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.
Highlights
MicroRNAs are small non-coding RNAs of approximately 22 nucleotides in size that are related to critical regulatory functions in a plethora of biological processes, associated with healthy and dysfunctional physiological states [1, 2]
To explore the possible interaction between miRNAs and mRNAs of metabolic genes in cancer, we carried out a Multicellular Tumor Spheroids (MCTS) culture with the breast cancer cell line MCF7
We mainly used the human luminal A (ER+, PR+, HER2-) cell line due to its high incidence in women breast cancer patients worldwide [20]. In this MCTS model, MCF7 cell suspension was loaded on non-adherent plates to stimulate cell-cell adhesion and promote well-rounded spherical structures
Summary
MicroRNAs (miRNAs) are small non-coding RNAs of approximately 22 nucleotides in size that are related to critical regulatory functions in a plethora of biological processes, associated with healthy and dysfunctional physiological states [1, 2]. The most common and well-documented functions of miRNAs are to be endogenous negative regulators of the translation and contribute to the mRNAs instability This regulatory capacity is carried out through direct base pairing to the target sites in the 3′ untranslated regions of an mRNA [3]. There are more than 1,900 mature human miRNAs according to the latest build (build 22) of the Sanger Centre miRNA database miRBase (http:// www.mirbase.org). To highlight their regulatory relevance, last estimations suggest that this set of miRNAs target at least 60% of human mRNAs [4]. MiRNAs have surged as crucial post-transcriptional regulators whose dysregulation can be tightly associated with aberrant gene expression in complex human diseases such as cancer [5]
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