MicroRNA-Mediated Metabolic Reprograming in Renal Cancer.

Bogusławska Bogusławska,Głuchowska Głuchowska,Hanusek Hanusek,Piekiełko-Witkowska Piekiełko-Witkowska,Kędzierska Kędzierska,Rybicka Rybicka,Tański Tański,Alseekh Alseekh,Popławski Popławski,Koblowska Koblowska,Fernie Fernie,Iwanicka-Nowicka Iwanicka-Nowicka

doi:10.3390/cancers11121825

Abstract

Metabolic reprogramming is one of the hallmarks of renal cell cancer (RCC). We hypothesized that altered metabolism of RCC cells results from dysregulation of microRNAs targeting metabolically relevant genes. Combined large-scale transcriptomic and metabolic analysis of RCC patients tissue samples revealed a group of microRNAs that contribute to metabolic reprogramming in RCC. miRNAs expressions correlated with their predicted target genes and with gas chromatography-mass spectrometry (GC-MS) metabolome profiles of RCC tumors. Assays performed in RCC-derived cell lines showed that miR-146a-5p and miR-155-5p targeted genes of PPP (the pentose phosphate pathway) (G6PD and TKT), the TCA (tricarboxylic acid cycle) cycle (SUCLG2), and arginine metabolism (GATM), respectively. miR-106b-5p and miR-122-5p regulated the NFAT5 osmoregulatory transcription factor. Altered expressions of G6PD, TKT, SUCLG2, GATM, miR-106b-5p, miR-155-5p, and miR-342-3p correlated with poor survival of RCC patients. miR-106b-5p, miR-146a-5p, and miR-342-3p stimulated proliferation of RCC cells. The analysis involving >6000 patients revealed that miR-34a-5p, miR-106b-5p, miR-146a-5p, and miR-155-5p are PanCancer metabomiRs possibly involved in global regulation of cancer metabolism. In conclusion, we found that microRNAs upregulated in renal cancer contribute to disturbed expression of key genes involved in the regulation of RCC metabolome. miR-146a-5p and miR-155-5p emerge as a key “metabomiRs” that target genes of crucial metabolic pathways (PPP (the pentose phosphate pathway), TCA cycle, and arginine metabolism).

Highlights

Renal cell cancer (RCC) is the most common subtype of kidney malignancies, affecting 300,000 people annually worldwide [1]
We present a group of microRNAs that regulate genes involved in key metabolic pathways and contribute to enhanced proliferation of renal cancer cells
We show that microRNAs can affect the renal cell cancer (RCC) metabolome both directly and indirectly, by cooperative regulation of the expression of NFAT5, a transcription factor governing the expression of transporters that control osmolality

Summary

Introduction

Renal cell cancer (RCC) is the most common subtype of kidney malignancies, affecting 300,000 people annually worldwide [1]. Current therapeutic options include tyrosine kinase receptors inhibitors (TKIs), inhibitors of the mTOR (the mammalian target of rapamycin) pathway, or recently introduced inhibitors of immune checkpoints. All these treatments, prolong patients’ life by only up to two years [2]. Apart from changes in levels of intracellular metabolites in RCC tumors, we found significant alterations in expressions of genes encoding key metabolic pathways. The causes of these alterations remain unknown

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Discussion

Conclusion