Dataset Information

MicroRNAs Are Key Molecules Involved in the Gene Regulation Network of Colorectal Cancer.

ABSTRACT: Colorectal cancer (CRC) is one of the most common types of cancer and one of the leading causes of mortality worldwide. MicroRNAs (miRNAs) play central roles in normal cell maintenance, development, and other physiological processes. Growing evidence has illustrated that dysregulated miRNAs can participate in the initiation, progression, metastasis, and therapeutic resistance that confer miRNAs to serve as clinical biomarkers and therapeutic targets for CRC. Through binding to the 3'-untranslated region (3'-UTR) of target genes, miRNAs can lead to target mRNA degradation or inhibition at a post-transcriptional level. During the last decade, studies have found numerous miRNAs and their potential targets, but the complex network of miRNA/Targets in CRC remains unclear. In this review, we sought to summarize the complicated roles of the miRNA-target regulation network (Wnt, TGF-β, PI3K-AKT, MAPK, and EMT related pathways) in CRC with up-to-date, high-quality published data. In particular, we aimed to discuss the downstream miRNAs of specific pathways. We hope these data can be a potent supplement for the canonical miRNA-target regulation network.

SUBMITTER: Yang F

PROVIDER: S-EPMC9023807 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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MicroRNAs Are Key Molecules Involved in the Gene Regulation Network of Colorectal Cancer.

Yang Fangfang F Xuan Guoyun G Chen Yixin Y Cao Lichao L Zhao Min M Wang Chen C Chen Erfei E

Frontiers in cell and developmental biology 20220408

Colorectal cancer (CRC) is one of the most common types of cancer and one of the leading causes of mortality worldwide. MicroRNAs (miRNAs) play central roles in normal cell maintenance, development, and other physiological processes. Growing evidence has illustrated that dysregulated miRNAs can participate in the initiation, progression, metastasis, and therapeutic resistance that confer miRNAs to serve as clinical biomarkers and therapeutic targets for CRC. Through binding to the 3'-untranslate ...[more]

PMID: 35465317

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Project description:ObjectivesCancer cells differ from normal body cells in their ability to divide indefinitely and to evade programmed cell death. Crosstalk between apoptosis and cell cycle processes promotes balance between proliferation and death, and limits population growth and survival of cells. However, intricate relationships between them and how they are able to manipulate the fate of cancer cells still remain to be clarified. Identification of key factors involved in both apoptosis and cell cycle regulation may help to address this problem.Materials and methodsIdentification of such key proteins was carried out, using a series of bioinformatics methods, such as network construction and key protein identification.ResultsIn this study, we computationally constructed human apoptotic/cell cycle-related protein-protein interactions (PPIs) networks from five experimentally supported protein interaction databases, and further integrated these high-throughput data sets into a Naïve Bayesian model to predict protein functional connections. On the basis of modified apoptotic/cell cycle related PPI networks, we calculated and ranked all protein members involved in apoptosis and cell cycle regulation. Our results not only identified some already known key proteins such as p53, Rb, Myc and Src but also found that the proteasome, Cullin family members, kinases and transcriptional repressors play important roles in regulating apoptosis and the cell cycle. Furthermore, we found that the top 100 proteins ranked by PeC were enriched in some pathways such as those of cancer, the proteasome, the cell cycle and Wnt signalling.ConclusionsWe constructed the global human apoptotic/cell cycle related PPI network based on five online databases, and a Naïve Bayesian model. In addition, we systematically identified apoptotic/cell cycle related key proteins in cancer cells. These findings may uncover intricate relationships between apoptosis and cell cycle processes and thus provide further new clues towards future anticancer drug discovery.

Project description:A number of studies have revealed that there is an increasing incidence of early-onset colorectal cancer (CRC) in young adults (before the age of 50 years) and a progressive decline in CRC among older patients, after the age of 50 years (late-onset CRC). However, the etiology of early-onset CRC is not fully understood. The aim of the present study was to identify key genes associated with the development of early-onset CRC through weighted gene co-expression network analysis (WGCNA). The GSE39582 dataset was downloaded from the Gene Expression Omnibus database, and the data profiles of tissues from patients diagnosed before the age of 50 years were selected. The top 10,000 genes with the highest variability were used to construct the WGCNA. Hub genes were identified from the modules associated with clinical traits using gene significance >0.2 and module membership >0.8 as the cut-off criteria. Gene Ontology and pathway analyses were subsequently performed on the hub genes and a protein-protein interaction network (PPI) was constructed. The diagnostic value of module hub genes with a degree score >5 in the PPI network was verified in samples from patients with CRC diagnosed before the age of 50 years obtained from The Cancer Genome Atlas. Eight co-expressed gene modules were identified in the WGCNA and two modules (blue and turquoise) were associated with the tumor-node-metastasis stage. A total of 140 module hub genes were identified and found to be enriched in 'mitochondrial large ribosomal subunit', 'structural constituent of ribosome', 'poly (A) RNA binding', 'collagen binding', 'protein ubiquitination' and 'ribosome pathway'. Twenty-six module hub genes were found to have a degree score >5 in the PPI network, seven of which [secreted protein acidic and cysteine rich (SPARC), decorin (DCN), fibrillin 1 (FBN1), WW domain containing transcription regulator 1 (WWTR1), transgelin (TAGLN), DEAD-box helicase 28 (DDX28) and cold shock domain containing C2 (CSDC2)], had good prognostic values for patients with early-onset CRC, but not late-onset CRC. Therefore, SPARC, DCN, FBN1, WWTR1, TAGLN, DDX28 and CSDC2 may contribute to the development of early-onset CRC and may serve as potential diagnostic biomarkers.

Project description:BackgroundMicroRNAs (miRNAs) are small non-coding RNA molecules that repress the translation of messenger RNAs (mRNAs) or degrade mRNAs. These functions of miRNAs allow them to control key cellular processes such as development, differentiation and apoptosis, and they have also been implicated in several cancers such as leukaemia, lung, pancreatic and ovarian cancer (OC). Unfortunately, the specific machinery of miRNA regulation, involving transcription factors (TFs) and transcription co-factors (TcoFs), is not well understood. In the present study we focus on computationally deciphering the underlying network of miRNAs, their targets, and their control mechanisms that have an influence on OC development.ResultsWe analysed experimentally verified data from multiple sources that describe miRNA influence on diseases, miRNA targeting of mRNAs, and on protein-protein interactions, and combined this data with ab initio transcription factor binding site predictions within miRNA promoter regions. From these analyses, we derived a network that describes the influence of miRNAs and their regulation in human OC. We developed a methodology to analyse the network in order to find the nodes that have the largest potential of influencing the network's behaviour (network hubs). We further show the potentially most influential miRNAs, TFs and TcoFs, showing subnetworks illustrating the involved mechanisms as well as regulatory miRNA network motifs in OC. We find an enrichment of miRNA targeted OC genes in the highly relevant pathways cell cycle regulation and apoptosis.ConclusionsWe combined several sources of interaction and association data to analyse and place miRNAs within regulatory pathways that influence human OC. These results represent the first comprehensive miRNA regulatory network analysis for human OC. This suggests that miRNAs and their regulation may play a major role in OC and that further directed research in this area is of utmost importance to enhance our understanding of the molecular mechanisms underlying human cancer development and OC in particular.

Dataset Information

MicroRNAs Are Key Molecules Involved in the Gene Regulation Network of Colorectal Cancer.

Publications

MicroRNAs Are Key Molecules Involved in the Gene Regulation Network of Colorectal Cancer.

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