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Computational Analysis of N6-Methyladenosine Regulators and Long Non-Coding RNAs in Bladder Cancer - Expert Commentary

N6-methyladenine (m6A) is a frequent modification of messenger RNA (mRNA) that regulates splicing, degradation, and translation processes. In addition, long non-coding RNAs (lncRNAs), non-translated RNA molecules that act as functional proteins, also regulate gene expression. Proteins regulating m6A modification, labeled ‘writers,’ ‘readers,’ and ‘erasers,’ have been shown to interact with lncRNAs during tumor initiation and progression. However, this phenomenon is understudied in bladder cancer. A recent study by Huang et al. applied computational methods to investigate these modifications in bladder cancer samples.

The researchers collected data from The Cancer Genome Atlas (TCGA) for 408 tumor samples and 19 normal samples. Transcriptomic data revealed an association between 8 distinct m6A regulators and 79 lncRNAs, with 29 exhibiting a link to prognosis. Among these, three lncRNAs were also significantly differentially expressed between tumor and normal samples. Subsequent clustering analysis was conducted based on the expression of these three prognostic lncRNAs. Cluster 2 patients exhibited significantly lower overall survival rates and higher frequency of high-grade tumors than cluster 1 patients. Moreover, the percentage of tumor-infiltrating lymphocytes (TILs) was significantly higher in cluster 2. The immune checkpoint gene PD-L1 also exhibited significant upregulation in cluster 2.

Gene ontology analysis revealed that immune genes that were upregulated were involved in innate immune response regulation, defense response stimulation, receptor-ligand activity, and cadherin binding. Downregulated genes involved MAP kinase activity regulation, lymphocyte activation, leukocyte activation, receptor-ligand activity, and growth factor activity. Both up-and-down-regulated genes exhibited involvement in cellular components like vesicle lumen and secretory granule lumen. The main pathways affected by identified genes included proteoglycans, MAPK signaling, PI3K-Akt signaling, PD-L1 and PD-1 checkpoint pathway, and chemokine signaling. As an additional validation using immunohistochemistry, the expression levels of two proteins, HSP90AA1 and PAK2, were correlated with disease-free survival. These proteins were highly expressed in high-grade but not low-grade or normal samples. 

This study highlights the potential need for additional studies of epi transcriptomic modification and lncRNAs as prognostic biomarkers in bladder cancer.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine

References:
  1. Huang Z, Wang G, Wu Y, et al. N6-methyladenosine-related lncRNAs in combination with computational histopathology and radiomics predict the prognosis of bladder cancer. Transl Oncol. 2023;27:101581. doi:10.1016/j.tranon.2022.101581
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