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      Exploring VEGF-Linked Pathways: Investigating Multiple miRNAs for Their Therapeutic Potential in Angiogenesis Targets and as Biomarkers in Recurrent Glioblastoma Multiforme

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          Abstract

          Alternative pathways frequently operate as the origins of resistance to drugs that block the vascular endothelial growth factor (VEGF) pathway. To find possible therapeutic targets and indicators, this study explored the VEGF pathway and how miRNAs control it in recurrent glioblastoma multiforme (rGBM). Differentially expressed miRNAs (DEmiRNAs) were identified by using GBM GSE profiles (GSE32466). To find pathways containing DEmiRNAs, VEGF pathway genes, and their related genes, DIANA-miRPath v3.0 and the ToppGene database were utilized. miRNAs linked to VEGF signaling pathway genes, interactional genes, and DEmiRNAs were discovered by extracting common pathways. The ability of these miRNAs to distinguish rGBM patients from those with primary GBM was assessed using ROC analysis. The study revealed that in rGBM, 30 miRNAs were significantly up-regulated and 49 miRNAs were considerably down-regulated. Among them, the VEGF pathway was connected to 22 up-regulated miRNAs and 29 down-regulated miRNAs. The MAPK pathway shared the most genes with the VEGF pathway, accounting for 1,014 of the interacting genes, which were discovered to have interactions with VEGF signaling pathway genes. Furthermore, 14 miRNAs were identified as having a great deal of potential as molecular biomarkers and therapeutic targets for rGBM. The results indicate that the VEGF pathway in rGBM is regulated by a number of interrelated pathways. The discovered miRNAs hold promise as rGBM biomarkers and therapeutic targets, offering possibilities for novel therapy strategies and aiding rGBM diagnosis and prognosis.

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          Most cited references27

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          limma powers differential expression analyses for RNA-sequencing and microarray studies

          limma is an R/Bioconductor software package that provides an integrated solution for analysing data from gene expression experiments. It contains rich features for handling complex experimental designs and for information borrowing to overcome the problem of small sample sizes. Over the past decade, limma has been a popular choice for gene discovery through differential expression analyses of microarray and high-throughput PCR data. The package contains particularly strong facilities for reading, normalizing and exploring such data. Recently, the capabilities of limma have been significantly expanded in two important directions. First, the package can now perform both differential expression and differential splicing analyses of RNA sequencing (RNA-seq) data. All the downstream analysis tools previously restricted to microarray data are now available for RNA-seq as well. These capabilities allow users to analyse both RNA-seq and microarray data with very similar pipelines. Second, the package is now able to go past the traditional gene-wise expression analyses in a variety of ways, analysing expression profiles in terms of co-regulated sets of genes or in terms of higher-order expression signatures. This provides enhanced possibilities for biological interpretation of gene expression differences. This article reviews the philosophy and design of the limma package, summarizing both new and historical features, with an emphasis on recent enhancements and features that have not been previously described.
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            Tumor Development and Angiogenesis in Adult Brain Tumor: Glioblastoma

            Angiogenesis is the growth of new capillaries from the preexisting blood vessels. Glioblastoma (GBM) tumors are highly vascularized tumors, and glioma growth depends on the formation of new blood vessels. Angiogenesis is a complex process involving proliferation, migration, and differentiation of vascular endothelial cells (ECs) under the stimulation of specific signals. It is controlled by the balance between its promoting and inhibiting factors. Various angiogenic factors and genes have been identified that stimulate glioma angiogenesis. Therefore, attention has been directed to anti-angiogenesis therapy in which glioma proliferation is inhibited by inhibiting the formation of new tumor vessels using angiogenesis inhibitory factors and drugs. Here, in this review, we highlight and summarize the various molecular mediators that regulate GBM angiogenesis with focus on recent clinical research on the potential of exploiting angiogenic pathways as a strategy in the treatment of GBM patients.
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              MicroRNA in Glioblastoma: An Overview

              Glioblastoma is the most aggressive brain tumor and, even with the current multimodal therapy, is an invariably lethal cancer with a life expectancy that depends on the tumor subtype but, even in the most favorable cases, rarely exceeds 2 years. Epigenetic factors play an important role in gliomagenesis, are strong predictors of outcome, and are important determinants for the resistance to radio- and chemotherapy. The latest addition to the epigenetic machinery is the noncoding RNA (ncRNA), that is, RNA molecules that are not translated into a protein and that exert their function by base pairing with other nucleic acids in a reversible and nonmutational mode. MicroRNAs (miRNA) are a class of ncRNA of about 22 bp that regulate gene expression by binding to complementary sequences in the mRNA and silence its translation into proteins. MicroRNAs reversibly regulate transcription through nonmutational mechanisms; accordingly, they can be considered as epigenetic effectors. In this review, we will discuss the role of miRNA in glioma focusing on their role in drug resistance and on their potential applications in the therapy of this tumor.
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                Author and article information

                Journal
                Int J Mol Cell Med
                Int J Mol Cell Med
                IJMCM
                International Journal of Molecular and Cellular Medicine
                Babol University of Medical Sciences (Babol, Iran )
                2251-9637
                2251-9645
                2022
                : 11
                : 4
                : 306-319
                Affiliations
                [1 ] Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
                [2 ] Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
                [3 ] Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, FL, USA.
                [4 ] Department of Applied Matemathics, Faculty of Mathematical Sciences, Shahrood University of Technology, Semnan, Iran.
                Author notes
                [* ]Corresponding Author: Sorayya Ghasemi Address: Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran. E-mail: sorayya.ghasemi@gmail.com
                Article
                10.22088/IJMCM.BUMS.11.4.306
                10506677
                37727644
                32267095-fa6b-4ef5-b7cf-c613d6b6110d
                © The Author(s).

                This work is published as an open access article distributed under the terms of the Creative Commons Attribution 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/). Non-commercial uses of the work are permitted, provided the original work is properly cited.

                History
                : 24 May 2023
                : 22 July 2023
                : 30 July 2023
                Categories
                Original Article

                vegf,recurrent gbm,angiogenesis,signaling pathways,gse32466,biomarker

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