MicroRNA-16-1-3p Represses Breast Tumor Growth and Metastasis by Inhibiting PGK1-Mediated Warburg Effect

Tianxing Ye,Deyu Zhang,Yingchun Liang,Xuewu Zhang

doi:10.3389/fcell.2020.615154

Tianxing Ye, Deyu Zhang + Show 2 more

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https://doi.org/10.3389/fcell.2020.615154

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Abstract

The Warburg effect (aerobic glycolysis) is a hallmark of cancer and is becoming a promising target for diagnosis and therapy. Phosphoglycerate kinase 1 (PGK1) is the first adenosine triphosphate (ATP)-generating glycolytic enzyme in the aerobic glycolysis pathway and plays an important role in cancer development and progression. However, how microRNAs (miRNAs) regulate PGK1-mediated aerobic glycolysis remains unknown. Here, we show that miR-16-1-3p inhibits PGK1 expression by directly targeting its 3′-untranslated region. Through inhibition of PGK1, miR-16-1-3p suppressed aerobic glycolysis by decreasing glucose uptake, lactate and ATP production, and extracellular acidification rate, and increasing oxygen consumption rate in breast cancer cells. Aerobic glycolysis regulated by the miR-16-1-3p/PGK1 axis is critical for modulating breast cancer cell proliferation, migration, invasion and metastasis in vitro and in vivo. In breast cancer patients, miR-16-1-3p expression is negatively correlated with PGK1 expression and breast cancer lung metastasis. Our findings provide clues regarding the role of miR-16-1-3p as a tumor suppressor in breast cancer through PGK1 suppression. Targeting PGK1 through miR-16-1-3p could be a promising strategy for breast cancer therapy.

Highlights

The Warburg effect is a phenomenon predominantly observed in tumor cells which give priority to glycolysis to provide energy even when oxygen is sufficient (Schwartz et al, 2017; Tekade and Sun, 2017; Lu, 2019; Pereira-Nunes et al, 2020)
To investigate whether the inhibitory effect of miR-16-1-3p on Phosphoglycerate kinase 1 (PGK1) was mediated through direct binding of PGK1 3 -untranslated region (UTR), ZR75-1 and MDA-MB-231 cells were transfected with wild-type PGK1 3 -UTR or mutated PGK1 3 -UTR luciferase reporter and miR-16-1-3p mimics
Overexpression of miR-16-1-3p decreased the wild-type 3 -UTR luciferase activity, but not the reporter activity of mutated 3 -UTR (Figure 1E). These results suggest that miR-16-1-3p inhibits PGK1 expression by targeting PGK1 3 -UTR

Summary

Introduction

The Warburg effect ( known as aerobic glycolysis) is a phenomenon predominantly observed in tumor cells which give priority to glycolysis to provide energy even when oxygen is sufficient (Schwartz et al, 2017; Tekade and Sun, 2017; Lu, 2019; Pereira-Nunes et al, 2020). Phosphoglycerate kinase 1 (PGK1) is one of the key enzymes in the Warburg effect (He et al, 2019; Qian et al, 2019). PGK1 catalyzes the reversible transfer of the high-energy phosphate group from 1,3-bisphosphoglycerate (1,3-BPG) to ADP, producing 3-phosphoglycerate (3-PG) and adenosine triphosphate (ATP). PGK1 promotes glucose uptake and lactate production in cancer cells. Many studies show that PGK1 is highly expressed in various

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