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Multiple m6A RNA methylation modulators promote the malignant progression of hepatocellular carcinoma and affect its clinical prognosis.

ABSTRACT: BACKGROUND:Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death in the world. N6-methyladenosine (m6A) RNA methylation is dynamically regulated by m6A RNA methylation modulators ("writer," "eraser," and "reader" proteins), which are associated with cancer occurrence and development. The purpose of this study was to explore the relationships between m6A RNA methylation modulators and HCC. METHODS:First, using data from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases, we compared the expression levels of 13 major m6A RNA methylation modulators between HCC and normal tissues. Second, we applied consensus clustering to the expression data on the m6A RNA methylation modulators to divide the HCC tissues into two subgroups (clusters 1 and 2), and we compared the clusters in terms of overall survival (OS), World Health Organization (WHO) stage, and pathological grade. Third, using least absolute shrinkage and selection operator (LASSO) regression, we constructed a risk signature involving the m6A RNA methylation modulators that affected OS in TCGA and ICGC analyses. RESULTS:We found that the expression levels of 12 major m6A RNA methylation modulators were significantly different between HCC and normal tissues. After dividing the HCC tissues into clusters 1 and 2, we found that cluster 2 had poorer OS, higher WHO stage, and higher pathological grade. Four m6A RNA methylation modulators (YTHDF1, YTHDF2, METTL3, and KIAA1429) affecting OS in the TCGA and ICGC analyses were selected to construct a risk signature, which was significantly associated with WHO stage and was also an independent prognostic marker of OS. CONCLUSIONS:In summary, m6A RNA methylation modulators are key participants in the malignant progression of HCC and have potential value in prognostication and treatment decisions.

SUBMITTER: Qu N

PROVIDER: S-EPMC7047390 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Multiple m<sup>6</sup>A RNA methylation modulators promote the malignant progression of hepatocellular carcinoma and affect its clinical prognosis.

Qu Nanfang N Qin Sanyu S Zhang Xuemei X Bo Xiaotong X Liu Zhengchun Z Tan Chao C Wen Guiqiong G Jiang Haixing H

BMC cancer 20200228 1

<h4>Background</h4>Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death in the world. N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) RNA methylation is dynamically regulated by m<sup>6</sup>A RNA methylation modulators ("writer," "eraser," and "reader" proteins), which are associated with cancer occurrence and development. The purpose of this study was to explore the relationships between m<sup>6</sup>A RNA methylation modulators and HCC.<h4>Methods</h4>First, u ...[more]

PMID: 32111180

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Project description:RNA methylation accounts for over 60% of all RNA modifications, and N6-methyladenosine (m6A) is the most common modification on mRNA and lncRNA of human beings. It has been found that m6A modification occurs in microRNA, circRNA, rRNA, and tRNA, etc. The m6A modification plays an important role in regulating gene expression, and the abnormality of its regulatory mechanism refers to many human diseases, including cancers. Pitifully, as it stands there is a serious lack of knowledge of the extent to which the expression and function of m6A RNA methylation can influence prostate cancer (PC). Herein, we systematically analyzed the expression levels of 35 m6A RNA methylation regulators mentioned in literatures among prostate adenocarcinoma patients in the Cancer Genome Atlas (TCGA), finding that most of them expressed differently between cancer tissues and normal tissues with the significance of p < 0.05. Utilizing consensus clustering, we divided PC patients into two subgroups based on the differentially expressed m6A RNA methylation regulators with significantly different clinical outcomes. To appraise the discrepancy in total transcriptome between subgroups, the functional enrichment analysis was conducted for differential signaling pathways and cellular processes. Next, we selected five critical genes by the criteria that the regulators had a significant impact on prognosis of PC patients from TCGA through the last absolute shrinkage and selection operator (LASSO) Cox regression and obtained a risk score by weighted summation for prognosis prediction. The survival analysis curve and receiver operating characteristic (ROC) curve showed that this signature could excellently predict the prognosis of PC patients. The univariate and multivariate Cox regression analyses proved the independent prognostic value of the signature. In summary, our effort revealed the significance of m6A RNA methylation regulators in prostate cancer and determined a m6A gene expression classifier that well predicted the prognosis of prostate cancer.

Project description:We have used genome-wide methylation microarrays to analyze differences in CpG methylation patterns in cells relevant to the pathogenesis of myeloma plasma cells, including B cells, normal plasma cells, MGUS, presentation myeloma, and plasma cell leukemia (PCL). We show that methylation patterns in these cell types are capable of distinguishing non-malignant from malignant cells and that the main reason for this difference is hypomethylation of the genome at the transition from MGUS to presentation myeloma. In addition, gene-specific hypermethylation was evident at the myeloma stage. Differential methylation was also evident at the transition from myeloma to PCL with re-methylation of the genome, specifically of genes involved in cell-cell signaling and cell adhesion, which may contribute to independence from the bone marrow microenvironment. There was a high degree of methylation variability within presentation myeloma samples and this was associated with the cytogenetic differences between samples. More specifically, we found that methylation subgroups were defined by translocations and hyperdiploidy, with t(4;14) myeloma having the largest impact on DNA methylation. Two groups of hyperdiploid samples were identified, based on unsupervised clustering, which had an impact on overall survival. Overall, DNA methylation has a large impact on disease progression and on myeloma cytogenetic subgroups. Bone marrow aspirates were obtained after informed consent. B cells (n=6) from normal individuals were selected from peripheral blood using CD19. Plasma cells (PC) from non-myeloma patients (normal plasma cell controls, n=3) as well as MGUS (n=4) and presentation myeloma patients (n=161) were selected to a purity of >90% using CD138 microbeads and magnet-assisted cell sorting (Miltenyi Biotech, Bisley, UK). Samples from PCL patients (n=7) were not CD138 selected but contained >90% plasma cell infiltration as determined by microscopy. In order to achieve a sufficient quantity of DNA some normal plasma cell control samples were pooled.

Project description:Objectives: This study aims to explore the roles of 13 m6A RNA methylation regulators in clear cell renal cell carcinoma (ccRCC), and identify a risk signature and prognostic values of m6A RNA methylation regulators in ccRCC. Materials and Methods: RNA sequence data of ccRCC was obtained from The Cancer Genome Atlas (TCGA) database. Differentially expressed of 13 m6A RNA methylation regulators in ccRCC stratified by different clinicopathological characteristics were unveiled using "limma" package in R version 3.6.0. Cox regression and LASSO analyses were conducted to identify the powerful independent prognostic factors in ccRCC associated with overall survival (OS). Protein-protein interaction (PPI) network and correlation analyses of the 13 m6A RNA methylation regulators were performed using "STRING" and R package, respectively. Principal component analysis (PCA) was also done using R. In addition, gene ontology (GO), GSEA and Kyoto Encyclopedia of Genes and Genomes pathways were used to functionally annotate the differentially expressed genes in different subgroups. Results: Most of the 13 m6A RNA methylation regulators are differentially expressed in ccRCC tissue samples stratified by different clinicopathological characteristics in 537 patients. Next, a risk signature for predicting prognosis of ccRCC patients, was established based on two powerful independent prognostic m6A RNA methylation regulators (METTL14 and METTL3). Then, two subgroups (cluster1 and 2) were identified by consensus clustering to the two powerful independent factors and the cluster1 had a poorer prognosis than cluster2. Furthermore, the genes in cluster1 were significantly enriched in cancer-related pathways, biological process, and hallmarks, including "cell adhesion molecules (CAMs)," "leukocyte migration," "Wnt/β-catenin signaling," and so on. Conclusion: M6A RNA methylation regulators play important roles in the initiation and progression of ccRCC and provide a novel sight to understand m6A RNA modification in ccRCC.

Dataset Information

Multiple m6A RNA methylation modulators promote the malignant progression of hepatocellular carcinoma and affect its clinical prognosis.

Publications

Multiple m<sup>6</sup>A RNA methylation modulators promote the malignant progression of hepatocellular carcinoma and affect its clinical prognosis.

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