MicroRNA - Volume 9, Issue 2, 2020

Aim: To provide a review considering microRNAs regulating oncogenes and tumor suppressor genes during the different stages of cell cycle, controlling carcinogenesis. Methods: The role of microRNAs involved as oncogenes’ and tumor suppressor genes’ regulators in cancer was searched in the relevant available literature in MEDLINE, including terms such as “microRNA”, “oncogenes”, “tumor suppressor genes”, “metastasis”, “cancer” and others. Results: MicroRNAs determine the expression levels of multiple cell cycle regulators, such as cyclins, cyclin dependent kinases and other major cell cycle activators including retinoblastoma 1 (RB- 1) and p53, resulting in alteration and promotion/inhibition of the cell cycle. Conclusion: MicroRNAs are proven to have a key role in cancer pathophysiology by altering the expression profile of different regulator proteins during cell division cycle and DNA replication. Thus, by acting as oncogenes and tumor suppressor genes, they can either promote or inhibit cancer development and formation, revealing their innovative role as biomarkers and therapeutic tools.

Background: Signaling pathways including gene silencing, cellular differentiation, homeostasis, development and apoptosis are regulated and controlled by a wide range of miRNAs. Objective: Due to their potential binding sites in human-protein coding genes, many studies have also linked their altered expressions in various cancer types making them tumor suppressors agents. Methods: Moreover, each miRNA is predicted to have many mRNA targets indicating their extensive regulatory role in cell survival and developmental processes. Nowadays, diagnosis of early cancer stage development is now dependent on variable miRNA expression levels as potential oncogenic biomarkers in validating and targeting microRNAs for cancer therapy. Results: As the majority of miRNA, transcripts are derived from RNA polymerase II-directed transcription, stress response could result on a general reduction in the abundance of these transcripts. Over expression of various microRNAs have lead to B cell malignancy, potentiated KrasG12Dinduced lung tumorigenesis, chronic lymphocytic leukemia, lymphoproliferative disease and autoimmunity. Conclusion: Altered miRNA expressions could have a significant impact on the abundance of proteins, making them attractive candidates as biomarkers for cancer detection and important regulators of apoptosis.

Background: Along with the description of tumorigenesis processes in endometriosisrelated ovarian cancer, identifying dysregulated miRNAs, the target genes of these miRNAs, and the processes abnormally affected by dysregulated miRNAs is essential, which was our goal. Methods: Two reviewers individually evaluated the articles which collected relevant information including genes and miRNAs involved in the transformation of endometriosis into ovarian cancer. To assess the mature sequence of miRNAs and also their chromosomal positions, miRPathDB software was employed. To determine the main target gene predicted for each considered miRNAs, the TargetScanS Web server was applied. The interaction of each gene with other genes associated with endometrial- related ovarian cancer was determined by GeneMANIA software. Finally, to design integrated model of miRNAs-targeted genes interaction network, the Cytoscape software was used. Results: The final number of studies available for analysis was 6 manuscripts including 22 miRNAs described as involved in the transformation of endometriosis into different subtypes of ovarian cancers (14 miRNAs up-regulated and 8 miRNAs down-regulated). Three miRNAs of miR-141 (upregulated), miR-205 (down-regulated), and miR-125b (down-regulated) were revealed as the originator for genetic interactions leading to carcinogenesis. We could show some common loops and pathways including uncontrolled cell proliferation and abnormal apoptosis (mediated by PTEN gene induced by miR-21 and miR-214), and disaggregation and epithelialization (mediated by ZEB1 and ZEB2 genes induced by miR-200). Conclusion: According to our analysis, up-regulation of miR-141 and down-regulation of miR-205 and miR-125b have a central role in transforming endometriosis to ovarian cancer.

Introduction: Alcoholic Cardiomyopathy (ACM) is a disease with a difficult diagnosis. The real mechanisms related to its pathophysiology are not fully understood. Objective: The aims of this study were to investigate whether miR-133b and miR-138 could be associated with ACM. Methods: Forty-four patients were included comprising 24 with ACM and 20 with cardiomyopathies of different etiologies (control group). Real-time PCR was performed to verify the relative expression among the studied groups. In the statistical analysis, the quantitative variables t-student Mann- Whitney and correlation of Pearson tests were carried out, while the qualitative variable comprised the chi-square test, with p<0.05 being considered statistically significant. Results: There was no association between clinical and sociodemographic characteristics of the groups. The patients with ACM presented downregulation of miR-133b in comparison with control patients (p=0.004). On the other hand, for the miR-138, there was no association when the ACM group was compared with the control group. The presence of miR-133b among cases and controls was not correlated with any of the echocardiographic parameters. However, the increase in the expression of miR-138 was correlated with an increase in the ejection fraction (r=0.28, p=0.01) and the diameter of the left atrium (r=0.23, p=0.04) in patients with ACM. Conclusion: The downregulation of miR-133b might be a marker for ACM and, in addition, miR- 138 could be used to correlate the increase in ejection fraction with and normalization of the diameter of the left atrium diameter in patients with this disease.

Background and Aim: Hepatic phase I drug-metabolizing enzymes CYP2E1, CYP1A2 and CYP3A4 catalyze the biotransformation of Acetaminophen (APAP) and are important in the mediation of toxicity. The potential role of other hepatic and non-hepatic Phase I enzymes in APAP toxicity has not been established. Methods: PCR array containing 84 genes involved in phase I drug metabolism was examined in subgroups of hospitalized children for APAP overdose, categorized as no toxicity (ALT ≤ 45 IU/L, n=5) and moderate toxicity (ALT ≥ 500 IU/L, n=5). Results: Significant downregulation was observed for ALDH6A1, CYP4F12 and GZMB in the no toxicity subgroup and ALDH1A1, CYP27A1 and GZMB in the moderate toxicity subgroup. qRTPCR confirmed significant downregulation for ALDH1A1, CYP4F12, and GZMB. In-silico analysis identified GZMB 3’UTR to be a target of miR-378a-5p. Overexpression of miR-378a-5p reduced the luciferase activity of GZMB 3’UTR reporter plasmid reportedly by 50%. NK-92 cells transfected with the miR-378a-5p mimic extended the effect of APAP on GZMB protein expression compared to mimic controls. In addition, miR-378a-5p was significantly upregulated in blood samples of children with APAP overdose undergoing NAC treatment. Conclusion: Overall, our study suggests the presence of a novel signaling pathway, whereby miR- 378a-5p inhibits GZMB expression in children with APAP overdose.

Background: MicroRNAs (miRNAs) are noncoding RNA molecules, which directly regulate gene expression. It has been documented that single nucleotide polymorphisms in miRNA genes could alter the regulation of miRNA expression and function. Objective: In this study, the allele and genotype frequency of miR-605 rs2043556 and its association with breast cancer were investigated in the Iranian population. Methods: Genotyping was performed in 162 females affected with breast cancer and 180 healthy individuals. Genotyping was performed using Restriction Fragment Length Polymorphism (RFLP) followed by Sanger sequencing. Results: The data showed the presence of Hardy Weinberg equilibrium (HWE) for this marker in the Iranian population. Allelic frequency for A and G allele was 0.75 and 0.25, respectively. Odd ratios for the association between miR-605 rs2043556 AG/GG genotypes was 3.86 with p-value= 0. Conclusion: The results indicated an increased risk for breast cancer susceptibility for miR-605 rs2043556 in the Iranian population.

Background: Accumulating evidence points to the functional roles of rRNA derived Fragments (rRFs), often considered degradation byproducts. Small RNAs, including miRNAs and tRNA-derived Fragments (tRFs), have been implicated in the aging process and we considered rRFs in this context. Objective: We performed a computational analysis of Argonaute-loaded rRFs in Drosophila melanogaster to study rRF changes with age. We determined rRF abundance in Ago1 and Ago2 at 3 and 30 days to identify Ago1-guided and Ago2-guided fragments. We searched for putative seed sequences in rRFs based on frequent matches of sliding k-mer windows to the conserved regions of 12 Drosophila genomes. We predicted putative targets (containing matches to seeds identified in four rRFs) and studied their functional enrichments using Gene Ontology. Results: We identified precise cleavage sites of distinct rRF isoforms from both nuclear and mitochondrial rRNAs. The most prominent rRF isoforms were enriched in Ago2 at 3 days and that loading strongly decreased with age. For less abundant rRFs, loading of Ago2-guided rRFs generally increased in Ago2, whereas Ago1-guided rRFs revealed diverse patterns. The distribution of seed matches in targets suggested that rRFs may bind to various conserved regions of many genes, possibly via miRNA-like seed-based mechanisms. Conclusion: Our observations suggest that rRFs may be functional molecules, with age-dependent Argonaute loading, comparable to that of miRNAs and tRFs. The putative rRF targets showed significant enrichment in developmental processes and biological regulation, similar to tRFs and consistent with a possible involvement of these newly identified small RNAs in the Drosophila aging.

Background: Rectal Cancer (RC) is a common type of cancer with poor prognosis. The identification of biomarkers regarding RC diagnosis, monitoring, and prognosis is crucial. Objectives: The purpose of the present study was to evaluate the differential expression of the Aquaporin (AQP) gene family network in RC, and the effect of Radiotherapy (RT) on their expression profile, to indicate novel biomarkers and prognostic factors. Methods: We used data mining techniques to construct the network of the AQP-associated genes to determine the Differentially Expressed Genes (DEGs) in RC and in irradiated as compared to nonirradiated RC patients. Furthermore, survival data of The Cancer Genome Atlas (TCGA) were analysed to assess the prognostic role of the DEGs, along with the functional enrichment of gene ontologies and miRNAs related to the DEGs in RC. Results: Microarray data of one PubMed GEO dataset was extracted, incorporating 22 RC and 20 normal rectal tissue samples. Eight DEGs were reported. Four DEGs were up-regulated and four downregulated in RC. Correlations were identified among the DEGs. Deming regression analysis was performed in order to demonstrate the equations describing these correlations. One gene (Aquaporin 3) was downregulated in irradiated RC samples compared with non-irradiated samples. The most significantly affected biological pathways and miRNAs were identified by functional enrichment analysis. Conclusion: The present study demonstrates an eight-gene molecular panel that could facilitate as biomarkers regarding RC patients, which are potential targets of five miRNA families. Finally, our results highlight the effect of radiotherapy on AQPs and the associated pathways in RC.