MicroRNAs Regulate Metabolic Phenotypes During Multicellular Tumor Spheroids Progression

Abstract

During tumor progression, cancer cells rewire their metabolism to face their bioenergetic demands. In recent years, microRNAs (miRNAs) have emerged as regulatory elements that inhibit the translation and stability of crucial mRNAs, some of them causing direct metabolic alterations in cancer. In this study, we investigated the relationship between miRNAs and their targets mRNAs that control metabolism, and how this fine-tuned regulation is diversified depending on the tumor stage. To do so, we implemented a paired analysis of RNA-seq and small RNA-seq in a breast cancer cell line (MCF7). The cell line was cultured in multicellular tumor spheroid (MCTS) and monoculture conditions. For MCTS, we selected two-time points during their development to recapitulate a proliferative and quiescent stage and contrast their miRNA and mRNA expression patterns associated with metabolism. As a result, we identified a set of new direct putative regulatory interactions between miRNAs and metabolic mRNAs representative for proliferative and quiescent stages. Notably, our study allows us to suggest that miR-3143 regulates the carbon metabolism by targeting hexokinase-2. Also, we found that the overexpression of several miRNAs could directly overturn the expression of mRNAs that control glycerophospholipid and N-Glycan metabolism. While this set of miRNAs downregulates their expression in the quiescent stage, the same set is upregulated in proliferative stages. This last finding suggests an additional metabolic switch of the above mentioned metabolic pathways between the quiescent and proliferative stages. Our results contribute to a better understanding of how miRNAs modulate the metabolic landscape in breast cancer MCTS, which eventually will help to design new strategies to mitigate cancer phenotype.

Recent insights into the effects of metabolism on breast cancer cell dormancy

“…miRs have also been implicated in BC metabolic changes, through their regulation of key mRNAs involved in metabolism. A recent study by Muciño-Olmos et al identified regulatory interactions between miRs and metabolic mRNAs representative for proliferative and quiescent BC phenotypes [ 31 ]. The miR and mRNA expression patterns of three-dimensional (3D) spheroid cultures of the BC cell line MCF7 (ER+) were compared.…”

“…1a ). While these miR sets caused downregulation in the quiescent BCC models, the same sets were upregulated in their proliferative BC model, further suggesting a metabolic switch in the miRNA BC landscape which directly affects glycerophospholipid, N-Glycan and glucose metabolism [ 31 ].…”

“…1a ). Conversely, their dormant model showed that the overexpression of these miRs could downregulate amino acid synthesis, causing a dependence on glycolysis and lipid metabolism [ 31 ]. Thereby, this study suggests that lipid metabolism and glycolysis are associated with a shift in BCCs towards quiescence.…”

Extracellular vesicle cargo metabolome changes in response to the mesenchymal stromal cell microenvironment and influences cell quiescence and activation in a human breast cancer cell model

“…Yet, research into the metabolic properties of dormant BCCs is limited, and the studies performed to date are contradictory (35). For example, several reports have concluded that a shift in BCCs towards glycolysis is responsible for BCC dormancy, whereas others have reported that a BCC shift towards OXPHOS induces dormancy (35,(67)(68)(69)(70). Notably, none of these studies explained a metabolic mechanism for BCC recurrence.…”

Differential Expression of Serum Proinflammatory Cytokine TNF-α and Genetic Determinants of TNF-α, CYP2C19*17, miR-423 Genes and Their Effect on Coronary Artery Disease Predisposition and Progression

“…This binding causes suppression of translation and mRNA degradation of the target genes [17]. MicroRNAs regulate the genes involved in important physiological processes such as metabolism, cell division, differentiation, and apoptosis [18,19]. MiR-423-5p is found on chromosome 17 [20]; it regulates insulin receptor substrates 2 and Phosphoinositide-3-Kinase Regulatory Subunit 3 PIK3R3 gene and, therefore, may be involved glucose and lipid metabolism [21].…”