Exosomal microRNA-503-3p derived from macrophages represses glycolysis and promotes mitochondrial oxidative phosphorylation in breast cancer cells by elevating DACT2

Shulin Huang,Chaojie Zhang,Peizhi Fan,Shanshan Lei,Xiaowen Gu,Zhongcheng Huang,Jing Xie,Zihua Chen

doi:10.1038/s41420-021-00492-2

Abstract

MicroRNAs (miRNAs) are emerging drivers in tumor progression, while the role of miR-503-3p in breast cancer (BC) remains largely unknown. We aimed to explore the impact of macrophage-derived exosomal miR-503-3p in the development of BC by regulating disheveled-associated binding antagonist of beta-catenin 2 (DACT2). miR-503-3p and DACT2 expression in BC tissues and cells was assessed, and the expression of Wnt/β-catenin signaling pathway-related proteins in BC cells was also evaluated. Macrophages were induced and exosomes were extracted. The screened BC cell lines were, respectively, treated with exosomes, miR-503-3p inhibitor/mimic or upregulated/inhibited DACT2, and then the phenotypes, glucose intake, oxygen consumption rate, and adenosine-triphosphate (ATP) level of BC cells were determined. Cell growth in vivo was also observed. MiR-503-3p was elevated, DACT2 was reduced, and Wnt/β-catenin signaling pathway was activated in BC cells. Macrophage-derived exosomes, upregulated miR-503-3p or inhibited DACT2 promoted malignant behaviors of BC cells, glucose intake, and activity of the Wnt/β-catenin signaling pathway, while repressed oxygen consumption rate and ATP level in BC cells. Reversely, reduced miR-503-3p or upregulated DACT2 exerted opposite effects. This study revealed that reduction of macrophage-derived exosomal miR-503-3p repressed glycolysis and promoted mitochondrial oxidative phosphorylation in BC by elevating DACT2 and inactivating Wnt/β-catenin signaling pathway. Our research may provide novel targets for BC treatment.

Highlights

Breast cancer (BC) is the most common malignancy in women and is a main cause of death
MiR-503-3p and disheveled-associated binding antagonist of beta-catenin 2 (DACT2) expression in breast cancer (BC) and normal tissues were determined using Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and it came out that (Fig. 1A, B) miR-503-3p expression was increased while DACT2 mRNA expression was decreased in BC tissues versus the normal mammary epithelial tissues
Outcomes of dual-luciferase reporter gene assay reflected that (Fig. 2B) cells that had been co-transfected with DACT2-wild type (WT) and miR-503-3p mimic had a decreased luciferase activity (P < 0.05); the co-transfection of DACT2-mutant type (MUT) and miR503-3p mimic did not influence the luciferase activity (P > 0.05), indicating that DACT2 was a direct target of miR503-3p

Summary

Introduction

Breast cancer (BC) is the most common malignancy in women and is a main cause of death. There were 1.6 million cases diagnosed with BC in the world every year[1]. Patients with early and advanced-stage BC are treated with surgery combined with radiotherapy and chemotherapy. The prognosis of most patients to some chemotherapy drugs is poor because of multidrug resistance[5]. Novel biomarkers of BC remain to be explored. Exosomes derived from differentially activated macrophages have been reported to affect dormancy or resurgence

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