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.
Highlights
Bladder cancer is the most common malignancy of the urinary system
Using the “gencode.v22.annotation”, we identified 14247 long non-coding RNA (lncRNA) in the The Cancer Genome Atlas (TCGA) dataset and 2322 lncRNAs in the IMvigor210 dataset
Accumulating studies have demonstrated the indispensable roles of the m6A modifications and lncRNAs in tumorigenesis and innate m6A-Related lncRNAs in Bladder Cancer immunity
Summary
Bladder cancer is the most common malignancy of the urinary system. Approximately 75% of bladder cancers are non-muscleinvasive tumors characterized by high frequency of recurrence, whereas the remaining 25% are muscle-invasive tumors characterized by poor prognosis [1]. Despite the great improvement in antitumor treatment in the past three decades, the 5-year survival rate of muscle-invasive bladder cancer remains largely unchanged [2, 3]. Immunotherapy with checkpoint inhibitors has revolutionized cancer treatment; the response rate remains unsatisfactory with only a small proportion of patients responding to this treatment [4, 5]. METTL14 has been reported to inhibit tumorigenesis through the m6A modification of Notch, inhibiting its mRNA stability in bladder cancer [12]. Studies have emerged revealing regulation of tumor microenvironment (TME), cell infiltration, immune activity, and the antitumor efficacy of immune checkpoint inhibitors through m6A modifications [13]. The relationship of m6A modification with cancer progression and immune response remains unclear in bladder cancer
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