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M⁶A RNA Methylation Regulators Act as Potential Prognostic Biomarkers in Lung Adenocarcinoma.

ABSTRACT: N⁶-methyladenosine [m(6)A/m⁶A] methylation is one of the most common RNA modifications in eukaryotic cell mRNA and plays an important regulatory role in mRNA metabolism, splicing, translocation, stability, and translation. Previous studies have demonstrated that the m⁶A modification is highly associated with tumor cell proliferation, migration, and invasion. In the present study, five m⁶A regulatory factors have been revealed, namely heterogeneous nuclear ribonucleoprotein A2/B1(HNRNPA2B1), heterogeneous nuclear ribonucleoprotein C (HNRNPC), Vir like m⁶A methyltransferase associated protein (KIAA1429/VIRMA), RNA binding motif protein 15 (RBM15) and methyltransferase like 3 (METTL3), which are closely related to the overall survival (OS) of patients with lung adenocarcinoma (LUAD). These five m⁶A regulatory factors exhibited potential prognostic value for the 1, 3, and 5-years survival outcomes of LUAD patients. Our findings revealed that several signaling pathways, such as cell cycle, DNA replication, RNA degradation, RNA polymerase, nucleotide excision repair and basal transcription factors, are activated in the high-risk group of LUAD patients.

SUBMITTER: Wang H

PROVIDER: S-EPMC7902930 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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m6A RNA Methylation Regulators Act as Potential Prognostic Biomarkers in Lung Adenocarcinoma.

Wang Hongbo H Zhao Xiangxuan X Lu Zaiming Z

Frontiers in genetics 20210210

N6-methyladenosine [m(6)A/m6A] methylation is one of the most common RNA modifications in eukaryotic cell mRNA and plays an important regulatory role in mRNA metabolism, splicing, translocation, stability, and translation. Previous studies have demonstrated that the m6A modification is highly associated with tumor cell proliferation, migration, and invasion. In the present study, five m6A regulatory factors have been revealed, namely heterogeneous nucl ...[more]

PMID: 33643384

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Project description:Background: N6-methyladenosine (m6A) RNA methylation is dynamically and reversibly regulated by methyl-transferases ("writers"), binding proteins ("readers"), and demethylases ("erasers"). The m6A is restored to adenosine and thus to achieve demethylation modification. The abnormality of m6A epigenetic modification in cancer has been increasingly attended. However, we are rarely aware of its diagnostic, progressive and prognostic performance in lung adenocarcinoma (LUAD). Methods and Results: The expression of 13 widely reported m6A RNA regulators in LUAD and normal samples were systematically analyzed. There were 12 m6A RNA methylation genes displaying aberrant expressions, and an 11-gene diagnostic score model was finally built (Diagnostic score =0.033*KIAA1429+0.116*HNRNPC+0.115*RBM15-0.067* METTL3-0.048*ZC3H13-0.221*WTAP+0.213*YTHDF1-0.132*YTHDC1-0.135* FTO+0.078*YTHDF2+0.014*ALKBH5). Receiver operating characteristic (ROC) analysis was performed to demonstrate superiority of the diagnostic score model (Area under the curve (AUC) was 0.996 of training cohort, P<0.0001; AUC was 0.971 of one validation cohort-GSE75037, P<0.0001; AUC was 0.878 of another validation cohort-GSE63459, P<0.0001). In both training and validation cohorts, YTHDC2 was associated with tumor stage (P<0.01), while HNRNPC was up expressed in progressed tumor (P<0.05). Besides, WTAP, RBM15, KIAA1429, YTHDF1, and YTHDF2 were all up expressed for TP53 mutation. Furthermore, using least absolute shrinkage and selection operator (lasso) regression analysis, a ten-gene risk score model was built. Risk score=0.169*ALKBH5-0.159*FTO+0.581*HNRNPC-0.348* YTHDF2-0.265*YTHDF1-0.123*YTHDC2+0.434*RBM15+0.143*KIAA1429-0.200*WTAP-0.310*METTL3. There existed correlation between the risk score and TNM stage (P<0.01), lymph node stage (P<0.05), gender (P<0.05), living status (P<0.001). Univariate and multivariate Cox regression analyses of relevant clinicopathological characters and the risk score revealed risk score was an independent risk factor of lung adenocarcinoma (HR: 2.181, 95%CI (1.594-2.984), P<0.001). Finally, a nomogram was built to facilitate clinicians to predict outcome. Conclusions: m6A epigenetic modification took part in the progression, and provided auxiliary diagnosis and prognosis of LUAD.

Project description:N6-methyladenosine (m6A) RNA modification is a reversible mechanism that regulates eukaryotic gene expression. Growing evidence has demonstrated an association between m6A modification and tumorigenesis and response to immunotherapy. However, the overall influence of m6A regulators on the tumor microenvironment and their effect on the response to immunotherapy in lung adenocarcinoma remains to be explored. Here, we comprehensively analyzed the m6A modification patterns of 936 lung adenocarcinoma samples based on 24 m6A regulators. First, we described the features of genetic variation in these m6A regulators. Many m6A regulators were aberrantly expressed in tumors and negatively correlated with most tumor-infiltrating immune cell types. Furthermore, we identified three m6A modification patterns using a consensus clustering method. m6A cluster B was preferentially associated with a favorable prognosis and enriched in metabolism-associated pathways. In contrast, m6A cluster A was associated with the worst prognosis and was enriched in the process of DNA repair. m6A cluster C was characterized by activation of the immune system and a higher stromal cell score. Surprisingly, patients who received radiotherapy had a better prognosis than patients without radiotherapy only in the m6A cluster C group. Subsequently, we constructed an m6A score model that qualified the m6A modification level of individual samples by using principal component analysis algorithms. Patients with high m6A score were characterized by enhanced immune cell infiltration and prolonged survival time and were associated with lower tumor mutation burden and PD-1/CTLA4 expression. The combination of the m6A score and tumor mutation burden could accurately predict the prognosis of patients with lung adenocarcinoma. Furthermore, patients with high m6A score exhibited greater prognostic benefits from radiotherapy and immunotherapy. This study demonstrates that m6A modification is significantly associated with tumor microenvironment diversity and prognosis. A comprehensive evaluation of m6A modification patterns in single tumors will expand our understanding of the tumor immune landscape. In addition, our m6A score model demonstrated that the level of immune cell infiltration plays a significant role in cancer immunotherapy and provides a basis to increase the efficiency of current immune therapies and promote the clinical success of immunotherapy.

Project description:BackgroundThe abnormal expression of genes is an essential factor affecting the prognosis of cancer. RNA modification is a way of regulating post-transcriptional levels, including m6A, m5C, m1A RNA methylation. Studies have found that RNA methylation regulates tumorigenesis development and stem cell regeneration. However, there are few studies on lung adenocarcinoma. This study aims to explore the clinical value of RNA methylation for lung adenocarcinoma.MethodsWe summarized thirty-one RNA methylation regulators. The training set was obtained from The Cancer Genome Atlas (TCGA) database, and the test set was obtained from the Gene Expression Omnibus (GEO) database. The Wilcoxon test was used to analyze the expression of RNA methylation regulators. We constructed tumor subgroup models and risk models based on the expression of those regulators. Principal component analysis (PCA) and the receiver operating characteristic (ROC) confirmed the accuracy of the models. Real-time polymerase chain reaction (PCR) validates the results in vitro.ResultsMost RNA methylation regulators had distinct expressions in tumor tissues and adjacent tissues (P<0.05). All the models showed high predictive performance (AUC: 0.65-0.82), and the five-year survival of patients in each group was statistically different (P<0.05). The patients in the high-risk group were more likely to have a higher stage, more lymph node metastases, and distant metastases, showing a poor clinical outcome. Patients with high expression of NOP2 or HNRNP were more likely to have a poorly differentiated in vitro experiment.ConclusionsWith our study, we found that the expressions of most RNA methylation regulators were significantly different in cancer and para-cancerous tissues. Different molecular phenotypes constructed by RNA methylation regulators can be independent risk factors for the prognosis of lung adenocarcinoma. Our study demonstrates the critical role of RNA methylation in lung adenocarcinoma, and it is expected to supply a reference for the prognostic stratification and treatment strategy development of lung adenocarcinoma.

Project description:BackgroundLung adenocarcinoma (LUAD) is the leading cause of cancer-related death. This study aimed to develop and validate reliable prognostic biomarkers and signature.MethodsDifferentially expressed genes were identified based on three Gene Expression Omnibus (GEO) datasets. Based on 1052 samples' data from our cohort, GEO and The Cancer Genome Atlas, we explored the relationship of clinicopathological features and NEIL3 expression to determine clinical effect of NEIL3 in LUAD. Western blotting (22 pairs of tumor and normal tissues), Real-time quantitative PCR (19 pairs of tumor and normal tissues), and immunohistochemical analyses (406-tumor tissues subjected to microarray) were conducted. TIMER and ImmuCellAI analyzed relationship between NEIL3 expression and the abundance of tumor-infiltrating immune cells in LUAD. The co-expressed-gene prognostic signature was established based on the Cox regression analysis.ResultsThis study identified 502 common differentially expressed genes and confirmed that NEIL3 was significantly overexpressed in LUAD samples (P < 0.001). Increased NEIL3 expression was related to advanced stage, larger tumor size and poor overall survival (p < 0.001) in three LUAD cohorts. The proportions of natural T regulatory cells and induced T regulatory cells increased in the high NEIL3 group, whereas those of B cells, Th17 cells and dendritic cells decreased. Gene set enrichment analysis indicated that NEIL3 may activate cell cycle progression and P53 signaling pathway, leading to poor outcomes. We identified nine prognosis-associated hub genes among 370 genes co-expressed with NEIL3. A 10-gene prognostic signature including NEIL3 and nine key co-expressed genes was constructed. Higher risk-score was correlated with more advanced stage, larger tumor size and worse outcome (p < 0.05). Finally, the signature was verified in test cohort (GSE50081) with superior diagnostic accuracy.ConclusionsThis study suggested that NEIL3 has the potential to be an immune-related therapeutic target and an independent predictor of LUAD prognosis. We also developed a prognostic signature for LUAD with a precise diagnostic accuracy.

Dataset Information

M⁶A RNA Methylation Regulators Act as Potential Prognostic Biomarkers in Lung Adenocarcinoma.

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m<sup>6</sup>A RNA Methylation Regulators Act as Potential Prognostic Biomarkers in Lung Adenocarcinoma.

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Dataset Information

M6A RNA Methylation Regulators Act as Potential Prognostic Biomarkers in Lung Adenocarcinoma.

Publications

m<sup>6</sup>A RNA Methylation Regulators Act as Potential Prognostic Biomarkers in Lung Adenocarcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

M⁶A RNA Methylation Regulators Act as Potential Prognostic Biomarkers in Lung Adenocarcinoma.