Abstract
BackgroundStudies have shown that N6-methyl adenosine (m6A) plays an important role in cancer progression; however, the underlying mechanism of m6A modification in tumor microenvironment (TME) cell infiltration of bladder cancer remains unclear. This study aimed to investigate the role of m6A modification in TME cell infiltration of bladder cancer.MethodsThe RNA expression profile and clinical data of bladder cancer were obtained from The Cancer Genome Atlas and Gene Expression Omnibus. We assessed the m6A modification patterns of 664 bladder cancer samples based on 20 m6A regulators through unsupervised clustering analysis and systematically linked m6A modification patterns to TME cell infiltration characteristics. Gene ontology and gene set variation analyses were conducted to analyze the underlying mechanism based on the assessment of m6A methylation regulators. Principal component analysis was used to construct the m6A score to quantify m6A modification patterns of bladder cancer.ResultsThe genetic and expression alterations in m6A regulators were highly heterogeneous between normal and bladder tissues. Three m6A modification patterns were identified. The cell infiltration characteristics were highly consistent with the three immune phenotypes, including immune rejection, immune inflammation, and immune desert. The biological functions of three m6A modification patterns were different. Cox regression analyses revealed that the m6A score was an independent signature with patient prognosis (HR = 1.198, 95% CI: 1.031–1.390). Patients with a low-m6A score were characterized by increased tumor mutation burden, PD-L1 expression, and poorer survival. Patients in the low-m6A score group also showed significant immune responses and clinical benefits in the CTLA-4 immunotherapy cohort (p =0.0069).ConclusionsThe m6A methylation modification was related to the formation of TME heterogeneity and complexity. Assessing the m6A modification pattern of individual bladder cancer will improve the understanding of TME infiltration characteristics.
Highlights
Post-transcriptional modification is an important regulatory step in many physiological and disease progressions
The m6A-related gene difference analysis between normal samples and tumor samples indicated that copy number variation (CNV) mutations may be significantly related to m6A modulator expression disorder
We developed an m6 score based on the m6Arelated signature to quantify the m6A modification patterns in individual bladder cancer patients
Summary
Post-transcriptional modification is an important regulatory step in many physiological and disease progressions. N6-methyl adenosine (m6A), one of the most abundant modifications in eukaryotic cells, has been identified as a post-transcriptional regulatory factor in various types of RNA, including messenger RNA, microRNA, and long non-coding RNA. It is considered to be the most common RNA molecule with abundant modifications and plays an important role in the development of tumors [2]. The m6A regulatory factor is closely related to the activity of the urinary system tumor-related signaling pathways [6]; exploring the relationship between m6A regulatory molecules and target gene RNA modification will help in understanding the mechanism behind the occurrence and development of bladder cancer. Studies have shown that N6-methyl adenosine (m6A) plays an important role in cancer progression; the underlying mechanism of m6A modification in tumor microenvironment (TME) cell infiltration of bladder cancer remains unclear. This study aimed to investigate the role of m6A modification in TME cell infiltration of bladder cancer
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