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Biochem Biophys Res Commun. 2018 Jul 2;501(4):885-892. doi: 10.1016/j.bbrc.2018.05.069. Epub 2018 May 19.

MiR-216a-5p/Hexokinase 2 axis regulates uveal melanoma growth through modulation of Warburg effect.

Author information

1
Department of Ophthalmology, Chinese PLA General Hospital, Beijing, 100853, China; School of Medicine, Nankai University, Tianjin, 300071, China; Department of Ophthalmology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, China. Electronic address: liuying5322@163.com.
2
Department of Ophthalmology, Chinese PLA General Hospital, Beijing, 100853, China.
3
Department of Pathology, 307 PLA Hospital, Beijing, 100853, China.
4
Department of Pathology, Chinese PLA General Hospital, Beijing, 100853, China.
5
Department of Ophthalmology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, China.
6
Department of Radiology, Affiliated Hospital of Guizhou Medical University, Guiyang, PR China.
7
Department of Oncology, The General Hospital of the PLA Rocket Force, Beijing, 100088, China. Electronic address: zhao.wei@stu.xjtu.edu.cn.
8
Department of Oncology, Chinese PLA General Hospital, Beijing, 100853, China. Electronic address: dunan05@yahoo.com.cn.
9
Department of Ophthalmology, Chinese PLA General Hospital, Beijing, 100853, China. Electronic address: 301yk@sina.com.

Abstract

Hexokinase-2 (HK2), the initial as well as the rate-limiting step in glycolysis, is overexpressed in many human cancers, and correlates with poor clinical outcomes. Aerobic glycolysis is a hallmark of cancer, and drugs targeting its enzymes, including HK2, are being developed. However, the mechanisms of HK2 inhibition and the physiological significance of the HK2 inhibitors in cancer cells are rarely reported. Here, we show that microRNA-216a-5p (miR-216a-5p) inhibits HK2 expression by directly targeting its 3'-UTR in uveal melanoma cells. Through inhibition of HK2, miR-216a-5p dampens glycolysis by reducing HK activity, glucose uptake, lactate production, ATP generation, extracellular acidification rate (ECAR), and increasing oxygen consumption rate (OCR) in uveal melanoma cells. Importantly, glycolysis regulated by miR-216a-5p is critical for its regulating uveal melanoma tumor growth both in vitro and in vivo. miR-216a-5p expression is negatively correlated with HK2 expression and predicts better outcome in uveal melanoma patients. Our findings provide clues regarding the role of miR-216a-5p as a tumor suppressor in uveal melanoma through the inhibition of HK2. Targeting HK2 through miR-216a-5p could be a promising therapeutic strategy in uveal melanoma.

KEYWORDS:

HK2; MiR-216a-5p; Uveal melanoma; Warburg effect

PMID:
29763606
DOI:
10.1016/j.bbrc.2018.05.069
[Indexed for MEDLINE]

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