Construction and validation of N6-methyladenosine long non-coding RNAs signature of prognostic value for early biochemical recurrence of prostate cancer

Liu, Jingchao; Zhang, Wei; Wang, Jiawen; Lv, Zhengtong; Xia, Haoran; Zhang, Zhipeng; Zhang, Yaoguang; Wang, Jian‐Ye

doi:10.1007/s00432-022-04040-y

Cited by 6 publications

(2 citation statements)

References 60 publications

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“…In addition, a recent paper found that m 6 A reader HNRNPC can regulate Treg cell abundance as a possible mechanism for m 6 A methylation-mediated response against CTLA-4, indicating that activation of the immune microenvironment by targeting m 6 A regulators may serve as a potential therapeutic approach for advanced PCa( 52 ).Our study synthetically analyzed the relationship between the expression of m 6 A regulators and immune characteristics and drug sensitivity of PCa patients. In accordance with the previous reports, we confirmed that resting memory CD4+ T cells and Tregs are highly correlated with m 6 A-related genes ( 53 , 54 ), while both high- and low-risk groups are sensitive to a number of therapeutic drugs. Some of these drugs are known to be effective in the treatment of PCa and have even been approved for clinical use ( 55 – 57 ).…”

Section: Discussionsupporting

confidence: 92%

The m6A methylation landscape, molecular characterization and clinical relevance in prostate adenocarcinoma

Peng

Gan

et al. 2023

Front. Immunol.

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BackgroundDespite the recent progress of therapeutic strategies in treating prostate cancer (PCa), the majority of patients still eventually relapse, experiencing dismal outcomes. Therefore, it is of utmost importance to identify novel viable targets to increase the effectiveness of treatment. The present study aimed to investigate the potential relationship between N6-methyladenosine (m6A) RNA modification and PCa development and determine its clinical relevance.MethodsThrough systematic analysis of the TCGA database and other datasets, we analyzed the gene expression correlation and mutation profiles of m6A-related genes between PCa and normal tissues. Patient samples were divided into high- and low-risk groups based on the results of Least Absolute Shrinkage and Selection Operator (LASSO) Cox analysis. Subsequently, differences in biological processes and genomic characteristics of the two risk groups were determined, followed by functional enrichment analysis and gene set enrichment (GSEA) analysis. Next, we constructed the protein-protein interaction (PPI) network of differentially expressed genes between patients in high- and low-risk groups, along with the mRNA-miRNA-lncRNA network. The correlation analysis of tumor-infiltrating immune cells was further conducted to reveal the differences in immune characteristics between the two groups.ResultsA variety of m6A-related genes were identified to be differentially expressed in PCa tissues as compared with normal tissues. In addition, the PPI network contained 278 interaction relationships and 34 m6A-related genes, and the mRNA-miRNA-lncRNA network contained 17 relationships, including 91 miRNAs. Finally, the immune characteristics analysis showed that compared with the low-risk group, the levels of M1 and M2 macrophages in the high-risk group significantly increased, while the levels of mast cells resting and T cells CD4 memory resting significantly decreased.ConclusionsThis study provides novel findings that can further the understanding of the role of m6A methylation during the progression of PCa, which may facilitate the invention of targeted therapeutic drugs.

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Section: Discussionsupporting

confidence: 92%

The m6A methylation landscape, molecular characterization and clinical relevance in prostate adenocarcinoma

Peng

Gan

et al. 2023

Front. Immunol.

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“…Furthermore, a novel signature related to APPCAF in prostate cancer was established. Compared with previously published CAFassociated prostate cancer signatures [61,78], our signature is more reliable and clinically instructive, based on clinical specimens and derived from a group of potential CAF subtypes. Meanwhile, our findings revealed that the APPCAF-based signature had predictive potential for both prognosis and treatment response.…”

Section: Discussionmentioning

confidence: 99%

Integrating single-cell and bulk RNA sequencing data unveils antigen presentation and process-related CAFS and establishes a predictive signature in prostate cancer

Wang,

Li,

Xie

et al. 2024

J Transl Med

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Background Cancer-associated fibroblasts (CAFs) are heterogeneous and can influence the progression of prostate cancer in multiple ways; however, their capacity to present and process antigens in PRAD has not been investigated. In this study, antigen presentation and process-related CAFs (APPCAFs) were identified using bioinformatics, and the clinical implications of APPCAF-related signatures in PRAD were investigated. Methods SMART technology was used to sequence the transcriptome of primary CAFs isolated from patients undergoing different treatments. Differential expression gene (DEG) screening was conducted. A CD4 + T-cell early activation assay was used to assess the activation degree of CD4 + T cells. The datasets of PRAD were obtained from The Cancer Genome Atlas (TCGA) database and NCBI Gene Expression Omnibus (GEO), and the list of 431 antigen presentation and process-related genes was obtained from the InnateDB database. Subsequently, APP-related CAFs were identified by nonnegative matrix factorization (NMF) based on a single-cell seq (scRNA) matrix. GSVA functional enrichment analyses were performed to depict the biological functions. A risk signature based on APPCAF-related genes (APPCAFRS) was developed by least absolute shrinkage and selection operator (LASSO) regression analysis, and the independence of the risk score as a prognostic factor was evaluated by univariate and multivariate Cox regression analyses. Furthermore, a biochemical recurrence-free survival (BCRFS)-related nomogram was established, and immune-related characteristics were assessed using the ssGSEA function. The immune treatment response in PRAD was further analyzed by the Tumor Immune Dysfunction and Exclusion (TIDE) tool. The expression levels of hub genes in APPCAFRS were verified in cell models. Results There were 134 upregulated and 147 downregulated genes, totaling 281 differentially expressed genes among the primary CAFs. The functions and pathways of 147 downregulated DEGs were significantly enriched in antigen processing and presentation processes, MHC class II protein complex and transport vesicle, MHC class II protein complex binding, and intestinal immune network for IgA production. Androgen withdrawal diminished the activation effect of CAFs on T cells. NMF clustering of CAFs was performed by APPRGs, and pseudotime analysis yielded the antigen presentation and process-related CAF subtype CTSK + MRC2 + CAF-C1. CTSK + MRC2 + CAF-C1 cells exhibited ligand‒receptor connections with epithelial cells and T cells. Additionally, we found a strong association between CTSK + MRC2 + CAF-C1 cells and inflammatory CAFs. Through differential gene expression analysis of the CTSK + MRC2 + CAF-C1 and NoneAPP-CAF-C2 subgroups, 55 significant DEGs were identified, namely, APPCAFRGs. Based on the expression profiles of APPCAFRGs, we divided the TCGA-PRAD cohort into two clusters using NMF consistent cluster analysis, with the genetic coefficient serving as the evaluation index. Four APPCAFRGs, THBS2, DPT, COL5A1, and MARCKS, were used to develop a prognostic signature capable of predicting BCR occurrence in PRAD patients. Subsequently, a nomogram with stability and accuracy in predicting BCR was constructed based on Gleason grade (p = n.s.), PSA (p < 0.001), T stage (p < 0.05), and risk score (p < 0.01). The analysis of immune infiltration showed a positive correlation between the abundance of resting memory CD4 + T cells, M1 macrophages, resting dendritic cells, and the risk score. In addition, the mRNA expression levels of THBS2, DPT, COL5A1, and MARCKS in the cell models were consistent with the results of the bioinformatics analysis. Conclusions APPCAFRS based on four potential APPCAFRGs was developed, and their interaction with the immune microenvironment may play a crucial role in the progression to castration resistance of PRAD. This novel approach provides valuable insights into the pathogenesis of PRAD and offers unexplored targets for future research.

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RNA N6-methyladenosine modifications in urological cancers: from mechanism to application

Yang,

Ying,

Tao

et al. 2024

Nat Rev Urol

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Construction and validation of N6-methyladenosine long non-coding RNAs signature of prognostic value for early biochemical recurrence of prostate cancer

Cited by 6 publications

References 60 publications

The m6A methylation landscape, molecular characterization and clinical relevance in prostate adenocarcinoma

The m6A methylation landscape, molecular characterization and clinical relevance in prostate adenocarcinoma

Integrating single-cell and bulk RNA sequencing data unveils antigen presentation and process-related CAFS and establishes a predictive signature in prostate cancer

RNA N6-methyladenosine modifications in urological cancers: from mechanism to application

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