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- Volume 9, Issue 5, 2020
MicroRNA - Volume 9, Issue 5, 2020
Volume 9, Issue 5, 2020
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MicroRNA-Mutant P53 Crosstalk in Chemoresistance: A Hint to Monitor Therapy Outcome
Authors: Andrea Speciale, Paola Monti, Gilberto Fronza, Alberto Izzotti and Paola MenichiniThe chemoresistance of cancer cells is a multifactorial mechanism in which de-regulated apoptotic pathways, the oxidative response and cancer cell migration play a crucial role. A key player in the control of such pathways is the tumor suppressor gene TP53, also defined as the “guardian of the genome”, encoding the P53 tetrameric transcription factor. P53, following cell injuries, can activate the transcription of several target genes crucial for the induction of apoptosis, cell cycle arrest, modulation of senescence, DNA repair, autophagy and metabolism. Importantly, TP53 gene is mutated in nearly 50% of human cancers, implying an altered expression of target genes in cancer cells. The presence of TP53 mutations can also affect the expression of several small noncoding RNAs (microRNAs or miRNAs) involved in the same regulation of the apoptotic signaling, cell cycle regulation and cell migration. In mutant P53 expressing tumors, some miRNAs resulted in being down-regulated, while others appeared to be up-regulated as demonstrated by in vitro and in vivo studies. Thus, the expression level of specific P53 responsive miRNAs could be used as a marker of cancer progression and therapy performance. In the present review, we will summarize the role of P53-related miRNAs and their clinical relevance in monitoring therapy outcome and progression of cancers with mutant P53.
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Noncoding RNAs and Colorectal Cancer: A General Overview
Colorectal cancer (CRC) is the second most prevalent cancer in the world in which nonmelanoma skin cases are not considered. Different epigenetic mechanisms play a role in the development of cancer. Noncoding RNAs (ncRNAs) are RNA molecules transcribed from noncoding regions of the genome. These are divided into sncRNAs (small noncoding RNAs: <200 nucleotides - including miRNAs [microRNAs], siRNAs [small interfering RNAs], piRNAs [piwi-interacting RNAs], snoRNAs [small nucleolar RNAs]) and lncRNAs (long noncoding RNAs: >200 nucleotides - includingcircular RNAs [circRNAs]). NcRNAs can act as oncogenes or as tumor suppressor genes in CRC and are potential biomarkers of diagnosis, with possible clinical implications. This article aims to conduct a general review of all types of non-coding RNAs and their influence in colorectal cancer, focus on biomarkers of CRC and their possible applications in clinical practice, as well as review their biogenesis and functions. Furthermore, we seek to summarize possible databases available for new searches and studies that require sequence annotation, comparison sequences and target prediction for ncRNAs with the hope of gathering information that can aid in the process of understanding and translating the use of ncRNAs into clinical practice.
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miRNA-506-3p Directly Regulates rs10754339 (A/G) in the Immune Checkpoint Protein B7-H4 in Breast Cancer
Authors: Germine S. El Din, Rana Ahmed Youness, Reem Amr Assal and Mohamed Zakaria GadBackground: B7-H4 is a novel immune checkpoint protein that negatively regulates T cell activation and function. It is overexpressed in many malignant tumors, including Breast Cancer (BC). It was reported that the presence of the single nucleotide polymorphism rs10754339 (A/G) within the 3' UTR of the B7-H4 gene has a great influence on the risk and progression of BC as well as lymph node metastasis. On the other hand, mounting evidence demonstrated the potential of miR-506-3p to be employed in the diagnosis and treatment of a wide range of human malignancies. It is frequently down-regulated in BC despite its tumor suppressor role. Moreover, Myc, E2F and Rb proteins are key players in cell cycle regulation. In BC, the CDK-RB-E2F axis is extensively deregulated by several genetic mutations. Additionally, the potent proto-oncogene Myc is highly expressed in BC. Aim: The main aims of the study were to investigate the potential role of miR-506-3p in the regulation of B7-H4 SNP rs10754339 (A/G) in BC and to uncover the influence of miR-506-3p on cell cycle and tumor progression in BC cell lines. Methods: This study employed different BC cell lines, including MDA-MB-231 and MCF7 cells. Several bioinformatics analysis was performed to identify the miRNA that could potentially target B7-H4 SNP rs10754339 (A/G). To confirm the binding Relative luciferase activity was measured using Dual Luciferase Reporter Assay. Transfection experiments were performed using miR-506-3p oligonucleotides using lipofection technique. Furthermore, vital cell cycle regulatory proteins such as cMyc, Rb, and E2F were transfected into BC cells using superfect. Finally, several functional analysis experiments were performed, such as MTT and wound healing assays. Results: miR-506-3p down-regulates the disease-associated rs10754339 “G” allele in B7-H4 gene. It also inhibits cell cycle progression by simultaneously regulating important cell cycle proteins, including RB, E2F and c-Myc. Moreover, miR-506-3p decreased cellular viability and migration capacity of MDA-MB-231 TNBC cells and hormone receptor positive MCF-7 cells. Conclusion: miR-506-3p is a potential tumor suppressor miRNA in BC that has a potential role in regulating B7-H4 SNP rs10754339 (A/G).
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Over-Expression of MicroRNA-122 Inhibits Proliferation and Induces Apoptosis in Colon Cancer Cells
Authors: Sarubala Malayaperumal, Sushmitha Sriramulu, Antara Banerjee and Surajit PathakBackground: MicroRNA, a non-coding RNA molecule plays a vital role in post transcriptional gene expression. MicroRNA-122, a liver specific microRNA was found to be downregulated in liver cancer and is associated with hepatocarcinogenesis. Being confirmed as tumor suppressor microRNA in liver carcinogenesis, we aimed to study the expression of microRNA-122 in colon cancer cell lines and the role of microRNA-122 in cell proliferation, invasion and migration of colon cancer cells. Methods: The expression of microRNA-122 is quantified using qRT-PCR by TaqMan universal primers. Colon cancer cell lines (SW480, SW620, HCT116) were transfected with microRNA-122 mimic and further studied for determining cell proliferation using CCK-8 kit, migration using Scratch assay, invasion using Transwell assay, apoptosis using Annexin-V FITC kit, and also gene expression. Results: Gene expression results displayed decreased expression of microRNA-122 in colon cancer cell lines. Transfection with microRNA-122 mimics impaired the cell proliferation and migration compared with control. FACS analysis confirmed that the percentage of microRNA-122 mimic transfected cells undergoing early apoptosis was increased. Gene expression of AEG-1, PI3K, CDK6, and PCNA were found to be downregulated in microRNA-122 overexpressed cells. Migratory and invasion potential of transfected cells was lessened in mimic transfected cells compared to control. Conclusion: The overexpression of microRNA-122 inhibited the cellular proliferation, migration, invasion and increased percentage of cells undergoing early apoptosis, suggesting its anti-cancer potential. Studying the role of microRNA-122 and its interactions with oncogenes might pave the way to understand the underlying mechanism in colon cancer.
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Molecular Evaluation of MicroRNA-146 Gene Variability (rs2910164 C> G) and its Association with Increased Susceptibility to Coronary Artery Disease
Aim: Apart from the modifiable risk factors, genetic factors are believed to influence the outcome of Coronary Artery Diseases (CAD). Under the genetic factors, miRNA polymorphisms, namely Hsa-miR-146a-5p (rs2910164) have become an important tool to study the mechanism that underlies the pathogenesis of this disease. Therefore, we investigated the association of miR-146a gene variations with susceptibility of coronary artery diseases. Methodology: This study was conducted on 100 CAD patients and 117 matched healthy individuals. Genotyping of the Hsa-miR-146a-5p C>G gene variation was performed by using Amplification Refractory Mutation System PCR method (ARMS-PCR). Results: The distribution of Hsa-miR-146a-5p rs2910164 C>G genotypes observed between patients and controls was significantly different (P=0.048). Moreover, the frequency of G allele (fG) was found to be significantly higher among patients than in controls (0.36 vs. 0.25). Our findings showed that the Hsa-miR-146a-5p C>G variant was associated with an increased risk of CAD in codominant inheritance model CC vs. CG genotype (OR = 1.84, 95% CI, 1.02-3.31; p=0.040) and (OR = 3.18, 95% CI, 1.02-9.9; p=0.045) for CC vs. GG genotype in dominant inheritance model. Whereas the G allele significantly increased the risk of coronary artery disease (OR =1,81, 95% CI, 1.18-2.78; p=0.006) compared to C allele. Taken together, these results demonstrated that miR-146a/rs2910164 is associated with susceptibility to coronary artery disease, providing novel insights into the genetic etiology and underlying biology of coronary artery disease. Conclusion: Our findings indicated that Hsa-miR-146a-5p rs2910164 GG genotype and G allele are associated with increased susceptibility to Coronary Artery Disease. A larger sample size can be the key to progress in establishing the genetic co-relation of miRNA gene polymorphisms and cardiovascular diseases.
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The Potential Role of miRNA-19b-3p and miRNA-320c in Patients with Moderate Bronchial Asthma
Authors: Akmaral Aripova, Almira Akparova and Rakhmetkazhy BersimbaevBackground: Bronchial Asthma (BA) is a complex heterogeneous disease with a number of molecular immunopathological mechanisms underlying airway inflammation, hyperreactivity, and bronchial remodeling. MicroRNAs are important regulators in the pathogenesis and progression of chronic respiratory diseases, including BA. Objective: The aim of the study is to investigate the level of expression of cell-free circulating miR-19b-3p and miR-320c in the blood plasma by comparing their plasma levels with IL-4 in the moderate BA patients and control group. Methods: The level of expression miR-19b-3p and miR-320c were evaluated by qRT-PCR using the comparative threshold cycle (Ct) method. U6 small nuclear RNA was taken as an endogenous control. The content of IL - 4 in blood plasma was determined by using ELISA. Results: miR-19b-3p and miR-320c were significantly dysregulated in moderate asthmatic patients in comparison with control group. The area under the ROC curve of miR-19b-3p and miR-320c showed 0.8088 (95% CI 0.6925 to 0.9251, P value =0.0001) and 0,9048 (95% CI 0,7792 to 1,000, P value <0,0001), respectively. BA patients showed a considerably positive correlation between the expression level of microRNA-320c and IL-4 levels. Conclusion: These cell-free circulating microRNAs are probably deregulated in other inflammatory/ pathological diseases, so they could be useful to understand the molecular pathogenesis of BA or to investigate the “inflammatory reaction” in this disease.
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Fragmentation and Matching of Human MicroRNA Sequences in 3’utr
More LessAims: Definition of sense and antisense microRNA matches in 3’utr. Background: Matches of mature microRNAs (m-miRs) in human 3’utr could be traced to mutations producing fragments of original m-miR sequences without physical separation. (The m-miR matches in 5’utr and cds should be by far fewer, but could follow similar patterns). Objective: To ascertain if the sense and antisense m-miR fragments in 3’utr occur at similar or different levels. Methods: Frequency of sense and antisense m-miR matches in 3'utr was examined in the range of 7-22 nucleotides. Results: The fragmentation occurs at gene level by mutation within one of the paired m-miRs, which upon transcription results in increased interactive capability for both former pre-micro (premir) RNA stem partners. The non-mutated stem partner can persist in 3’utr sequences, as is apparent from significant presence of miR-619-5p and miR-5096 and some conservation of 20 other simian- specific m-miR sequences. However, most of m-mir sequences in 3’utr are extensively fragmented, with low preservation of long matches. In flanks of individual m-miR embeds the mutated pre-mir positions are to a degree defined specifically. Conclusion: The m-mir matches of various sizes in 3’utr apparently reflect accumulation, on a phylogenetic time scale, of in-sequence point mutations. Across human 3’utr this fragmentation is significantly less for evolutionarily recent human m-miRs that originate in simians compared to human m-miRs first appearing in lower primates, and especially to human m-miRs introduced in nonprimates.
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