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.

HNRNPA2B1, as a m6A Reader, Promotes Tumorigenesis and Metastasis of Oral Squamous Cell Carcinoma

“…Further, through RIP assay we found that HNRNPA2B1 could enrich LINE-1 mRNA, implying that LINE-1 may be regulated in protein level upon interaction with HNRNPA2B1. The results were consistent with previous studies that HNRNPA2B1 acts as an m 6 A reader, binding and affecting m 6 A methylated transcripts, and then regulating the translation initiation, splicing, exportation, and other processes of the target gene to perform its functions (53)(54)(55)(56)(57). These results suggested that HNRNPA2B1 as an m 6 A reader may regulate the development of OSCC by targeting EMT via the LINE-1/TGF-b1/Snail signaling pathway.…”

Systematic Analysis Identifies a Specific RNA-Binding Protein-Related Gene Model for Prognostication and Risk-Adjustment in HBV-Related Hepatocellular Carcinoma

“…Time-independent ROCs of risk score, age, gender, grade, and stage were separately constructed and the predictive power was compared. In published literature, Fang and Chen (2020) proposed a two-m 6 A RNA methylation regulator prognostic model (HNRNPA2B1 and RBM15) for HBV-related HCC prognosis. By ROCs, the predictive efficacy was compared with our prognostic model.…”

Expression of m6A Regulators Correlated With Immune Microenvironment Predicts Therapeutic Efficacy and Prognosis in Gliomas

“…Besides, the "erasers" comprise fat mass and obesity-associated protein (FTO) and alkB homolog 5 (ALKBH5) (Jia et al, 2011;Zheng et al, 2013). Various studies have revealed that m6A regulators can be used as novel prognostic biomarkers in different types of cancer (Chen et al, 2019;Fang and Chen, 2020;Huang et al, 2020a;Li Z. et al, 2020;Lu et al, 2020). METTL3 was shown to promote the proliferation and migration of hepatocellular carcinoma via the YTHDF2-dependent pathway and its knockdown could inhibit tumor progression (Chen et al, 2018).…”