Pan-Cancer Analyses Identify the RRM2 Gene as a Biomarker with Diagnostic and Prognostic Roles in Multiple Human Cancers via Interactions with the hsa-let-7a-5p miRNA and EZH2

Abstract

Background: Pan-cancer research has recently been conducted to identify genomic differences in multiple cancers compared with those in normal tissues. Our aims were to determine common differentially expressed genes (DEGs) by analysing the genomes of multiple cancers and to identify common cancer biomarkers for both diagnosis and treatment by determining the effect of these commonly changed genes on survival. Methods: We performed DEG and survival analyses by considering differences in expression levels in tumour and related normal tissues using the R programme and bioinformatic webtools Gene Expression Profiling Interactive Analysis 2 (GEPIA2), UALCAN, TIMER2.0, KM-plot, ShinyGO 0.77, miRTargetLink, and CancerMIRNome. Results: In our study, 5 genes (ribonucleotide reductase regulatory subunit M2 (RRM2), enhancer of the zeste homolog 2 (EZH2), Proliferating cell nuclear antigen (PCNA) clamp associated factor (PCLAF), mitotic checkpoint serine/threonine kinase B (BUB1B), and centromere protein U (CENP-U)) were found to be upregulated in multiple cancers. Among these genes, the RRM2 gene was upregulated in more cancers and datasets. According to the gene enrichment analysis, the EZH2 gene also acted together with the RRM2 gene in terms of biological significance. Furthermore, instead of finding chemical agents that would inhibit the overexpression of both the RRM2 and EZH2 genes, miRNA screening targeting both genes were performed. As a result, hsa-let-7a-5p miRNA was found to have a strong interaction with both genes through the p53- and cell cycle-dependent pathways. Conclusion: The commonly upregulated RRM2 and EZH2 genes can be utilised as biomarkers for early diagnosis of multiple cancers. The joint interactions of the RRM2 and EZH2 genes with hsa-let-7a-5p may be a promising early treatment by inhibiting the expression levels of both genes by targeting hsa-let-7a-5p, an miRNA with low expression levels in cancers.