Immune infiltration-related N6-methyladenosine RNA methylation regulators influence the malignancy and prognosis of endometrial cancer.
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ABSTRACT:
SUBMITTER: Ma J
PROVIDER: S-EPMC8266343 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundMelanoma is an extremely aggressive type of skin cancer and experiencing a expeditiously rising mortality in a current year. Exploring new potential prognostic biomarkers and therapeutic targets of melanoma are urgently needed. The ambition of this research was to identify genetic markers and assess prognostic performance of N6-methyladenosine (m6A) regulators in melanoma.MethodsGene expression data and corresponding clinical informations of melanoma patients as well as sequence data of normal controls are collected from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases. Quantitative real-time PCR (qRT-PCR) analysis was carried out to detect the RNA expression of IGF2BP3 in A375 cell line, melanoma tissues, and normal tissues. Western blot, cell proliferation, and migration assays were performed to assess the ability of IGF2BP3 in A375 cell line.ResultsDifferently expressed m6A regulators between tumor samples and normal samples were analyzed. A three-gene prognostic signature including IGF2BP3, RBM15B, and METTL16 was constructed, and the risk score of this signature was identified to be an independent prognostic indicator for melanoma. In addition, IGF2BP3 was verified to promote melanoma cell proliferation and migration in vitro and associate with lymph node metastasis in clinical samples. Moreover, risk score and the expression of IGF2BP3 were positively associated with the infiltrating immune cells and these hub genes made excellent potential drug targets in melanoma.ConclusionWe identified the genetic changes in m6A regulatory genes and constructed a three-gene risk signature with distinct prognostic value in melanoma. This research provided new insights into the epigenetic understanding of m6A regulators and novel therapeutic strategies in melanoma.
| S-EPMC8393813 | biostudies-literature
Project description:N6-methyladenosine (m6A) RNA methylation regulators play an important role in the occurrence and development of tumors. Here, we aimed to identify the potential roles of m6A RNA methylation regulators in immune infiltrates of ovarian cancer. We obtained two distinct m6A patterns (m6Acluster.A and m6Acluster.B) based on the expression levels of all 21 m6A RNA methylation regulators from The Cancer Genome Atlas (TCGA) database using a consensus clustering algorithm. Differential analysis of m6Acluster.A and m6Acluster.B identified 196 m6A-related genes. We further validated the m6A regulation mechanism based on the 196 m6A-related genes using another consensus clustering algorithm. Considering individual differences, principal component analysis algorithms were used to calculate an m6A score for each sample in order to quantify the m6A patterns. A low m6A score was associated with immune activation and enhanced response to immune checkpoint inhibitors, whereas a high m6A score was associated with tumor progression. Finally, we successfully verified the correlation between m6A regulators and immune microenvironment in OC using our microarray analysis data. In summary, m6A regulators play non-negligible roles in immune infiltrates of ovarian cancer. Our investigation of m6A patterns may help to guide future immunotherapy strategies for advanced ovarian cancer.
| S-EPMC8295008 | biostudies-literature
Project description:Glioblastoma (GBM) is a group of intracranial neoplasms with intra-tumoral heterogeneity. RNA N6-methyladenosine (m6A) methylation modification reportedly plays roles in immune response. The relationship between the m6A modification pattern and immune cell infiltration in GBM remains unknown. Utilizing expression data of GBM patients, we thoroughly explored the potential m6A modification pattern and m6A-related signatures based on 21 regulators. Thereafter, the m6A methylation modification-based prognostic assessment pipeline (MPAP) was constructed to quantitatively assess GBM patients' clinical prognosis combining the Robustness and LASSO regression. Single-sample gene-set enrichment analysis (ssGSEA) was used to estimate the specific immune cell infiltration level. We identified two diverse clusters with diverse m6A modification characteristics. Based on differentially expressed genes (DEGs) within two clusters, m6A-related signatures were identified to establish the MPAP, which can be used to quantitatively forecast the prognosis of GBM patients. In addition, the relationship between 21 m6A regulators and specific immune cell infiltration was demonstrated in our study and the m6A regulator ELAVL1 was determined to play an important role in the anticancer response to PD-L1 therapy. Our findings indicated the relationship between m6A methylation modification patterns and tumor microenvironment immune cell infiltration, through which we could comprehensively understand resistance to multiple therapies in GBM, as well as accomplish precise risk stratification according to m6A-related signatures.
| S-EPMC7947873 | biostudies-literature
Project description:Succinylation is a newly discovered and multienzyme-regulated post-translational modification (PTM) that is associated with the initiation and progression of cancer. Currently, no systematic analyses on the role of succinylation regulators in tumors have been reported. In this study, we performed a comprehensive pan-cancer analysis on four well-known succinylation regulators (CPT1A, KAT2A, SIRT5, and SIRT7). We found that these regulators played specific and critical roles in the prognosis of clear cell renal cell carcinoma (ccRCC). We constructed a risk score (RS) based on two independent prognostic prediction factors, CPT1A and KAT2A, and subsequently developed a nomogram model containing the RS, which showed good accuracy in the prediction of overall survival (OS) in ccRCC patients. Furthermore, we used the similar expression pattern of four succinylation regulators according to consensus clustering analysis to divide the patients into three clusters that exhibited prominently different OS as well as clinicopathological characteristics. Differently expressed genes (DEGs) and pathway enrichment analyses of three clusters indicated that succinylation regulators might promote malignant progression of ccRCC by regulating the infiltration of immune cells and RNA N6-methyladenosine (m6A) methylation. Importantly, our data suggest that CPT1A and SIRT5 might up-regulate and down-regulate the expression of LRPPRC and EIF3B, respectively. Our study systematically analyzed the prognostic predictive values of four succinylation regulators and revealed their potential mechanisms in ccRCC aggressiveness. These data provide new insight into the understanding of succinylation modification and present clinical evidence for its role in ccRCC treatments.
| S-EPMC7935513 | biostudies-literature
Project description:Although it is widely accepted that N6-methyladenosine (m6A) RNA methylation plays critical roles in tumorigenesis and progression, the values of m6A modification are less known in hepatocellular carcinoma. The major purpose of our current studies is to investigate the role of m6A regulators in hepatocellular carcinoma and whether it can affect the prognosis of hepatocellular carcinoma. Here we demonstrate that most of the m6A regulators are highly expressed in hepatocellular carcinoma. Furthermore, we cluster hepatocellular carcinoma into two subgroups (cluster 1/2) by applying consensus clustering to m6A regulators. Compared with the cluster 1 subgroup, the cluster 2 subgroup was significantly associated with a higher pathological grade and survival. Based on these findings, we reveal a risk signature by using three m6A regulators, which are not only an independent prognostic marker but also a predictor of the clinicopathological features in hepatocellular carcinoma. In conclusion, m6A regulators are crucial participants in the malignant progression of hepatocellular carcinoma and are potential targets for prognosis.
| S-EPMC7438782 | biostudies-literature
Project description:N6-Methyladenosine-related long noncoding RNAs play an essential role in many cancers' development. However, the relationship between m6A-related lncRNAs and acute myelogenous leukemia (AML) prognosis remains unclear. We systematically analyzed the association of m6A-related lncRNAs with the prognosis and tumor immune microenvironment (TME) features using the therapeutically applicable research to generate effective treatment (TARGET) database. We screened 315 lncRNAs associated with AML prognosis and identified nine key lncRNAs associated with m6A by the LASSO Cox analysis. A model was established based on these nine lncRNAs and the predictive power was explored in The Cancer Genome Atlas (TCGA) database. The areas under the ROC curve of TARGET and TCGA databases for ROC at 1, 3, and 5 years are 0.701, 0.704, and 0.696, and 0.587, 0.639, and 0.685, respectively. The nomogram and decision curve analysis (DCA) showed that the risk score was more accurate than other clinical indicators in evaluating patients' prognoses. The clusters with a better prognosis enrich the AML pathways and immune-related pathways. We also found a close correlation between prognostic m6A-related lncRNAs and tumor immune cell infiltration. LAG3 expression at the immune checkpoint was lower in the worse prognostic cluster. In conclusion, m6A-related lncRNAs partly affected AML prognosis by remodeling the TME and affecting the anticarcinogenic ability of immune checkpoints, especially LAG3 inhibitors. The prognostic model constructed with nine key m6A-related lncRNAs can provide a method to assess the prognosis of AML patients in both adults and children.
| S-EPMC9115802 | biostudies-literature
Project description:LncRNAs and tumor microenvironment (TME) exert an important effect in antitumor immunity. Nonetheless, the role of m6A-related lncRNA clustering patterns in prognosis, TME and immunotherapy of cervical cancer (CC) remains unknown. Here, based on 7 m6A-related prognostic lncRNAs obtained from TCGA-CC dataset, two m6AlncRNA clustering patterns were determined. m6AlncRNA clusterA was characterized by immune cell infiltrates and immune activation. m6AlncRNA clusterB was characterized by enrichment of immune evasion and tumorigenic activation pathways as well as survival and clinical stage disadvantage. Then, principal component analysis algorithms were used to construct m6AlncRNAscore based on prognostic differentially expressed genes between two m6AlncRNA clusters to quantify m6AlncRNA clustering patterns. m6AlncRNAscore was an independent prognostic protective factor. Higher Th2 and Treg cells and enrichment of immunosuppressive pathways were observed in the low-m6AlncRNAscore group, with poorer survival. High-m6AlncRNAscore was characterized by increased infiltration of activated CD8 T cell, enrichment of immune activation pathways, lower IL-10 and TGF-beta1 levels, and higher immunophenscore values, indicating inflamed TME and better anti-tumor immunotherapy efficacy. Quantitative Real-Time Polymerase Chain Reaction was used for detection of m6A-related prognostic lncRNAs. Collectively, we identified two m6AlncRNA clustering patterns which play a nonnegligible role in the prognosis, TME heterogeneity and immunotherapy of CC patients.
| S-EPMC9568557 | biostudies-literature
Project description:BackgroundSeveral studies have revealed that N6-methyladenosine (m6A) regulation is involved in various biological processes and cancer progression. Nevertheless, the potential effects of m6A modifications in the tumor immune microenvironment (TIME) and on immune regulation in pancreatic adenocarcinoma (PAAD) remains unclear.MethodsA consensus clustering algorithm was used to identify different m6A modification patterns and construct an m6A-associated gene signature based on 23 m6A regulators in PAAD. The CIBERSORT and ssGSEA algorithms were used to estimate the components of the immune cells in each sample. The PCA algorithm was used to develop the m6Ascore system for the evaluation of m6A modification patterns in each sample.ResultsTwo m6A modification patterns with different biological properties and prognoses were identified in 176 PAAD patient samples. The features of TIME between the two patterns were similar, with two definite immune phenotypes: immune-inflamed and immune-excluded. Based on the m6A phenotype-associated signature genes, we constructed an m6Ascore system to investigate the m6A modification pattern of each sample, profile the dissection of physiological processes, immune infiltration, clinical prognosis, immunotherapy, and genetic variation. Patients with low m6Ascore scores had better clinical outcomes, enhanced immune infiltration, and lower expression of immunotherapeutic drug targets, such as CD274 and PDCD1LG2. Further research indicated that the m6Ascore and tumor mutation burden were significantly correlated, and patients with low m6Ascore had higher mutation rates in SMAD4 and TTN. Moreover, TNFRSF21 was significantly upregulated in PAAD tumor tissues and cell lines. Lower expression of TNFRSF21 had a prominent advantage in survival and was correlated with a low level of immune infiltration. PAAD samples with different TNFRSF21 expression levels showed significantly distinct sensitivities to chemotherapeutic agents.ConclusionsThis study revealed that m6A modification patterns could play an important role in the diversity and complexity of TIME, and the m6Ascore system could serve as an independent and powerful prognostic biomarker and is latently related to PAAD immunotherapies. Quantitative determination of m6A modification patterns in individual patients will be instrumental in mapping the TIME landscape and further optimizing precision immunotherapy.
| S-EPMC9125922 | biostudies-literature
Project description:BackgroundLung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer, which is one of the most commonly diagnosed tumors and the leading causes of death from cancer around the world. Since RNA methylation is a posttranscriptional modification and affects so much biological progress, it is urged to explore the role of N6-methyladenosine (m6A) methylation in LUAD.MethodsWe explored the expression of 24 m6A methylation genes, as well as their correlations with LAG3 in 561 LUAD samples from TCGA. Consensus clustering was applied to m6A methylation genes, and two LUAD subgroups were identified. The expression of m6A genes was analyzed by the Wilcoxon test. KEGG and GO enrichment analyses were performed to indicate the pathway affected by differentially expressed genes in the two groups. A prognostic model based on LASSO regression using an eleven-m6A gene signature was constructed according to the expression of these genes. Receiver operating characteristic (ROC) curve was used to confirm the accuracy of the model in the TCGA cohort, as well as in the test cohort from the Gene Expression Omnibus (GEO) database.ResultsCompared to cluster 1, cluster 2 showed poorer overall survival (OS) and higher LAG3 expression. In addition, KEGG and GO enrichment analyses indicated that differentially expressed genes are enriched in the immune response. We also observed that the expression of LAG3 is positively correlated with IGF2BP2, CBLL1, and HNRNPA2B1 and negatively correlated with YTHDF2, YTHDF3, and FTO. For patients in the TCGA cohort, the AUC score is 0.7, and the AUC score for the GSE50081 cohort is 0.675. Patients with lower risk scores exhibited better overall survival and lower expression of LAG3 than patients with higher risk scores.ConclusionsIn brief, our results indicated the important role of m6 methylation in affecting the tumor immune microenvironment and the survival of patients with LUAD. The m6A methylation gene signatures might serve as promising therapeutic targets and help the immunotherapy of LUAD in the future.
| S-EPMC9427291 | biostudies-literature
Project description:BackgroundColorectal cancer (CRC) is the third most common tumor worldwide. Aberrant N6-methyladenosine (m6A) modification can influence the progress of the CRC. Additionally, long noncoding RNA (lncRNA) plays a critical role in CRC and has a close relationship with m6A modification. However, the prognostic potential of m6A-related lncRNAs in CRC patients still remains to be clarified.MethodsWe use "limma" R package, "glmnet" R package, and "survival" R package to screen m6A-related-lncRNAs with prognostic potential. Then, we comprehensively analysed and integrated the related lncRNAs in different TNM stages from TCGA database using the LASSO Cox regression. Meanwhile, the relationship between functional enrichment of m6A-related lncRNAs and immune microenvironment in CRC was also investigated using the TCGA database. A prognostic model was constructed and validated to determine the association between m6A-related lncRNAs in different TNM stages and the prognosis of CRC.ResultWe demonstrated that three related m6A lncRNAs in different TNM stages were associated with the prognosis of CRC patients. Patients from the TCGA database were classified into the low-risk and the high-risk groups based on the expression of these lncRNAs. The patients in the low-risk group had longer overall survival than the patients in the high-risk group (P < 0.001). We further constructed and validated a prognostic nomogram based on these genes with a C-index of 0.80. The receiver operating characteristic curves confirmed the predictive capacity of the model. Meanwhile, we also found that the low-risk group has the correlation with the dendritic cell (DC). Finally, we discovered the relationship between the m6A regulators and the three lncRNAs.ConclusionThe prognostic model based on three m6A-related lncRNAs exhibits superior predictive performance, providing a novel prognostic model for the clinical evaluation of CRC patients.
| S-EPMC8568524 | biostudies-literature