Clinical and pathological information such as tumor grade (High Grade (HG), Low Grade (LG)), depth of invasion (Ta, T1, CIS), and response to BCG treatment was also obtained. Exosome Isolation and total RNA extraction including microRNAs from cell-free urine after centrifugation were obtained. Library preparation for miRNA expression was done (QIAseq® miRNA Library) for Next-Generation Sequencing (NGS) analysis in a NextSeq 2000 single read platform, 75 bp with 15-20 million reads per sample. Reads were then queried against miRDeep2 software for identification. Only miRNAs having at least 20 counts considering all samples were included. After normalization, significantly and deferentially expressed microRNAs (>2-Fold) were selected for analysis. Bioinformatic analysis including sequence alignment was performed under the STAR-based approach. Identified microRNAs were then used to classify/predict the response to treatment and its relationship with other clinicopathologic variables. Results: A total of 56 urine samples from 13 patients were available/used for analysis including 10 High Grade Ta and 3 High Grade T1 patients. Urine from normal healthy donors (N=3) was also included. Clinicopathological features were patients with HGTa=10, HGT1=3 and 3 control samples. Regarding treatment response 9 patients were BCG responders and 4 BCG unresponsive. When compared to BCG unresponsive patients, BCG responders showed 45 differentially expressed miRNAs. Statistically significant differentially expressed miRNAs (Fold-change >2, p value <0.05) were 12 miRNAs, upregulated were miR132-3p (p=0.042); miR-187-3p (p=0.021); miR-409-3p (p=0.043) and miR1301-3p (p=0.048). Downregulated miRNAs were miR-let7-5p (p=0.007), miR-3605-3p (p=0.047), miR-140-5p (p=0.031), miR-500a-5p (p=0.051), miR-629-5p (p=0.039), miR-454-3p (p=0.05), miR-2110 (p=0.049) and miR-30c-5p (p=0.03). Interestingly, miRPathDABv2.0 analysis predicted those microRNAs be related to cancer, including bladder cancer. They showed targeting important pathways as PI3K.Akt, Wnt/B catenin and P53 signaling related with disease progression and treatment response. Conclusion: Our study supports the value of urinary exosomal microRNAs as non-invasive biomarkers to predict BCG treatment response in nonmuscle-invasive bladder cancer. Citation Format: Vladimir Valera, Beatriz Walter, Maria J. Merino. Urinary exosome analysis as a marker of treatment response in bladder cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5831.

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Abdi, Jahangir, Yijun Yang, Patrick Meyer-Erlach, and Hong Chang. "Bone Marrow Stromal Cells Induce Bortezomib Resistance in Multiple Myeloma Cells through Downregulation of miRNA-101-3p Targeting Survivin." Blood 126, no. 23 (December 3, 2015): 1772. http://dx.doi.org/10.1182/blood.v126.23.1772.1772.

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Abstract INTRODUCTION It is not yet fully understood how bone marrow microenvironment components especially bone marrow stromal cells (BMSCs) induce drug resistance in multiple myeloma (MM). This form of drug resistance has been suggested to pave the way for intrinsic (de novo) resistance to therapy in early stages of the disease and contribute to acquired drug resistance in the course of treatment. Hence, deciphering the molecular mechanisms involved in induction of above resistance will help identify potential therapeutic targets in MM combined treatments. Our previous work showed that BMSCs (normal and MM patient-derived) induced resistance to bortezomib (BTZ) compared with MM cells in the absence of stroma. This resistance was associated with modulation of a transcriptome in MM cells, including prominent upregulation of oncogenes c-FOS, BIRC5 (survivin) and CCND1. However; whether these oncogenes mediate BTZ resistance in the context of BMSCs through interaction with miRNAs is not known. METHODS Human myeloma cell lines, 8226, U266 and MM.1s, were co-cultured with MM patient-derived BMSCs or an immortalized normal human line (HS-5) in the presence of 5nM BTZ for 24 h. MM cell monocultures treated with 5nM BTZ were used as controls. Co-cultures were then applied to magnetic cell separation (EasySep, Stem Cell Technologies) to isolate MM cells for downstream analyses (western blotting and qPCR). Total RNA including miRNAs was isolated from MM cell pellets (QIAGEN miRNeasy kit), cDNAs were synthesized (QIAGEN miScript RT II kit) and applied to miScript miRNA PCR Array (SABioscience, MIHS-114ZA). After normalization of all extracted Ct values to 5 different housekeeping genes, fold changes in miRNA expression were analyzed in co-cultures compared to MM cell monocultures using the 2-ΔΔCt algorithm. Moreover, survivin gene was silenced in MM cells using Ambion® Silencer® Select siRNA and Lipofectamine RNAiMAX transfection reagent. Survivin-silenced cells were then seeded on BMSCs and exposed to BTZ. Percent apoptosis of gated CD138+ MM cells was determined using FACS. For our overexpression and 3'UTR reporter experiments, we transiently transfected MM cells with pre-miR-101-3p, scrambled miRNA or pEZX-3'UTR constructs using Endofectin reagent (all from GeneCopoeia). RESULTS BMSCs upregulated survivin gene / protein (a member of inhibitors of apoptosis family) and modulated an array of miRNAs in MM cells compared to MM cells in the absence of stroma. The more noticeably downregulated miRNAs were hsa-miR-101-3p, hsa-miR-29b-3p, hsa-miR-32-5p, hsa-miR-16-5p (4-30 fold) and highly upregulated ones included hsa-miR-221-3p, hsa-miR-409-3p, hsa-miR-193a-5p, hsa-miR-125a-5p (80-330 fold). We focused on miRNA-101-3p as it showed the highest level of downregulation (30 fold) and has been shown to function as an important tumor suppressor in other malignancies. Real time RT-PCR confirmed downregulation of miRNA-101-3p. Moreover, microRNA Data Integration Portal (mirDIP) identified miRNA-101-3p as a putative target for survivin and Luciferase activity assays confirmed binding of miRNA-101-3p to 3'UTR of survivin. In addition, overexpression of miRNA-101-3p downregulated survivin and sensitized MM cells to BTZ-induced apoptosis. Furthermore, silencing of survivin upregulated miRNA-101-3p and increased BTZ-induced apoptosis in MM cell lines both in the absence of BMSCs (Apoptosis range in BTZ-treated conditions: 57.65% ± 4.91 and 28.66% ± 0.78 for si-survivin and scrambled control, respectively, p<0.05) and in the presence of BMSCs (41.23% ± 1.43 and 14.8% ± 0.66, for si-survivin and scrambled control, respectively, p<0.05). CONCLUSION Our results indicate that BMSCs downregulated miRNA-101-3p and upregulated survivin in MM cells compared to MM cells in the absence of stroma. Silencing of survivin or overexpression of miRNA-101-3p sensitized MM cells to BTZ in the presence of BMSCs. These findings suggest that miRNA-101-3p mediates BTZ response of MM cells in the presence of BMSCs by targeting survivin and disclose a role of survivin-miRNA-101-3p axis in regulation of BMSCs-induced BTZ resistance in MM cells, thus provide a rationale to further investigate the anti-myeloma activity of miRNA-101-3p in combination with BTZ as a potential novel therapeutic strategy in MM. Disclosures No relevant conflicts of interest to declare.

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Wu, Peng, Chunxiang Li, Dong mei Ye, Kenan Yu, Yuxuan Li, Hailin Tang, Gaoshen Xu, Shuijing Yi, and Zhiwei Zhang. "Circular RNA circEPSTI1 accelerates cervical cancer progression via miR-375/409-3P/515-5p-SLC7A11 axis." Aging 13, no. 3 (February 2, 2021): 4663–73. http://dx.doi.org/10.18632/aging.202518.

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Yu, Xin, Xueyan Fu, Xia Zhang, Changcai Bai, and Yang Wang. "Circ_0001658 regulates gefitinib resistance of non-small cell lung cancer through miR-409-3p/TWIST1 axis." Anti-Cancer Drugs 33, no. 2 (October 22, 2021): 158–66. http://dx.doi.org/10.1097/cad.0000000000001257.

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Li, Yanyi, Li Chen, Beibei Zhang, Yuko Ohno, and Hua Hu. "miR-409-3p inhibits the proliferation and migration of human ovarian cancer cells by targeting Rab10." Cellular and Molecular Biology 66, no. 7 (October 31, 2020): 197. http://dx.doi.org/10.14715/cmb/2020.66.7.30.

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Dickson, David A., Patrizia Stohn, Lorena Saavedra Rodriguez, Arturo Hernandez, Anne Harrington, Lucy Liaw, and Larry A. Feig. "Involvement of early embryonic miR‐409‐3p in the establishment of anxiety levels in female mice." Developmental Neurobiology 80, no. 5-6 (May 2020): 160–67. http://dx.doi.org/10.1002/dneu.22756.

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Wu, Tianya, Chunrong Tang, Junwei Fan, and Jian Tao. "Administration of rTMS Alleviates Stroke-Induced Cognitive Deficits by Modulating miR-409-3p/CTRP3/AMPK/Sirt1 Axis." Journal of Molecular Neuroscience 72, no. 3 (October 16, 2021): 507–15. http://dx.doi.org/10.1007/s12031-021-01924-5.

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Josson, Sajni, Murali Gururajan, Peizhen Hu, Chen Shao, Gina Chia-Yi Chu, Haiyen E. Zhau, Chunyan Liu, et al. "miR-409-3p/-5p Promotes Tumorigenesis, Epithelial-to-Mesenchymal Transition, and Bone Metastasis of Human Prostate Cancer." Clinical Cancer Research 20, no. 17 (June 24, 2014): 4636–46. http://dx.doi.org/10.1158/1078-0432.ccr-14-0305.

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Zhang, Jun, Wengen Hou, Jinling Jia, Yilei Zhao, and Bin Zhao. "MiR-409-3p regulates cell proliferation and tumor growth by targeting E74-like factor 2 in osteosarcoma." FEBS Open Bio 7, no. 3 (January 27, 2017): 348–57. http://dx.doi.org/10.1002/2211-5463.12177.

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Ma, Yan, Dina Suolitiken, Bobin Chen, Xiaoping Xu, Hui Kang, and Lin Zhiguang. "Circulating microRNAs Is a Potential Prognostic Biomarker in Primary Central Nervous System Lymphoma." Blood 136, Supplement 1 (November 5, 2020): 40–41. http://dx.doi.org/10.1182/blood-2020-135966.

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Backgrounds and purposes Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin's lymphoma. The prognosis of PCNSL is poor and heterogeneous. MicroRNA is associated with prognosis of various cancers. Our study is the first time to compare circulating microRNAs of PCNSL patients with different prognosis using miRNA microarray scanning and find novel microRNAs associated with prognosis of PCNSL by further large-scale validation. Materials and methods From a retrospective cohort, we collected the clinical data of patients who were diagnosed as PCNSL in Huashan Hospital between January 2007 and June 2016. We collected clinical data and blood samples from residual blood routine test of PCNSLs. First, we compared circulating microRNAs between patients with different overall survival (OS) using miRNA microarray scanning. Second, PCR assay was used for miRNAs quantification in blood sample from 6 patients that had long overall survival and other 6 patients that had short overall survival. Further miRNA validation was made by PCR assay in blood sample from 94 patients to validate prognostic value of miRNAs in PCNSLs. The Kruskal-Wallis and Mann-Whitney U tests were used for quantitative parameters and the χ2 square test was used for non-quantitative parameters. Univariate analysis was performed using log-rank test, and survival distributions were analyzed by the Kaplan-Meier curve and log-rank test. Multivariate analysis was done by Cox regression model. Results A total of 90 differentially expressed miRNAs were identified, including 24 up-regulated miRNAs and 66 down-regulated miRNAs using miRNA microarray scanning. Then PCR assay was used for 10 differentially expressed miRNAs quantification in blood sample from 6 patients that had long overall survival and 6 patients that had short overall survival. Mir-21, mir-129-5p, mir-144-5, mir-363-5p, mir-409-3p, mir-1246, mir-1299 and mir-1825 showed no differences between 2 groups, while the expression of mir-455-3P and mir-940 between 2 groups are significantly different (P<0.05). Further validation in 94 patients showed median OS in miR-940 overexpression group was 91 months and in miR-940 low-expression group was 28 months (P=0.0005), while median PFS in miR-940 overexpression group was 25 months and in miR-940 low-expression group was 16 months (P =0.0292). Multivariate analysis of COX model showed miR-940 was independent factors for OS and PFS. Conclusion Circulating mir-940 had prognostic value in PCNSL and was an independent prognostic factor for PCNSL. Figure 1 Disclosures No relevant conflicts of interest to declare.

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Sun, Rui, Wanli Xue та Juzhen Zhao. "Hsa_circ_0054633 mediates apoptosis and insulin secretion in human pancreatic β cells through miR-409-3p/caspase-8 axis". Diabetes Research and Clinical Practice 176 (червень 2021): 108837. http://dx.doi.org/10.1016/j.diabres.2021.108837.

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42

Tan, X., J. Tan, F. Ming, L. Lv, H. Zhang, B. Tang, W. Yan, et al. "Up-regulation of miR-409-3p in cerebrospinal fluid of Parkinson's disease reduce the apoptosis of dopamine neurons." Parkinsonism & Related Disorders 79 (October 2020): e10-e11. http://dx.doi.org/10.1016/j.parkreldis.2020.06.065.

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Wang, Yongjun, Yanfa He, Hongzhong Bai, Yi Dang, Jiangyan Gao, and Pei Lv. "Phosphoinositide‐dependent kinase 1–associated glycolysis is regulated by miR‐409‐3p in clear cell renal cell carcinoma." Journal of Cellular Biochemistry 120, no. 1 (September 14, 2018): 126–34. http://dx.doi.org/10.1002/jcb.27152.

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Pandita, Aakriti, Alina Basnet, Poornima Ramadas, Aarati Poudel, Ankit Anand, Nibal Saad, Syed A. Akbar, Salman I. Chaudhry, Frank Middleton, and Diana M. Gilligan. "Micro RNAs in Acute Myeloid Leukemia." Blood 128, no. 22 (December 2, 2016): 5252. http://dx.doi.org/10.1182/blood.v128.22.5252.5252.

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Abstract Acute leukemia is a life-threatening condition that occurs in MDS, MPD or de novo. Although progress has been made with regard to cytogenetics, little is known about the epigenetic biology of leukemia. MicroRNA (miR) plays a role in regulation of gene expression in many cellular processes, including hematopoiesis. About 19- 25 nucleotides in length, miRs target specific mRNAs and influence their stability, degradation, or translation. miR profiling has begun to contribute to the understanding of the complex regulatory events that occur during normal hematopoiesis and are disrupted during the emergence of the leukemic clone. In particular, miR expression may be useful to understanding normal cytogenetic AMLs and developing novel treatments for AML. Our study was approved by the IRB and informed consent was obtained from patients and controls. We collected peripheral blood samples from 10 patients with newly diagnosed AML, prior to induction therapy, and 8 controls. Two ml of whole blood was collected in Paxgene RNA tubes and frozen for later processing. miRNA was purified using standard Trizol method, followed by RNeasy mini column (Qiagen). Quality of the RNA samples was assessed using the Agilent Bioanalyzer prior to library construction using the Illumina TruSeq Small RNA Sample Prep protocol (Illumina; San Diego, California). Multiplexed samples of RNA that exceeded quality control metrics (RIN > 6.0) were run on an Illumina NextSeq500 instrument at a targeted depth of 10 million reads per sample. After filtering and trimming of index and adapter sequences, whole genome alignment of the miR FASTQ reads was performed using the Homo sapiens/hg19 reference genome in the SHRiMPS aligner included in the miRNAs Analysis application available in BaseSpace (Illumina), as well as the sRNA Toolbox application suite. Quantification and normalization of aligned reads to the miRBase 21 database was performed, and differential expression between AML and control groups performed using DESeq2, NOIseq, and EdgeR algorithms. Consensus changes were seen using all three algorithms after correcting for multiple testing using the Benjamni-Hochberg False Discovery Rate (FDR) algorithm and were examined for use as potential diagnostic markers and for evidence of association with medical/demographic measures. Finally, systems-level analysis of consensus miR findings was performed using the proprietary Core Analysis workflow of the Qiagen Ingenuity® Pathway Analysis (IPA) software to identify leukemia-specific pathways and networks, and to predict the activation or inhibition of specific mRNA targets. We sequenced approximately 800 miRs from our 10 patients with AML and 8 control samples. We identified 44 miRs that showed a statistically significant increase in expression in AML patients versus controls and 33 miRs that showed a statistically significant decrease in expression in AML patients versus controls. Among these 77 differentially expressed miRs, only 10 were previously described in leukemia, including miR 181, miR 199b, miR 10a-5p, miR 22-3p, miR 23b-3p, miR 28-3p, miR 34a-5p, miR 409-3p, miR 500a-3p, miR 744-5p, and miR 126-5p. Finding these 10 miRs confirmed the validity of our approach. The remaining 67 of the miRs that showed differential expression in our study have not been described in relation to AML. Most of these have been found in association with colorectal, breast, cervical, NSCLC. Others have been reported in neurodegerative diseases and cardiac pathologies. Four of the patients with AML also had remission samples sequenced. Comparison of this subset of samples before and after treatment revealed statistically significant differences in three additional miRs. We are currently analyzing our data further to determine possible linkage between specific miRs and subtypes of AML. We are continuing to accrue patients to this study and we are following them over time in order to analyze miR expression as a biomarker that may predict relapse prior to usual indicators, i.e. cbc. Our approach of global sequencing of miRs as opposed to microarray analysis provides an unbiased approach regarding which miRs to assay and has demonstrated discovery of new associations of miRs with AML. We are hopeful that our study will provide further information about the molecular changes that lead to evolution of the leukemic clone and offer new targets for treatments. [ Disclosures No relevant conflicts of interest to declare.

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Becker-Greene, Dakota, Hao Li, Daniel Perez-Cremades, Winona Wu, Furkan Bestepe, Denizhan Ozdemir, Carolyn E. Niosi, et al. "MiR-409-3p targets a MAP4K3-ZEB1-PLGF signaling axis and controls brown adipose tissue angiogenesis and insulin resistance." Cellular and Molecular Life Sciences 78, no. 23 (October 26, 2021): 7663–79. http://dx.doi.org/10.1007/s00018-021-03960-1.

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Fredsøe, Jacob, Anne K. I. Rasmussen, Peter Mouritzen, Marianne T. Bjerre, Peter Østergren, Mikkel Fode, Michael Borre, and Karina D. Sørensen. "Profiling of Circulating microRNAs in Prostate Cancer Reveals Diagnostic Biomarker Potential." Diagnostics 10, no. 4 (March 28, 2020): 188. http://dx.doi.org/10.3390/diagnostics10040188.

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Early detection of prostate cancer (PC) is paramount as localized disease is generally curable, while metastatic PC is generally incurable. There is a need for improved, minimally invasive biomarkers as current diagnostic tools are inaccurate, leading to extensive overtreatment while still missing some clinically significant cancers. Consequently, we profiled the expression levels of 92 selected microRNAs by RT-qPCR in plasma samples from 753 patients, representing multiple stages of PC and non-cancer controls. First, we compared plasma miRNA levels in patients with benign prostatic hyperplasia (BPH) or localized prostate cancer (LPC), versus advanced prostate cancer (APC). We identified several dysregulated microRNAs with a large overlap of 59 up/down-regulated microRNAs between BPH versus APC and LPC versus APC. Besides identifying several novel PC-associated dysregulated microRNAs in plasma, we confirmed the previously reported upregulation of miR-375 and downregulation of miR-146a-5p. Next, by randomly splitting our dataset into a training and test set, we identified and successfully validated a novel four microRNA diagnostic ratio model, termed bCaP (miR-375*miR-33a-5p/miR-16-5p*miR-409-3p). Combined in a model with prostate specific antigen (PSA), digital rectal examination status, and age, bCaP predicted the outcomes of transrectal ultrasound (TRUS)-guided biopsies (negative vs. positive) with greater accuracy than PSA alone (Training: area under the curve (AUC), model = 0.84; AUC, PSA = 0.63. Test set: AUC, model = 0.67; AUC, PSA = 0.56). It may be possible in the future to use this simple and minimally invasive bCaP test in combination with existing clinical parameters for a more accurate selection of patients for prostate biopsy.

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Benoit, Charlotte, Hassina Ould-Hamouda, Delphine Crepin, Arieh Gertler, Laurence Amar, and Mohammed Taouis. "Early leptin blockade predisposes fat-fed rats to overweight and modifies hypothalamic microRNAs." Journal of Endocrinology 218, no. 1 (April 10, 2013): 35–47. http://dx.doi.org/10.1530/joe-12-0561.

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Perinatal leptin impairment has long-term consequences on energy homeostasis leading to body weight gain. The underlying mechanisms are still not clearly established. We aimed to analyze the long-term effects of early leptin blockade. In this study, newborn rats received daily injection of a pegylated rat leptin antagonist (pRLA) or saline from day 2 (d2) to d13 and then body weight gain, insulin/leptin sensitivity, and expression profile of microRNAs (miRNAs) at the hypothalamic level were determined at d28, d90, or d153 (following 1 month of high-fat diet (HFD) challenge). We show that pRLA treatment predisposes rats to overweight and promotes leptin/insulin resistance in both hypothalamus and liver at adulthood. pRLA treatment also modifies the hypothalamic miRNA expression profile at d28 leading to the upregulation of 34 miRNAs and the downregulation of four miRNAs. For quantitative RT-PCR confirmation, we show the upregulation of rno-miR-10a at d28 and rno-miR-200a, rno-miR-409-5p, and rno-miR-125a-3p following HFD challenge. Finally, pRLA treatment modifies the expression of genes involved in energy homeostasis control such as UCPs and AdipoRs. In pRLA rat muscle,Ucp2/3andAdipor1/r2are upregulated at d90. In liver, pRLA treatment upregulatesAdipor1/r2following HFD challenge. These genes are known to be involved in insulin resistance and type 2 diabetes. In conclusion, we demonstrate that the impairment of leptin action in early life promotes insulin/leptin resistance and modifies the hypothalamic miRNA expression pattern in adulthood, and finally, this study highlights the potential link between hypothalamic miRNA expression pattern and insulin/leptin responsiveness.

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Qu, Ruize, Xiaomin Chen, and Chao Zhang. "LncRNA ZEB1-AS1/miR-409–3p/ZEB1 feedback loop is involved in the progression of non-small cell lung cancer." Biochemical and Biophysical Research Communications 507, no. 1-4 (December 2018): 450–56. http://dx.doi.org/10.1016/j.bbrc.2018.11.059.

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Wang, Qian, Xiaojing Zhang, and Dehong Chen. "circ_VMA21 protects WI-38 cells against LPS-induced apoptotic and inflammatory injury by acting on the miR-409-3p/KLF4 axis." General physiology and biophysics 40, no. 04 (2021): 275–87. http://dx.doi.org/10.4149/gpb_2021011.

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Sommerova, Lucia, Milan Anton, Pavla Bouchalova, Hedvika Jasickova, Vladimir Rak, Eva Jandakova, Iveta Selingerova, Martin Bartosik, Borivoj Vojtesek, and Roman Hrstka. "The role of miR-409-3p in regulation of HPV16/18-E6 mRNA in human cervical high-grade squamous intraepithelial lesions." Antiviral Research 163 (March 2019): 185–92. http://dx.doi.org/10.1016/j.antiviral.2019.01.019.

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