Abstract
Cellular senescence is a state of permanent growth arrest that arises once cells reach the limit of their proliferative capacity. It creates an inflammatory microenvironment favouring the initiation and progression of various age-related diseases, including prostate cancer. Non-coding RNAs (ncRNAs) have emerged as important regulators of cellular gene expression. Nonetheless, very little is known about the interplay of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) and how deregulation of ncRNA networks promotes cellular senescence. To investigate this, human prostate epithelial cells were cultured through different passages until senescent, and their RNA was extracted and sequenced using RNA sequencing (RNAseq) and microRNA sequencing (miRNA-seq) miRNAseq. Differential expression (DE) gene analysis was performed to compare senescent and proliferating cells with Limma, miRNA-target interactions with multiMiR, lncRNA-target interactions using TCGA data and network evaluation with miRmapper. We found that miR-335-3p, miR-543 and the lncRNAs H19 and SMIM10L2A all play central roles in the regulation of cell cycle and DNA repair processes. Expression of most genes belonging to these pathways were down-regulated by senescence. Using the concept of network centrality, we determined the top 10 miRNAs and lncRNAs, with miR-335-3p and H19 identified as the biggest hubs for miRNAs and lncRNA respectively. These ncRNAs regulate key genes belonging to pathways involved in cell senescence and prostate cancer demonstrating their central role in these processes and opening the possibility for their use as biomarkers or therapeutic targets to mitigate against prostate ageing and carcinogenesis.
Highlights
Somatic cells possess a limited proliferative capacity and after a certain number of cell divisions, they reach a state of permanent growth arrest termed cellular senescence [1]
Pathway impact analysis found that these genes mapped to gene ontology (GO) terms related to the cell cycle (Table 1 and Supplemental Table S2)
Consistent with the results described above, the majority of the ncRNA-gene interactions are concentrated in Cell Cycle arrest and the Cell Senescence pathway
Summary
Somatic cells possess a limited proliferative capacity and after a certain number of cell divisions, they reach a state of permanent growth arrest termed cellular senescence [1]. Accumulation of senescent cells is a feature observed in aged organisms and excessive buildup of these cells in tissues can cause deleterious effects on secretion, metabolism, and regenerative capacities, creating an inflammatory microenvironment that favours the initiation and progression of various age-related diseases, including cancer [1,2]. Prostate cancer is the most common cancer in males [4]. This disease has age as its most significant risk factor, with 70% to 90% of men over 80 years of age harbouring undetected foci for the disease [5]. Race represents another risk factor for prostate cancer. African American men have increased prostate cancer risk and a greater mortality rate than European-American men and have higher expression of genes associated with immune response and inflammation [6]
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