MicroRNAs: Beyond Post-transcriptional Regulation of mRNAs

MicroRNAs (miRNAs), small non-coding RNAs, participate in the transcriptional and post-transcriptional regulation of eukaryotic genes, and are potential biomarkers for diseases. Mature miRNAs can be located in both the nucleus and cytoplasm, where they perform their regulatory function. The discovery of new miRNAs and the identification of their targets and functions are fundamental to understanding the biological processes regulated by them, as well as the role they play in diseases. This present study researched miRNAs function at nuclear level and as circulating molecules.

Analysis of Overexpressed miRNA in Circulation and Cancer Tissue to Develop a Potential microRNA Panel for the Diagnosis of Colorectal Cancer

Background: Colorectal cancer (CRC) represents the world’s fourth deadly cancer, but its early diagnosis can be curative with considerable success rates. This study was aimed to identify CRC specific microRNAs (miRNAs) in tissue and serum samples to develop a miRNA-based diagnostics panel for the minimal invasive detection of CRC in early condition. Methods: By integrating four microarrays in tissue and serum samples of CRC from Gene Expression Omnibus (GEO) database, we screened out the highly expressed miRNAs in each dataset by using limma R package. Two important upregulated miRNAs namely hsa-miR-1246 and hsa-miR-1825 were overlapped in both tissue and serum samples of CRC, and were investigated to target identification, followed by functional annotation and protein- protein interaction (PPI) study for the target genes through DAVID and STRING respectively. Finally, hub target genes were retrieved by Cytoscape analysis. Results: It was shown that target genes of hsa-miR-1246 and hsa-miR-1825 were involved with core KEGG pathways (such as cAMP, PI3K-Akt and calcium signaling pathway). In addition, biological processes (such as cell adhesion and cell proliferation), cellular components (such as plasma membrane and cytosol), molecular functions (such as protein binding and metal ion binding), were mostly associated with the target genes. Their top 5 target genes were retrieved and their biological function towards tumor progression was shown using Cancer Hallmarks Analytics Tool. Conclusion: This study suggested that hsa-miR-1246 and hsa-miR-1825, as overlapped upregulated tissue and circulating miRNAs might have a vital role in the development of CRC and their five hub target genes were identified.

The microRNA days: The COVID-19 pandemic from the point of view of short RNAs

Despite their biological simplicity, microRNA-based organisms, such as RNA viruses, are currently shown to be unexpected threats to mammals, including humans. This situation is exemplified by the COVID-19 pandemic triggered by the spread of SARS-CoV-2. RNA viruses are older than DNA viruses. Indeed, from an evolutionary standpoint, RNA is an older molecule than DNA. The strength of RNA viruses, compared to DNA viruses, resides in their simplicity and instability. The instability of RNA viruses, such as human immunodeficiency virus (HIV) and flu viruses, generates mutants to escape the host’s defense mechanisms. A formidable combination of lethality and infectivity was recently achieved by SARS-CoV-2. Complex DNAbased defense systems use Toll-like receptors to intercept viral RNA inside a cell. Activation of Toll-like receptors triggers inflammation and activates lymphocytes and monocytes, causing thromboxane release. In the case of SARS-CoV-2 infection, this process results in cytokine storms and lung thromboembolism. The ongoing pandemic can be envisioned as a struggle between highly evolved complex DNA organisms, i.e., humans, and poorly evolved simple RNA organisms, i.e., SARS-CoV-2 virus. Quite surprisingly, the complex organism has a serious problem defeating the simplistic organism. However, humans are finally developing a new effective weapon in fighting the SARS-CoV-2 virus, paradoxically, RNA-based vaccines. These considerations underscore the relevance of microRNAs as powerful tools in therapeutic and preventive medicine.

The regulatory network played by miRNAs during normal pregnancy and preeclampsia: a comparative study

Background: Preeclampsia is a pregnancy-specific syndrome, characterized by hypertension, proteinuria, and edema. Affecting between 2% and 8% of gestations worldwide, it accounts for 10% to 15% of maternal deaths. Although its etiology remains unclear, it includes complex pathological processes involving microRNAs, small non-coding RNA molecules with post-transcriptional repression effects on target mRNAs. Objective: To assess the expression of miRNAs during normal pregnancies and those complicated by preeclampsia, a sample of Venezuelan women were studied. Method: Nine placental microRNAs (hsa-miR- 20a-5p, 21-3p, 26a-5p, 181a-5p, 199a-5p, 210-3p, 222-5p, 223-3p, 424-3p) were measured in maternal plasma during the second and third trimesters of normal pregnancies, using a SYBR Green®-based real-time PCR, and compared the results against women affected by preeclampsia. Results: All assessed miRNAs were detected in maternal plasma in pregnancies with and without preeclampsia. All except miR-222 were over-expressed during disease when compared to the second and to third-trimester controls. miR-20a, miR-21, miR-26a, and miR-223 were down-regulated in the third trimester in comparison to the second trimester in normal pregnancies. Conclusion: The variation of the miRNAs expression through normal pregnancies suggested their involvement in normal physiological pregnancy processes. In contrast, the significant deregulation of the nine studied miRNAs during preeclampsia indicated the involvement of their target genes in the pathogenesis of the disease. miR-199a and miR-21-3p showed the greatest changes in expression. This study shows for the first time the presence of miR-20a, miR-199, and miR-424 and the variations they undergo in the plasma of pregnant women with preeclampsia.

Vitamin D regulates the expression of immune and stress response genes in dengue virus-infected macrophages by inducing specific microRNAs

Background: The pathogenesis associated with Dengue virus (DENV) infection is marked by the impairment of host immune response. Consequently, the modulation of immune response has emerged as an important therapeutic target for the control of DENV infection. Vitamin D has been shown to regulate the immune response in DENV infection, although the molecular mechanism remains poorly understood. Post-transcriptional regulation of mRNA by miRNAs offers an opportunity to gain insight into the immunomodulation mediated by vitamin D Objective: Previously, it has been observed that a high dose of vitamin D (4000 IU) decreased DENV-2 infection and inflammatory response in monocyte-derived macrophages (MDMs). Here, we examine whether high or low doses of vitamin D supplements exert differential effect on miRNA expression in DENV-infected macrophages Methods: We analyzed miRNA expression profiles in MDMs isolated from healthy individuals who were given either 1000 or 4000 IU/day of vitamin D for 10 days. MDMs before or after vitamin D supplementation were challenged with DENV-2, and miRNAs profiles were analyzed by qPCR arrays. Results: DENV-2 infected MDMs supplemented with 4000 IU, showed up-regulation of miR-374a-5p, miR-363-3p, miR-101-3p, miR-9-5p, miR-34a-5p, miR-200a-3p, and the family of miRNAs miR-21-5p, and miR-590-p. The miRNA profile and predicted target mRNAs suggested regulatory pathways in MDMs obtained from healthy donors who received higher doses of vitamin D. These DENV-2 infected MDMs expressed a unique set of miRNAs that target immune and cellular stress response genes. Conclusion: The results suggest vitamin D dose-dependent differential expression of miRNAs target key signaling pathways of the pathogenesis of dengue disease.

An Overview of C19MC Cluster Subgroup 3 and Cancer

: The primate-specific microRNA gene cluster on chromosome 19 (C19MC) is composed of 56 mature microRNAs (miRNAs), which are divided into three subgroups according to the sequence similarity. This cluster is principally expressed in the placenta but not in other tissues. C19MC is involved in the regulation of proliferation, migration, and invasion of trophoblastic cells, which are important for the development of the placenta. There is a growing number of studies that have found an altered expression of some miRNAs of the C19MC cluster in cancer, suggesting that these could play an important role in the development of this disease. Therefore, in this work, we provided an overview of the C19MC cluster’s role in cancer through a systematic review of published articles. In particular, we focused on miRNAs of subgroup 3. These studies suggest that miRNAs such as miR-512-3p, miR-512-5p, miR-516a-5p, miR-516b-5p, and miR-498-5p could play a pivotal role in the development of therapies for cancer. Future studies are necessary to elucidate the molecular processes and pathways regulated by subgroup 3 miRNAs.

An Overview on the Role of miR-451 in Lung Cancer: Diagnosis, Therapy, and Prognosis

: MicroRNAs (miRNAs) are highly conserved non-coding RNAs involved in many physiological processes such as cell proliferation, inhibition, development of apoptosis, differentiation, suppresses tumorigenicity, and regulating cell growth. The description of the alterations of miRNA expression patterns in cancers will be helpful to recognize biomarkers for early detection and possible therapeutic intervention in the treatment of cancers. Recent studies have shown that miR-451 is broadly dysregulated in lung cancer and is a crucial agent in lung tumor progression. This review summarizes recent advances of the potential role of miR-451 in lung cancer diagnosis, prognosis, and treatment and provides an insight into the potential use of miR-451 for the development of advanced therapeutic methods in lung cancer.

In-Silico Analysis of rSNPsin miRNA:mRNA Duplex Involved in Insulin Signaling Genes Shows a Possible Pathogenesis of Insulin Resistance

Background: Insulin resistance is a condition in which the body produces insulin but is unable to use it effectively. Aberrations in insulin signaling are known to play a crucial role in pathogenesis of this disease state. Eventually patients will have glucose build up in their blood instead of being absorbed by the cells, leading to type 2 diabetes. Objective: In the current study we focus on understanding the role of rSNP mediated miRNA:mRNA dysregulation and its impact on the above metabolic condition. Methods: More than 30 genes involved in insulin signaling pathway were found using KEGG database. The 3’UTR end of genes was studied by using RegRNA and Ensembl, whereas TargetScan along with miRbase were used to identify their target miRNAs.Binding free energy was used as a parameter to analyze the affect of polymorphism on the miRNA:mRNA duplex formation.Further, UNA fold was used to determine the heat capacity changes. Results: The following genes INSR, INS, GLUT4, FOXO1, IL6, TRIB3 and SREBF1 were selected for analysis. Multiple miRNAs, hsa-miR-16-5p, hsa-miR-15a-15p were identified in the SNP occurring region for INSR. INS too showed similar results.INSR, INS and TRIB3 were found to have the maximum change in their binding free energy due to rSNP variation. A destabilisation in the heat capacity values was observed too, contributed due to rSNP induction. Conclusion: A direct relationship between miRNA target polymorphism and the stability of the miRNA:mRNA duplex was observed. The current methodology used to study insulin resistance pathogenesis could elaborate on our existing knowledge of miRNA mediated disease states.