Cancer Cells’ Metabolism Dynamics in Renal Cell Carcinoma Patients’ Outcome: Influence of GLUT-1-Related hsa-miR-144 and hsa-miR-186

Abstract

Simple Summary Renal cell carcinoma (RCC) is a metabolic associated cancer and the most common and lethal neoplasia in the adult kidney. This study aimed to understand the potential role of hsa-miR-144-5p and hsa-miR-186-3p (which target Glucose Transporter 1—GLUT-1) in clear cell RCC (ccRCC) glycolysis status, as well as their potential as biomarkers. A decrease of intracellular levels of these miRNAs and increase of their excretion was associated with an increase of GLUT-1’s levels and glycolysis’ markers. RCC patients presented higher plasmatic levels of hsa-miR-186-3p than healthy individuals and hsa-miR144-5p’s higher levels were associated with early clinical stages of RCC. Additionally, patients with low plasmatic levels of hsa-miR-144-5p and high plasmatic levels of hsa-miR-186-3p (high-risk group) showed a worse overall survival. Overall, these results indicate that circulating hsa-miR-144-5p and hsa-miR-186-3p may be potential biomarkers of ccRCC prognosis. Abstract The cancer cells’ metabolism is altered due to deregulation of key proteins, including glucose transporter 1 (GLUT-1), whose mRNA levels are influenced by microRNAs (miRNAs). Renal cell carcinoma (RCC) is the most common and lethal neoplasia in the adult kidney, mostly due to the lack of accurate diagnosis and follow-up biomarkers. Being a metabolic associated cancer, this study aimed to understand the hsa-miR-144-5p and hsa-miR-186-3p’s potential as biomarkers of clear cell RCC (ccRCC), establishing their role in its glycolysis status. Using three ccRCC lines, the intra- and extracellular levels of both miRNAs, GLUT-1’s mRNA expression and protein levels were assessed. Glucose consumption and lactate production were evaluated as glycolysis markers. A decrease of intracellular levels of these miRNAs and increase of their excretion was observed, associated with an increase of GLUT-1’s levels and glycolysis’ markers. Through a liquid biopsy approach, we found that RCC patients present higher plasmatic levels of hsa-miR-186-3p than healthy individuals. The Hsa-miR144-5p’s higher levels were associated with early clinical stages. When patients were stratified according to miRNAs plasmatic levels, low plasmatic levels of hsa-miR-144-5p and high plasmatic levels of hsa-miR-186-3p (high-risk group) showed the worst overall survival. Thus, circulating levels of these miRNAs may be potential biomarkers of ccRCC prognosis.