N6-Methylandenosine-Related lncRNAs Predict Prognosis and Immunotherapy Response in Bladder Cancer

Abstract

Both lncRNAs and the N6-methyladenosine (m6A) modification are key regulators of tumorigenesis and innate immunity. However, little is known about the m6A modification of lncRNAs and their clinical and immune relevance in bladder cancer. In this study, we identified m6A-related lncRNAs using Pearson correlation analysis in The Cancer Genome Atlas (TCGA) and the IMvigor210 datasets. Next, univariate Cox regression was performed using the TCGA dataset to filter prognostic m6A-related lncRNAs, which were further subjected to the least absolute shrinkage and selection operator (LASSO) Cox regression to establish a 12 m6A-related lncRNA prognostic score (m6A-LRS). The m6A-LRS was validated in the IMvigor210 dataset. In addition, high m6A-LRS tumors, characterized by decreased tumor mutation load and neoantigen load, showed poorer response to immunotherapy than those with low m6A-LRS in the IMvigor210 dataset. Further, we constructed an m6A-LRS-based nomogram that demonstrated a strong ability to predict overall survival in patients with bladder cancer. Moreover, enrichment analysis revealed that tumor-associated biological processes, oncogenic signaling, and tumor hallmarks were commonly associated with a high m6A-LRS. Gene set variation analysis also indicated that high m6A-LRS was associated with activation of canonical oncogenic signatures, such as the epithelial-to-mesenchymal transition, cell cycle regulators, and DNA replication, as well as activation of immunosuppressive signatures, such as the T-cell exhaustion and pan-fibroblast-TGF-β response signatures. Furthermore, we observed distinct tumor microenvironment cell infiltration characteristics between high- and low-risk tumors. High m6A-LRS tumors showed reduced infiltration of CD8+ T-cells and enhanced infiltration of macrophages and fibroblasts. Additionally, we established a competing endogenous RNA network based on the12 m6A-related lncRNAs. Finally, three lncRNAs (SNHG16, SBF2-AS1, and BDNF-AS) were selected for further validation. The qualitative PCR assay on 10 pairs of bladder cancer and adjacent normal control samples validated the differential expression, and methylated RNA immunoprecipitation (MeRIP) analysis demonstrated a robust m6A enrichment in T24 bladder cancer cells compared with normal uroepithelial cells (SVHUC-1). In conclusion, this study introduced an m6A-related lncRNA signature that identified a subgroup of patients with poor prognoses and suboptimal immune responses, thus providing novel approaches for treatment response prediction and patient stratification in bladder cancer.

Predicting Prognosis and Distinguishing Cold and Hot Tumors in Bladder Urothelial Carcinoma Based on Necroptosis-Associated lncRNAs

“…In ROC curves of risk scores and traditional clinical factors, the area of risk scores under the ROC curve was higher than our conventional clinical indicators. Compared with current models, such as model of N6-methylandenosine-related lncRNAs, our model predicts 1, 3, and 5-year survival rates with higher accuracy than N6-methylandenosine-related lncRNAs model ( 22 ). All of these results showed the rationality and superiority of our 7 lncRNAs model.…”

Construction and verification of a novel hypoxia-related lncRNA signature related with survival outcomes and immune microenvironment of bladder urothelial carcinoma by weighted gene co-expression network analysis

“…M6A is the most common internal RNA modification in several species ( Jia et al, 2011 ). The m6A lncRNA alteration and its involvement in BLCA patients are rarely reported ( Zhang et al, 2021b ). Zhou et al (2021) reported that FTO promoted tumor development in BLCA via the FTO/miR-576/CDK6 axis in an m6A-dependent manner.…”

Methyladenosine Modification in RNAs: From Regulatory Roles to Therapeutic Implications in Cancer

“…Conversely, downregulation of METTL14 in rectal cancer is correlated with poor outcome in patients [112]. When it comes to lower-grade glioma, lung adenocarcinoma, breast cancer, and bladder cancer, risk models including m 6 A-mediated lncRNAs were built, revealing an effective value in predicting the prognoses [113][114][115][116]. More recently, Shen et al, conducted comprehensive analyses for the predictive value of 23 m 6 A regulators and 83 mRNAs and noncoding RNAs among 9804 pan-cancer samples [117].…”