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M⁶A RNA Methylation Regulators Impact Prognosis and Tumor Microenvironment in Renal Papillary Cell Carcinoma.

ABSTRACT: Accumulating evidence has proven that N6-methyladenosine (m⁶A) RNA methylation plays an essential role in tumorigenesis. However, the significance of m⁶A RNA methylation modulators in the malignant progression of papillary renal cell carcinoma (PRCC) and their impact on prognosis has not been fully analyzed. The present research set out to explore the roles of 17 m⁶A RNA methylation regulators in tumor microenvironment (TME) of PRCC and identify the prognostic values of m⁶A RNA methylation regulators in patients afflicted by PRCC. We investigated the different expression patterns of the m⁶A RNA methylation regulators between PRCC tumor samples and normal tissues, and systematically explored the association of the expression patterns of these genes with TME cell-infiltrating characteristics. Additionally, we used LASSO regression to construct a risk signature based upon the m⁶A RNA methylation modulators. Two-gene prognostic risk model including IGF2BP3 and HNRNPC was constructed and could predict overall survival (OS) of PRCC patients from the Cancer Genome Atlas (TCGA) dataset. The prognostic signature-based risk score was identified as an independent prognostic indicator in Cox regression analysis. Moreover, we predicted the three most significant small molecule drugs that potentially inhibit PRCC. Taken together, our study revealed that m⁶A RNA methylation regulators might play a significant role in the initiation and progression of PRCC. The results might provide novel insight into exploration of m⁶A RNA modification in PRCC and provide essential guidance for therapeutic strategies.

SUBMITTER: Chen L

PROVIDER: S-EPMC8008109 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIncreasing evidence have highlighted the biological significance of mRNA N6-methyladenosine (m6A) modification in regulating tumorigenicity and progression. However, the potential roles of m6A regulators in tumor microenvironment (TME) formation and immune cell infiltration in liver hepatocellular carcinoma (LIHC or HCC) requires further clarification.MethodRNA sequencing data were obtained from TCGA-LIHC databases and ICGC-LIRI-JP databases. Consensus clustering algorithm was used to identify m6A regulators cluster subtypes. Weighted gene co-expression network analysis (WGCNA), LASSO regression, Random Forest (RF), and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) were applied to identify candidate biomarkers, and then a m6Arisk score model was constructed. The correlations of m6Arisk score with immunological characteristics (immunomodulators, cancer immunity cycles, tumor-infiltrating immune cells (TIICs), and immune checkpoints) were systematically evaluated. The effective performance of nomogram was evaluated using concordance index (C-index), calibration plots, decision curve analysis (DCA), and receiver operating characteristic curve (ROC).ResultsTwo distinct m6A modification patterns were identified based on 23 m6A regulators, which were correlated with different clinical outcomes and biological functions. Based on the constructed m6Arisk score model, HCC patients can be divided into two distinct risk score subgroups. Further analysis indicated that the m6Arisk score showed excellent prognostic performance. Patients with a high m6Arisk score was significantly associated with poorer clinical outcome, lower drug sensitivity, and higher immune infiltration. Moreover, we developed a nomogram model by incorporating the m6Arisk score and clinicopathological features. The application of the m6Arisk score for the prognostic stratification of HCC has good clinical applicability and clinical net benefit.ConclusionOur findings reveal the crucial role of m6A modification patterns for predicting HCC TME status and prognosis, and highlight the good clinical applicability and net benefit of m6Arisk score in terms of prognosis, immunophenotype, and drug therapy in HCC patients.

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.

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M⁶A RNA Methylation Regulators Impact Prognosis and Tumor Microenvironment in Renal Papillary Cell Carcinoma.

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Dataset Information

M6A RNA Methylation Regulators Impact Prognosis and Tumor Microenvironment in Renal Papillary Cell Carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

M⁶A RNA Methylation Regulators Impact Prognosis and Tumor Microenvironment in Renal Papillary Cell Carcinoma.