Dataset Information

The significance of m6A RNA methylation regulators in predicting the prognosis and clinical course of HBV-related hepatocellular carcinoma.

ABSTRACT:

Background

Hepatocarcinogenesis is reportedly correlated with abnormal m6A modifications; however, it is unknown whether m6A RNA methylation regulators facilitate the occurrence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Thus, we constructed an m6A-related model that may enhance HBV-related HCC prognosis.

Methods

Gene signatures of HNRNPA2B1 and RBM15 were generated by univariate and Lasso Cox regression analyses using the gene set and clinical information from The Cancer Genome Atlas (TCGA) database. High-risk and low-risk groups were confirmed based on the gene signature model. Furthermore, we validated the predictive roles of the two genes for overall survival (OS) in the GSE14520 dataset. The relative expression of 22 paired mRNAs was measured using quantitative real-time polymerase chain reaction (qRT-PCR) analysis to determine whether the two genes had a predictive role in our Guilin cohort.

Results

The differences in OS between the high-risk and low-risk groups were statistically significant in the TCGA (p =?0.003) and GSE14520 (p =?0.045) datasets, but not in the Guilin cohort, owing to differences in clinical information among the three cohorts (mainly the TNM stage and survival state). Stratified analysis of TNM stages showed that the two-gene signature acted as a prognostic indicator of HBV-related HCC patients in the early TNM stage; both TCGA and GSE14520 cohorts showed statistical significance. Moreover, multivariate Cox regression analysis indicated that the two-gene signature was an independent factor for predicting prognosis (HR?=?1.087, 95% CI: 1.007-1.172). Correlation analysis between the gene signature and clinical features revealed that the risk stratification was significantly correlated with grade and survival state. Finally, Gene Set Enrichment Analysis (GSEA) revealed that the KEGG pathways associated with the cell cycle, DNA replication, the spliceosome, repair, and metabolism-related processes were all significantly enriched in the high-risk group. Among the enriched genes, the expression levels of the replication protein RPA1 and the pre-mRNA splicing factor SF3B1 were significantly upregulated in the high-risk group. These results might help in elucidating the underlying molecular mechanisms of HBV-related HCC.

Conclusions

Our data may provide new predictive signatures and potential therapeutic targets to identify and treat HBV-related HCC patients in the early disease stage.

SUBMITTER: Fang Q

PROVIDER: S-EPMC7302147 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

The significance of m6A RNA methylation regulators in predicting the prognosis and clinical course of HBV-related hepatocellular carcinoma.

Fang Qiongxuan Q Chen Hongsong H

Molecular medicine (Cambridge, Mass.) 20200617 1

<h4>Background</h4>Hepatocarcinogenesis is reportedly correlated with abnormal m6A modifications; however, it is unknown whether m6A RNA methylation regulators facilitate the occurrence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Thus, we constructed an m6A-related model that may enhance HBV-related HCC prognosis.<h4>Methods</h4>Gene signatures of HNRNPA2B1 and RBM15 were generated by univariate and Lasso Cox regression analyses using the gene set and clinical information ...[more]

PMID: 32552682

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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.

Project description:PurposeN6-methyladenosine (m6A) modifications represent one of the most common methylation modifications, and they are mediated by m6A RNA methylation regulators. However, their functions in renal cell carcinoma (RCC) are not completely understood. The aim of this study was to investigate the effects of the regulators in RCC.Materials and methodsThe expression levels of the 13 main m6A RNA methylation regulators in RCC were detected and consensus clustering was performed to explore their relationships with RCC. Thereafter, a risk signature based on the regulators was established. This risk model was fully verified by conducting prognostic analyses using two datasets (The Cancer Genome Atlas [TCGA] and Gene Expression Omnibus [GEO] datasets) and a ROC curve analysis.ResultsOf the 13 main m6A regulators, six were significantly upregulated and four were significantly downregulated in 893 RCC cases compared to 128 normal controls in the TCGA database. Consensus clustering based on the regulators identified two clusters of RCC cases, which were significantly associated with a pathological characteristic (T status). Thus, these results indicated that m6A RNA methylation regulators were associated with RCC. Thereafter, a risk model involving two of the regulators (METTL14 and WTAP) was established. The alterations in the mRNA and protein expression levels of these two regulators were further confirmed based on Human Protein Atlas data and real-time PCR in RCC and normal cell lines. The results indicated that the risk model may serve as an independent prognostic marker of overall survival, and it was also associated with clinicopathological characteristics (T status, M status, pathological stage, and gender) in RCC.ConclusionCollectively, the results of this study indicated that the risk model (based on two m6A RNA methylation regulators) may serve as an independent prognostic indicator of RCC, which may aid further investigation into m6A RNA modification in RCC.

Dataset Information

The significance of m6A RNA methylation regulators in predicting the prognosis and clinical course of HBV-related hepatocellular carcinoma.

Background

Methods

Results

Conclusions

Publications

The significance of m6A RNA methylation regulators in predicting the prognosis and clinical course of HBV-related hepatocellular carcinoma.

Similar Datasets

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