MicroRNA-18a-5p regulates the Warburg effect by targeting hypoxia-inducible factor 1α in the K562/ADM cell line

Kun Wu; Chong Guo; Yixun Li; Jinrong Yang; Qiang Zhou; Shenju Cheng; Yanhong Li; Bo Nie; Yun Zeng

doi:10.3892/etm.2021.10503

MicroRNA-18a-5p regulates the Warburg effect by targeting hypoxia-inducible factor 1α in the K562/ADM cell line

Exp Ther Med. 2021 Oct;22(4):1069. doi: 10.3892/etm.2021.10503. Epub 2021 Jul 28.

Authors

Kun Wu^{1

2

3}, Chong Guo^{1

2

3}, Yixun Li^{1

2

3}, Jinrong Yang^{4

5}, Qiang Zhou^{4

5}, Shenju Cheng^{1

2

3}, Yanhong Li^{1

2

3}, Bo Nie^{4

5}, Yun Zeng^{4

5}

Affiliations

¹ Department of Clinical Laboratory, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.
² Yunnan Key Laboratory of Laboratory Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.
³ Yunnan Innovation Team of Clinical Laboratory and Diagnosis, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.
⁴ Department of Hematology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.
⁵ Hematology Research Center of Yunnan Province, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.

Abstract

The Warburg effect is involved in drug resistance and recurrence of cancer, and poses a challenge for the treatment of chronic myelogenous leukemia (CML). Hypoxia-inducible factor 1α (HIF-1α) plays a key role in the Warburg effect. microRNAs (miRs) targeting HIF-1α have potential of regulating such aberrant metabolic process. The present study demonstrated that miR-18a-5p was expressed at a low level in K562/ADM cells via reverse transcription-quantitative PCR (RT-qPCR). The results of the luciferase reporter assay indicated that miR-18a-5p could specifically bind the 3'-untranslated region of HIF-1α. Through RT-qPCR and western blotting, it was revealed that miR-18a-5p downregulated the expression of HIF-1α. By inhibiting HIF-1α, miR-18a-5p suppressed aerobic glycolysis in K562/ADM cells, according to the results produced by glucose uptake, lactate production, pyruvate level and ATP synthesis measurement, along with the results obtained from extracellular acidification rate and oxygen consumption rate assays. These results provided new evidence that miR-18a-5p may suppress the Warburg effect by targeting HIF-1α. Furthermore, via CCK-8 and flow cytometry assays, cells transfected with miR-18a-5p mimics were more sensitive to Adriamycin (AMD) compared with AMD group. Reversing the Warburg effect by miR-30a-5p might provide a potential therapeutic strategy for CML.

Keywords: chronic myelogenous leukemia; hypoxia-inducible factor 1α; microRNA-18a-5.

Grants and funding

Funding: The present study was supported by the Joint Special Fund of Yunnan Province (grant no. 2017FE468), and Health Science and Technology Program of Yunnan Province (grant nos. 2016NS047 and 2018NS0129).