Deregulation mechanisms and therapeutic opportunities of p53-responsive microRNAs in diffuse large B-cell lymphoma

Abstract

Here, we have discussed the molecular mechanisms of p53-responsive microRNAs dysregulation in response to genotoxic stress in diffuse large B-cell lymphoma (DLBCL) patients. The role of micro ribonucleic acids (microRNAs) in p53-signaling cellular stress has been studied. MicroRNAs are the small non-coding RNAs, which regulate genes expression at post-transcriptional level. Many of them play a crucial role in carcinogenesis and may act as oncogenes or suppressor of tumor growth. The understanding of the effect of p53-responsive microRNA dysregulation on oncogenesis achieved in recent decades opens wide opportunities for the diagnosis, prediction and of microRNA-based cancer therapy. Development of new bioinformatics tools and databases for microRNA supports DLBCL research. We overview the studies on the role of miRNAs in regulating gene expression associated with tumorigenesis processes, with particular emphasis on their role as tumor growth-suppressing factors. The starting point is a brief description of the classical microRNA biogenesis pathway and the role of p53 in regulating the expression of these molecules. We analyze various molecular mechanisms leading to this dysregulation, including mutations in the TP53 gene, DNA methylation, changes in host-genes expression or microRNA gene copy number, mutations in microRNA and microRNA biogenesis genes.

Keywords: Diffuse Large B-cell Lymphoma (DLBCL); Gene expression; microRNA regulation; microRNA-based cancer therapy; p53 response elements.

Figure 1. Somatic mutations in the TP53 gene in DLBCL.

(A) Distribution and characteristics of mutations in the TP53 gene in DLBCL according to the results of next generation sequencing (NGS) analysis of 1,295 samples presented in the cBioPortal for Cancer Genomics database (Gao et al., 2013); (B) impaired maturation of pri-miRNA to pre-miRNA in the case of mutations in codons 135, 175, 248 and 273, which are mutation hotspots in the TP53 gene.

Figure 2. Disturbance of genome copy number in the loci of p53-responsive microRNA genes.

(A) The frequency of detected chromosomal abnormalities (monosomies and deletions of microRNA gene loci) according to a classic cytogenetic study of 1,612 DLBCL samples with cytogenetic defects presented in the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer (Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer, 2024) (B) Cases with decrease in genome copy number in the loci of p53-responsive microRNA genes (rose color) presented in the cBioPortal for Cancer Genomics database (Gao et al., 2013).

Figure 3. Spectrum and frequency of detected aberrations in microRNA biogenesis genes according to the analysis of 1295 DLBCL samples presented in the cBioPortal for Cancer Genomics database (Gao et al., 2013).