miRNA Activity Research Articles

Interplay between LncRNAs and microRNAs in Breast Cancer.

(1) Although long noncoding RNAs (lncRNAs) are known to be precursors of microRNAs (miRNAs), they frequently act as competing endogoneous RNAs (ceRNAs), yet still their interplay with miRNA is not well known. However, their interaction with miRNAs may result in the modulation of miRNA action. (2) To determine the contribution of these RNA molecules in tumor resistance to chemotherapeutic drugs, it is essential to consider not only the oncogenic and tumor suppressive function of miRNAs but also the impact of lncRNAs on miRNAs. Therefore, we performed an extensive search in different databases including PubMed. (3) The present study concerns the interplay between lncRNAs and miRNAs in the regulatory post-transcriptional network and their impact on drugs used in the treatment of breast cancer. (4) Consideration of this interplay may improve the search for new drugs to circumvent chemoresistance.

Abstract 1405: Long non-coding RNA LINC01614 augments papillary thyroid cancer cell phenotype

Abstract Papillary thyroid cancer (PTC) accounts for the vast majority of thyroid cancer cases and despite high survival rates, disease recurrence and metastasis remain prominent issues. Therefore, there is a need to identify potential molecular markers associated with PTC that aid in early diagnosis, prognosis, and that may serve as therapeutic targets. One area of focus for cancer study is trending towards the epigenome and its functional regulators. The largest subclass of RNA molecules in the human genome consists of long intergenic non-coding RNAs (lincRNAs) with many of their functions yet to be identified. Evidence supports their roles in the regulation of gene expression, as these molecules can act as scaffolds for RNA and protein localization as well as act as molecular “sponges” for binding to and inhibiting action of specific miRNAs. Recently, long non-coding RNA molecules have been demonstrated to play roles in both the development and progression of cancer, deeming them as both attractive and specific biomarkers and/or therapeutic targets for study. Data from our patient sample biobank identified LINC01614 as being significantly upregulated (~12 fold increase) in PTC, when compared to normal, matched thyroid tissue. There was also ~30 fold increase in LINC01614 expression in male PTC, compared to ~5.5 fold increase in female PTC, highlighting a potential sex correlation for study. Thus, we are studying LINC01614 as a potential PTC biomarker. Functional analysis of LINC01614 in vitro found it to be upregulated in various thyroid cancer cell lines, specifically two PTC cell lines: TPC1 (~5 fold; RET/PTC rearrangement; female) and K1 (~2 fold; BRAFV600E; male) when compared to the immortalized “normal” thyroid cell line (Nthy-ori-3-1). To establish a phenotype for LINC01614 expression, we utilized the CRISPRi technique to knockdown expression of this lincRNA in both TPC1 and K1. Knockdown resulted in decreased healing capacity (~20% for both), clonogenicity (~50% and ~34%, respectively), and proliferation (~55% and ~45%, respectively) in both the TPC1 and K1 PTC cell lines. Studies are underway to further assess migration, invasion, and morphology in both cell lines as well as studies to elucidate potential protein interactions and mechanisms of action of LINC01614 in PTC. Studying lincRNAs and their regulatory roles in cancer cell function can aid in the identification of various molecular markers for therapeutic intervention. Elucidation of how these molecules impact PTC development and progression is a promising avenue of exploration. Citation Format: Danielle Quaranto, Michelle Carnazza, Nicole DeSouza, Sina Dadafarin, Augustine Moscatello, Raj Tiwari, Jan Geliebter. Long non-coding RNA LINC01614 augments papillary thyroid cancer cell phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1405.

Next-generation poly-L-histidine formulations for miRNA mimic delivery

Many diseases, especially cancer, are caused by the abnormal expression of non-coding microRNAs (miRNAs), which regulate gene expression, leading to the development of miRNA-based therapeutics. Synthetic miRNA inhibitors have shown promising efficacy in blocking the activity of aberrant miRNAs that are upregulated in disease-specific pathologies. On the other hand, miRNAs that aid in preventing certain diseases and are reduced in expression in the disease state need different strategies. To tackle this, miRNA mimics, which mimic the activity of endogenous miRNAs, can be delivered for those miRNAs downregulated in different disease states. However, the delivery of miRNA mimics remains a challenge. Here, we report a cationic polylactic-co-glycolic acid (PLGA)-poly-L-histidine delivery system to deliver miRNA mimics. We chose miR-34a mimics as a proof of concept for miRNA delivery. miR-34a-loaded PLGA-poly-L-histidine nanoparticles (NPs) were formulated and biophysically characterized to analyze the structural properties of miRNA mimic-loaded NPs. Invitro efficacy was determined by investigating miR-34a and downstream target levels and performing cell viability and apoptosis assays. We confirmed invivo efficacy through prolonged survival of miR-34a NP-treated A549-derived xenograft mice treated intratumorally. The results of these studies establish PLGA-poly-L-histidine NPs as an effective delivery system for miRNA mimics for treating diseases characterized by downregulated miRNAs.

A Comprehensive and Updated Review of MicroRNA Pathogenesis and Gene Expression in Cystic Fibrosis

MicroRNAs (miRNAs) are short (~22 nucleotides) non-coding sequences that regulate gene expression. It has been recently identified that miR-145 regulates cystic fibrosis transmembrane regulator (CFTR) expression, and response to first-generation miRNAs is recognized as major biomedical research in CF. Abnormal miRNA activity causes numerous diseases, thus the critical role of miRNA is to focus on miRNA bindings to target proteins. miRNA classifications depend on their genomic location and gene structure, and they include intergenic and intronic regions. Intronic miRNA location is in the introns of annotated genes. Intergenic and intronic miRNA genes are controlled with their promoters. Some miRNAs negatively regulate the cystic fibrosis transmembrane conductance regulator (CFTR) gene expression (e.g., miR-101) in adult lung cells and have no effect on fetal epithelial cells. MiR-145, miR-223, and miR-494 directly regulate the CFTR gene expression. MiR-509-3p and miR-494 regulate CFTR more strongly than the other miRNAs. MiR-138 enhances CFTR channels on the cell surface of epithelial cells. Polymorphisms in the 3′-UTR region of CFTR decrease the expression of CFTR. Mutations in the CF (CFTR) gene, located on chromosome 7, diminish ion transport. The consequent loss of chloride and bicarbonate secretion and absorption lead to a multi-organ disease called CF marked by mucus inspissation, chronic inflammation, and tissue destruction. The most affected organs are the lung and pancreas, but the liver, bowel, sinuses, and vas deferens, among others, are prominently involved as well. The loss of CFTR also results in an altered miRNA profile that regulates the response to therapy and disease pathogenesis. This review summarizes miRNA alterations in the CF tissue, the role of miRNA in disease pathogenesis, and the therapeutic opportunity for oligotherapeutic manipulation to improve CF outcomes.

Exposure to Moringa oleifera microRNAs induces proteomic changes linked to tumorigenesis and epithelial-mesenchymal transition in HeLa cells

Cervical cancer (CC) is one of the most frequent cancers in women worldwide. The epithelial-mesenchymal transition (EMT) and the extracellular release of TGF-β are phenomena typically associated with different tumorigenic processes, including tumour cell proliferation and metastatization. Specific human microRNAs (miRNAs; miRs) involved in these tumorigenic processes have been identified, becoming important diagnostic and prognostic markers, and even potential therapeutic targets. In parallel, different studies have also shown that plant miRNAs can mediate a cross-kingdom regulation (CKR) of mammalian genes and modulate host's gene expression under pathological conditions, restoring the regulatory activity of endogenous miRNAs lost in cancer. In our previous studies, the miRNome from Moringa oleifera Lam. (henceforth moringa or mol) has been sequenced, showing the presence of several conserved miRNAs in the plant kingdom, whose ability to differentially regulate proliferation and apoptosis in healthy and cancer cells has been demonstrated. Furthermore, the effects of mol-miR treatment on tumorigenesis and EMT have been proved in liver tumour cells. According to these premises, we here investigated the proteomic profile of CC-derived HeLa cells exposed to a mol-miRNA pool, demonstrating the down-representation of specific factors involved in tumorigenesis. The treatment with plant miRs was able to modulate proteins involved in several biological processes linked to EMT. Furthermore, it reduced the expression of TGF-β and significantly inhibited cell motility, as observed following Scratch test and cell viability measurements, with a significant increase of apoptotic events. In conclusion, our results suggest and pave the way for the development of new potential therapeutic approaches based on CKR mediated by plant miRNAs for contrasting human cervical cancer, even in the form of adjuvants to classic treatments for limiting their side effects.

The Role of MicroRNA in the Pathogenesis of Diabetic Nephropathy

Diabetic nephropathy is one of the most common and severe complications of diabetes mellitus, affecting one in every five patients suffering from diabetes. Despite extensive research, the exact pathogenesis of diabetic nephropathy is still unclear. Several factors and pathways are known to be involved in the development of the disease, such as reactive oxygen species or the activation of the renin-angiotensin-aldosterone system. The expression of those proteins might be extensively regulated by microRNA. Recent research suggests that in diabetic nephropathy patients, the profile of miRNA is significantly changed. In this review, we focus on the actions of miRNA in various pathways involved in the pathogenesis of diabetic nephropathy and the clinical usage of miRNAs as biomarkers and therapeutic targets.

Effect of epigenetic activating of Dlk1-Dio3 imprinted cluster on miR-370 expression due to folate deficiency during nerve development

Proper Dlk1-Dio3 imprinting plays a critical role in embryogenesis, and folic acid deficiency may affect the imprinting of this locus through epigenetic regulation. However, whether and how folic acid directly impacts the imprinting status of Dlk1-Dio3 to affect neural development remain unclear. Here, we found decreased IG-DMR (intergenic -differentially methylated regions) methylation in the folate-deficient encephalocele in humans, suggesting that abnormal Dlk1-Dio3 imprinting status is related to neural tube defects (NTDs) caused by folate deficiency. Similar results were obtained with folate-deficient embryonic stem cells. By miRNA chip analysis, folic acid deficiency led to changes in multiple miRNAs, including the upregulation of 15 miRNAs located in the Dlk1-Dio3 locus. Real-time PCR confirmed that seven of these miRNAs were upregulated, especially miR-370. In contrast to normal embryonic development, in which expression of miR-370 is highest at E9.5, the abnormally high and sustained expression of miRNA-370 in folate-deficient E13.5 embryos may contribute to NTDs. In addition, we found that DNMT3A (de novo DNA methyltransferases 3A) is a direct target gene of miR-370 in neural cells, and DNMT3A participates in the role of miR-370 in inhibiting cell migration. Finally, in the folate-deficient mouse model, Dlk1-Dio3 epigenetic activation was found in fetal brain tissue, along with the upregulation of miR-370 and the downregulation of DNMT3A. Collectively, our findings demonstrate a pivotal role of folate in the epigenetic regulation of Dlk1-Dio3 imprinting during neurogenesis, revealing an elegant mechanism for the activation of Dlk1-Dio3 locus miRNAs in folic acid deficiency.

MiRNA-21 Regulates Multiple Factors in the Pathogenesis of IBD: A Literature Review

Introduction: Inflammatory Bowel Disease (IBD) is characterized by chronic inflammation in the gastrointestinal tract (GIT) via dysbiosis of the gut microbiome and weakening of the epithelial and mucosal barriers. Although the causative nature of IBD remains unknown, several studies have demonstrated that aberrant host-microRNA (miRNA) activity contributes to its pathophysiology. For example, miRNA-21 contributes to IBD through three mechanisms. Firstly, by increasing gut permeability via the ARF4 pathway. Secondly, by decreasing gut mucosal secretions via interfering with host goblet cells. Finally, by regulating proteins that inhibit host autophagy and decreasing immune response via the Phosphatase and Tensin Homolog (PTEN) and Akt pathway. The proposed study aims to answer the following question: how does aberrant expression of miRNA-21 in IBD contribute to the disease? Methods: This review highlights and summarizes relevant studies on the miRNA-21 regulation of key pathways in the pathogenesis of IBD. Searches used electronic databases including PubMed, and Google Scholar for keywords such as “Inflammatory bowel disease” and “miRNA-21” and other additional relevant terms from years 2016 to 2022. Review papers that met our criteria and the relevant papers they referenced, regardless of their publication date, were manually searched for. Figures were made in part using KeyNote and Serveir Medical Art. Discussion: Intracellular pathways contribute to chronic inflammation in IBD such as the PTEN pathway and pro-inflammatory cytokines like TNF-α. These pathways have been shown to influence the mucosal barrier, epithelial barrier, and the immune system in the gut. These pathways are regulated by miRNA-21, demonstrating miRNA-21 as a key regulator in IBD. Both PTEN and TNF-α also contribute to levels of angiogenesis in the gut through the regulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF), further demonstrating the intricacies of the miRNA-21 pathway regulation in IBD. Conclusion: The research highlighted in this review provides insight into the mechanisms of aberrant miRNA expression in IBD. Furthermore, knowledge of such molecular mechanisms has clinical and research applications, including identifying diagnostic biomarkers, less invasive screening techniques, and novel drug therapies.

MiRNA-21 Regulates Multiple Factors in the Pathogenesis of IBD: A Literature Review

Introduction: Inflammatory Bowel Disease (IBD) is characterized by chronic inflammation in the gastrointestinal tract (GIT) via dysbiosis of the gut microbiome and weakening of the epithelial and mucosal barriers. Although the causative nature of IBD remains unknown, several studies have demonstrated that aberrant host-microRNA (miRNA) activity contributes to its pathophysiology. For example, miRNA-21 contributes to IBD through three mechanisms. Firstly, by increasing gut permeability via the ARF4 pathway. Secondly, by decreasing gut mucosal secretions via interfering with host goblet cells. Finally, by regulating proteins that inhibit host autophagy and decreasing immune response via the Phosphatase and Tensin Homolog (PTEN) and Akt pathway. The proposed study aims to answer the following question: how does aberrant expression of miRNA-21 in IBD contribute to the disease? Methods: This review highlights and summarizes relevant studies on the miRNA-21 regulation of key pathways in the pathogenesis of IBD. Searches used electronic databases including PubMed, and Google Scholar for keywords such as “Inflammatory bowel disease” and “miRNA-21” and other additional relevant terms from years 2016 to 2022. Review papers that met our criteria and the relevant papers they referenced, regardless of their publication date, were manually searched for. Figures were made in part using KeyNote and Serveir Medical Art. Discussion: Intracellular pathways contribute to chronic inflammation in IBD such as the PTEN pathway and pro-inflammatory cytokines like TNF-α. These pathways have been shown to influence the mucosal barrier, epithelial barrier, and the immune system in the gut. These pathways are regulated by miRNA-21, demonstrating miRNA-21 as a key regulator in IBD. Both PTEN and TNF-α also contribute to levels of angiogenesis in the gut through the regulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF), further demonstrating the intricacies of the miRNA-21 pathway regulation in IBD. Conclusion: The research highlighted in this review provides insight into the mechanisms of aberrant miRNA expression in IBD. Furthermore, knowledge of such molecular mechanisms has clinical and research applications, including identifying diagnostic biomarkers, less invasive screening techniques, and novel drug therapies.

Expression profile of microRNAs related with viral infectivity, inflammatory response, and immune activation in people living with HIV

To evaluate the serum expression of microRNAs (miRNAs) with ability to modulate the human immunodeficiency (HIV) replication or inflammatory status in people living with HIV (PLWH). Forty healthy controls and two groups of PLWH were evaluated: (a) Group 1 (n = 30), patients with detectable viral load at inclusion, analyzed before receiving antiretroviral therapy (ART) and 12 months after initiating it; (b) Group 2 (n = 55), PLWH with prolonged undetectable viral load. Intestinal barrier disruption (I-FABP) and bacterial translocation (16S rDNA) markers, inflammatory markers such as interleukin (IL)-6 and sCD163, immune activation and expression of specific miRNAs were evaluated. Serum concentrations of I-FABP, 16S rDNA, IL-6, sCD163 and activated T lymphocytes were increased in PLWH. Serum miR-34a was overexpressed at inclusion and remained elevated after ART. The expression of the remaining miRNAs that modulate HIV infectivity (miR-7, mir-29a, miR-150, and miR-223) was similar in PLWH and controls. Related to miRNAs implicated in inflammation (miR-21, miR-155, and miR-210), significant overexpression were observed in miR-21 and miR-210 levels in untreated PLWH, but levels were restored in those patients treated for a long period. A sustained overexpression of miR-34a was detected even after prolonged HIV controlled replication. miR-21 and miR-210 can be considered new markers of inflammation with high sensitivity to its modifications.

The role of non-coding RNAs in the diagnosis of different stages (HCC, CHB, OBI) of hepatitis B infection.

Despite the availability of an effective hepatitis B virus (HBV) vaccine and universal immunization schedules, HBV has remained a health problem in various stages such as occult hepatitis B infection (OBI), chronic hepatitis B (CHB), and hepatocellular carcinoma (HCC), which is considered one of the possible phases during chronic HBV infection. OBI is defined as the persistence of HBV genomes in hepatocytes of patients with a negative HBV surface antigen (HBsAg) test and detectable or undetectable HBV DNA in the blood. OBI is occasionally associated with infection caused by mutant viruses that produce a modified HBsAg that is undetected by diagnostic procedures or with replication-defective variations. Many aspects of HBV (OBI more than any other stage) including prevalence, pathobiology, and clinical implications has remained controversial. According to a growing body of research, non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been linked to the development and progression of a number of illnesses, including viral infectious disorders. Despite a shortage of knowledge regarding the expression and biological activities of lncRNAs and miRNAs in HBV infection, Hepatitis B remains a major global public health concern. This review summarizes the role of lncRNAs in the diagnosis and treatment of different stages of hepatitis B infection.

Harnessing PUF-Based Reporters for Noninvasive Imaging of the MicroRNA Dynamics in Differentiation.

Precise characterization of miRNA expression patterns is critical to exploit the complexity of miRNA regulation in biology. Herein, we developed a Pumilio/FBF (PUF) protein-based engineering luciferase reporter system, PUF/miR, to quantitatively and non-invasively sense miRNA activity in living cells and animal models. We verified the feasibility of this reporter by monitoring the expression of several types of miRNAs (miRNA-9, 124a, 1, and 133a) in neural and muscle differentiated cells as well as subcutaneous or tibial anterior muscles in mice. The quantitative RT-PCR also validated the reliability and quantitative consistency of bioluminescence imaging in detecting miRNA expression. We further effectively employed this reporter system to visualize the expression of miRNA-1 and miRNA-133a in mouse models of skeletal muscle injury. As a non-invasive and convenient innovative approach, our results have realized the positive bioluminescence imaging of endogenous miRNAs in vitro and in vivo using the PUF/miR system. We believe that this approach would provide a potential means for noninvasive monitoring of disease-related miRNAs and could facilitate a deeper understanding of miRNA biology.

MiRNAs Action and Impact on Mitochondria Function, Metabolic Reprogramming and Chemoresistance of Cancer Cells: A Systematic Review

MicroRNAs (miRNAs) are involved in the regulation of mitochondrial function and homeostasis, and in the modulation of cell metabolism, by targeting known oncogenes and tumor suppressor genes of metabolic-related signaling pathways involved in the hallmarks of cancer. This systematic review focuses on articles describing the role, association, and/or involvement of miRNAs in regulating the mitochondrial function and metabolic reprogramming of cancer cells. Following the PRISMA guidelines, the articles reviewed were published from January 2010 to September 2022, with the search terms "mitochondrial microRNA" and its synonyms (mitochondrial microRNA, mitochondrial miRNA, mito microRNA, or mitomiR), "reprogramming metabolism," and "cancer" in the title or abstract). Thirty-six original research articles were selected, revealing 51 miRNAs with altered expression in 12 cancers: bladder, breast, cervical, colon, colorectal, liver, lung, melanoma, osteosarcoma, pancreatic, prostate, and tongue. The actions of miRNAs and their corresponding target genes have been reported mainly in cell metabolic processes, mitochondrial dynamics, mitophagy, apoptosis, redox signaling, and resistance to chemotherapeutic agents. Altogether, these studies support the role of miRNAs in the metabolic reprogramming hallmark of cancer cells and highlight their potential as predictive molecular markers of treatment response and/or targets that can be used for therapeutic intervention.

Downregulation of microRNA-330-5p induces manic-like behaviors in REM sleep-deprived rats by enhancing tyrosine hydroxylase expression.

In our pilot study, we found an increase in tyrosine hydroxylase (Th) mRNA expression in the prefrontal cortex of 72-h REM sleep-deprived (SD) rats, a mania model. Additionally, the expression levels of miR-325-3p, miR-326-3p, and miR-330-5p, the predicted target miRNAs on TH, were significantly decreased. Based on these results, in this study, we investigated whether miRNA-325-3p, miR-326-3p, and miR-330-5p modulate TH and manic-like behaviors in SD rats. Manic-like behaviors were assessed using the open field test (OFT) and elevated plus-maze (EPM) test. The direct binding activity of miRNAs to the 3'-untranslated region (3'-UTR) of the Th gene was measured in HEK-293 cells using a luciferase reporter system. We also examined mRNA and protein expression of TH after intracerebroventricular (ICV) injection of miR-330-5p agomir to SD rats, along with manic-like behaviors. We observed an upregulation in mRNA and protein expression of TH and downregulation in miRNA-325-3p, miR-326-3p, and miR-330-5p expressions in the prefrontal cortex of SD rats, together with increased manic-like behaviors. The luciferase reporter assay showed that miR-330-5p could repress TH expression through direct binding to its target site in the 3'-UTR of Th, whereas miR-326-3p and miR-330-5p could not. In addition, ICV injection of miR-330-5p agomir alleviated the increase in TH expression in the prefrontal cortex of SD rats and manic-like behaviors. TH expression regulation through miR-330-5p may be implicated in the pathophysiology of mania in SD rats.

Mechanisms of action of extracellular miRNAs

The mechanisms of action of extracellular miRNAs are given in the scientific review. To write the article, information was searched using Scopus, Web of Science, MedLine, PubMed, Google Scholar, EMBASE, Global Health, The Cochrane Library databases. The authors state that miRNAs are generated by producer cells and then packaged in extracellular vesicles and delivered to other cells by functionally active structures. Extracellular vesicles transport miRNA in a paracrine and endocrine manner. It is emphasized that the mechanism of action of extracellular microRNAs depends on their association with extracellular vesicles. MicroRNAs associated with extracellular vesicles are taken up by cells and act as intracellular microRNAs. MicroRNAs associated and not associated with extracellular vesicles, by interacting with specific receptors, induce the activation of intracellular signaling, most often pro-inflammatory pathways. Extracellular vesicles interact with the membrane of the recipient cell through their surface proteins in a ligand-receptor manner. It is shown that specific proteins of extracellular vesicles, such as major histocompatibility complex class I and class II proteins, transferrin receptors and tetraspanins, induce disruption of some signaling pathways of target cells. Scientists believe that exosomes and ectosomes are absorbed by recipient cells using clathrin-mediated endocytosis, phagocytosis, and/or macropinocytosis. After delivery to target cells, miRNAs regulate the translation of their target genes. Extracellular vesicles circulating in the blood serum of healthy people are believed to have antifibrogenic effects and contain miRNAs that inhibit the activity of hematopoietic stem cells or damaged hepatocytes. Scientists believe that receptor-independent penetration of the hepatitis C virus into hepatocytes can be carried out with the help of exosomes. Exosomal miRNAs and miRNAs not associated with exosomes are able to bind to certain cellular receptors and activate intracellular signaling pathways associated with them.

Overview of Repressive miRNA Regulation by Short Tandem Target Mimic (STTM): Applications and Impact on Plant Biology.

The application of miRNA mimic technology for silencing mature miRNA began in 2007. This technique originated from the discovery of the INDUCED BY PHOSPHATE STARVATION 1 (IPS1) gene, which was found to be a competitive mimic that prevents the cleavage of the targeted mRNA by miRNA inhibition at the post-transcriptional level. To date, various studies have been conducted to understand the molecular mimic mechanism and to improve the efficiency of this technology. As a result, several mimic tools have been developed: target mimicry (TM), short tandem target mimic (STTM), and molecular sponges (SPs). STTM is the most-developed tool due to its stability and effectiveness in decoying miRNA. This review discusses the application of STTM technology on the loss-of-function studies of miRNA and members from diverse plant species. A modified STTM approach for studying the function of miRNA with spatial-temporal expression under the control of specific promoters is further explored. STTM technology will enhance our understanding of the miRNA activity in plant-tissue-specific development and stress responses for applications in improving plant traits via miRNA regulation.

Expression pattern of circadian rhythm-related genes and its potential relationship with miRNAs activity in endometrial cancer.

The circadian clock is an autonomous oscillator that controls key aspects of cell physiology, including metabolism, transcriptional state, and cell signaling. Disturbances of circadian rhythms lead to disruption of cell and tissue homeostasis, which promotes carcinogenesis. The aim of the study was to determine the expression of circadian rhythm-related genes in endometrial cancer and to select miRNAs involved in the regulation of their expression. 50 endometrial tissue samples were collected from patients who underwent hysterectomy: 40 diagnosed with endometrial cancer and 10 without cancer. Expression profile of circadian rhythm-related genes was evaluated using microarrays and validated with RT-qPCR. MicroRNA expression was assessed using microarrays. Then mirTAR tool was used to identify miRNAs involved in the expression regulation of circadian rhythm-related genes. CLOCK expression is disrupted in endometrial cancer, which may be due to miR-15b, miR-331-3p and miR-200a overexpression. Elevated NPAS2 and CSNK1D levels may be associated with miR-432 silencing. In addition, high miR-874 and miR-200a expression may be potentially responsible for the reduction of PER3 level. Change of CLOCK, CSNK1D, NPAS2 and PER3 expression may suggest that circadian rhythms are disrupted in endometrial cancer. A possible mechanism of the observed changes may be related to miRNAs activity.

Dysregulated Cell Homeostasis and miRNAs in Human iPSC-Derived Cardiomyocytes from a Propionic Acidemia Patient with Cardiomyopathy.

Propionic acidemia (PA) disorder shows major involvement of the heart, among other alterations. A significant number of PA patients develop cardiac complications, and available evidence suggests that this cardiac dysfunction is driven mainly by the accumulation of toxic metabolites. To contribute to the elucidation of the mechanistic basis underlying this dysfunction, we have successfully generated cardiomyocytes through the differentiation of induced pluripotent stem cells (iPSCs) from a PCCB patient and its isogenic control. In this human cellular model, we aimed to examine microRNAs (miRNAs) profiles and analyze several cellular pathways to determine miRNAs activity patterns associated with PA cardiac phenotypes. We have identified a series of upregulated cardiac-enriched miRNAs and alterations in some of their regulated signaling pathways, including an increase in the expression of cardiac damage markers and cardiac channels, an increase in oxidative stress, a decrease in mitochondrial respiration and autophagy; and lipid accumulation. Our findings indicate that miRNA activity patterns from PA iPSC-derived cardiomyocytes are biologically informative and advance the understanding of the molecular mechanisms of this rare disease, providing a basis for identifying new therapeutic targets for intervention strategies.

Mechanisms of action of cytoplasmic microRNAs. Part 6. MicroRNA-mediated translation activation

In the scientific review, the mechanisms of action of cytoplasmic miRNAs, namely miRNA-mediated activation of translation, are given. To write the article, information was searched using Scopus, Web of Science, MedLine, PubMed, Google Scholar, EMBASE, Global Health, The Cochrane Library databases. Examples of direct activation of mRNA translation by miRNA are presented. One of them is miRNA-mediated activation of translation, which is associated with the peculiarities of the state of the cell (resting cell effect). It has been shown that protein 1 of the fragile X mental retardation (FMR1) syndrome, depending on the stage of the cell cycle, can participate in both inhibition and enhancement of translation. It is known that microRNAs can influence the activity of RNP by binding to the RNA-binding sites of specific mRNAs or directly to RBP molecules, directly inhibiting their activity. Poly (rC) binding protein 2 (PCBP2) is a multifunctional adapter molecule that binds to RNA and DNA, competing with other RNA-binding factors. The PCBP2 protein limits translation initiation by preventing ribosome recruitment. The authors provided information on miR-346-mediated activation of the translation of receptor-interacting protein 140. It is emphasized that some miRNAs, preventing the degradation of the mRNA molecule, increasе the level of its stability, which is accompanied by an enhancement in their translation. MicroRNAs stabilize specific mRNA targets, preventing the association of the ARE element degradation factor, tristetraprolin, with mRNA. Data are presented on the activation of mRNA target translation by factors that sequester miRNAs or compete with miRNAs. Various intracellular factors and proteins can enter into a competitive relationship with miRNA and interfere with or remove it from the target mRNA. It is known that activation of translation can occur due to microRNA inhibition of repressor proteins. The authors indicate that increased miR-145 expression is accompanied by activation of myocardin translation, which induces the proliferation and migration of smooth muscle cells.

Abstract 1915: Overturning the Paradigm of miRNA Regulation: Upregulation as a common mechanism of miRNA action

Abstract 1915: Overturning the Paradigm of miRNA Regulation: Upregulation as a common mechanism of miRNA action