Spotlight on Exosomal Non-Coding RNAs in Breast Cancer: An In Silico Analysis to Identify Potential lncRNA/circRNA-miRNA-Target Axis

Abstract

Breast cancer (BC) has recently become the most common cancer type worldwide, with metastatic disease being the main reason for disease mortality. This has brought about strategies for early detection, especially the utilization of minimally invasive biomarkers found in various bodily fluids. Exosomes have been proposed as novel extracellular vesicles, readily detectable in bodily fluids, secreted from BC-cells or BC-tumor microenvironment cells, and capable of conferring cellular signals over long distances via various cargo molecules. This cargo is composed of different biomolecules, among which are the novel non-coding genome products, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and the recently discovered circular RNA (circRNA), all of which were found to be implicated in BC pathology. In this review, the diverse roles of the ncRNA cargo of BC-derived exosomes will be discussed, shedding light on their primarily oncogenic and additionally tumor suppressor roles at different levels of BC tumor progression, and drug sensitivity/resistance, along with presenting their diagnostic, prognostic, and predictive biomarker potential. Finally, benefiting from the miRNA sponging mechanism of action of lncRNAs and circRNAs, we established an experimentally validated breast cancer exosomal non-coding RNAs-regulated target gene axis from already published exosomal ncRNAs in BC. The resulting genes, pathways, gene ontology (GO) terms, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis could be a starting point to better understand BC and may pave the way for the development of novel diagnostic and prognostic biomarkers and therapeutics.

Keywords: biomarkers; breast cancer; circular RNAs; exosomes; long non-coding RNA; microRNAs; non-coding RNA.

Figure 1

MiRNA sponging by circRNAs and lncRNAs. The central dogma proposes that protein-coding regions of the genome give rise to mRNAs, which are, in turn, translated into proteins. However, miRNAs, which are transcribed from the non-coding genome, could bind mRNAs via MREs and inhibit their translation. LncRNAs and, circRNAs, which are also transcribed from the non-coding genome, could bind and sponge miRNAs since they harbor MREs, resulting in the translation of the previously miRNA-inhibited mRNAs into proteins. MRE: MicroRNA response element. Figure was created with BioRender.com (accessed date: 24 July 2022).

Figure 2

The exosomal ncRNAs-mediated switch of BC cells from drug sensitivity to resistance. (A) Co-culture of drug-resistant with drug-sensitive cells leads to an exosomal ncRNAs-mediated switch into drug resistance. (B) Culture of drug-sensitive cells in drug-resistant BC-cells-conditioned media, which contains drug-resistant cell-secreted exosomes, leads to an exosomal ncRNAs-mediated switch into drug resistance.

Figure 3

The breast cancer exosomal lncRNA/circRNA-miRNA-target axis.

Figure 4

Strongly experimentally validated shared target genes downstream of the BC exosomal lncRNA/circRNA-miRNA-target axis. Green nodes indicate genes and blue nodes indicate miRNAs. Minimum miRNA threshold = 2.

Figure 5

Strongly and weakly experimentally validated BC-related shared target pathways downstream of the BC exosomal lncRNA/circRNA-miRNA-target axis. Orange nodes indicate pathways and blue nodes indicate miRNAs. Minimum miRNA threshold = 4. Only BC-related pathways are shown.

Figure 6

Implication of the strong experimentally validated shared target genes downstream of the BC exosomal lncRNA/circRNA-miRNA-target axis in BC KEGG pathway. Eight out of the twenty shared target genes were found to be implicated in BC KEGG pathway. Red stars indicate the shared target genes. Red font color indicates signature genetic alterations.

Figure 7

A timeline figure showing the discoveries and increase in interest reflected by the number of publications about exosomal non-coding RNAs in BC. # in the circles denotes the number of publications in PubMed per year.