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MicroRNA-124 suppresses proliferation and glycolysis in non-small cell lung cancer cells by targeting AKT-GLUT1/HKII.

Abstract Non-small cell lung cancer accounts for 85% of all types of lung cancer and is the leading cause of worldwide cancer-associated mortalities. MiR-124 is epigenetically silenced in various types of cancer and plays important roles in tumor development and progression. MiR-124 was also significantly downregulated in non-small cell lung cancer patients. Glycolysis has been considered as a feature of cancer cells; hypoxia-inducible factor 1-alpha/beta and Akt are key enzymes in the regulation of glycolysis and energy metabolism in cancer cells. However, the role of miR-124 in non-small cell lung cancer cell proliferation, glycolysis, and energy metabolism remains unknown. In this research, cell proliferation was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; furthermore, glucose consumption and lactic acid production were assessed; adenosine triphosphate content and NAD(+)/NADH were also detected. These tests were conducted using the normal non-small cell lung cancer cell line A549, which was transfected variedly with miR-mimics, miR-124 mimics, miR-124 inhibitor, pc-DNA3.1(+)-AKT1, and pc-DNA3.1(+)-AKT2 plasmid. Here, we show that miR-124 overexpression directly decreased cell growth, glucose consumption, lactate production, and energy metabolism. MiR-124 also negatively regulates glycolysis rate-limiting enzymes, glucose transporter 1 and hexokinase II. Our results also showed that miR-124 negatively regulates AKT1 and AKT2 but no regulatory effect on hypoxia-inducible factor 1-alpha/beta. Overexpression of AKT reverses the inhibitory effect of miR-124 on cell proliferation and glycolytic metabolism in non-small cell lung cancer. AKT inhibition blocks miR-124 silencing-induced AKT1/2, glucose transporter 1, hexokinase II activation, cell proliferation, and glycolytic or energy metabolism changes. In summary, this study demonstrated that miR-124 is able to inhibit proliferation, glycolysis, and energy metabolism, potentially by targeting AKT1/2-glucose transporter 1/hexokinase II in non-small cell lung cancer cells.
PMID
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Authors

Mayor MeshTerms
Keywords

AKT1/2

Non–small cell lung cancer

glycolysis

hypoxia-inducible factor 1-alpha/beta

miR-124

Journal Title tumour biology : the journal of the international society for oncodevelopmental biology and medicine
Publication Year Start




PMID- 28488541
OWN - NLM
STAT- MEDLINE
DA  - 20170510
DCOM- 20170612
LR  - 20170612
IS  - 1423-0380 (Electronic)
IS  - 1010-4283 (Linking)
VI  - 39
IP  - 5
DP  - 2017 May
TI  - MicroRNA-124 suppresses proliferation and glycolysis in non-small cell lung
      cancer cells by targeting AKT-GLUT1/HKII.
PG  - 1010428317706215
LID - 10.1177/1010428317706215 [doi]
AB  - Non-small cell lung cancer accounts for 85% of all types of lung cancer and is
      the leading cause of worldwide cancer-associated mortalities. MiR-124 is
      epigenetically silenced in various types of cancer and plays important roles in
      tumor development and progression. MiR-124 was also significantly downregulated
      in non-small cell lung cancer patients. Glycolysis has been considered as a
      feature of cancer cells; hypoxia-inducible factor 1-alpha/beta and Akt are key
      enzymes in the regulation of glycolysis and energy metabolism in cancer cells.
      However, the role of miR-124 in non-small cell lung cancer cell proliferation,
      glycolysis, and energy metabolism remains unknown. In this research, cell
      proliferation was investigated using
      3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; furthermore,
      glucose consumption and lactic acid production were assessed; adenosine
      triphosphate content and NAD+/NADH were also detected. These tests were conducted
      using the normal non-small cell lung cancer cell line A549, which was transfected
      variedly with miR-mimics, miR-124 mimics, miR-124 inhibitor, pc-DNA3.1(+)-AKT1,
      and pc-DNA3.1(+)-AKT2 plasmid. Here, we show that miR-124 overexpression directly
      decreased cell growth, glucose consumption, lactate production, and energy
      metabolism. MiR-124 also negatively regulates glycolysis rate-limiting enzymes,
      glucose transporter 1 and hexokinase II. Our results also showed that miR-124
      negatively regulates AKT1 and AKT2 but no regulatory effect on hypoxia-inducible 
      factor 1-alpha/beta. Overexpression of AKT reverses the inhibitory effect of
      miR-124 on cell proliferation and glycolytic metabolism in non-small cell lung
      cancer. AKT inhibition blocks miR-124 silencing-induced AKT1/2, glucose
      transporter 1, hexokinase II activation, cell proliferation, and glycolytic or
      energy metabolism changes. In summary, this study demonstrated that miR-124 is
      able to inhibit proliferation, glycolysis, and energy metabolism, potentially by 
      targeting AKT1/2-glucose transporter 1/hexokinase II in non-small cell lung
      cancer cells.
FAU - Zhao, Xiaojian
AU  - Zhao X
AD  - 1 Department of Thoracic Surgery, The First Hospital of Shijiazhuang,
      Shijiazhuang, China.
FAU - Lu, Caiping
AU  - Lu C
AD  - 2 Department of Endocrinology, The First Hospital of Shijiazhuang, Shijiazhuang, 
      China.
FAU - Chu, Weiwei
AU  - Chu W
AD  - 1 Department of Thoracic Surgery, The First Hospital of Shijiazhuang,
      Shijiazhuang, China.
FAU - Zhang, Bing
AU  - Zhang B
AD  - 1 Department of Thoracic Surgery, The First Hospital of Shijiazhuang,
      Shijiazhuang, China.
FAU - Zhen, Qiang
AU  - Zhen Q
AD  - 1 Department of Thoracic Surgery, The First Hospital of Shijiazhuang,
      Shijiazhuang, China.
FAU - Wang, Renfeng
AU  - Wang R
AD  - 1 Department of Thoracic Surgery, The First Hospital of Shijiazhuang,
      Shijiazhuang, China.
FAU - Zhang, Yaxiao
AU  - Zhang Y
AD  - 1 Department of Thoracic Surgery, The First Hospital of Shijiazhuang,
      Shijiazhuang, China.
FAU - Li, Zhe
AU  - Li Z
AD  - 1 Department of Thoracic Surgery, The First Hospital of Shijiazhuang,
      Shijiazhuang, China.
FAU - Lv, Baolei
AU  - Lv B
AD  - 1 Department of Thoracic Surgery, The First Hospital of Shijiazhuang,
      Shijiazhuang, China.
FAU - Li, Huixian
AU  - Li H
AD  - 1 Department of Thoracic Surgery, The First Hospital of Shijiazhuang,
      Shijiazhuang, China.
FAU - Liu, Jiabao
AU  - Liu J
AD  - 1 Department of Thoracic Surgery, The First Hospital of Shijiazhuang,
      Shijiazhuang, China.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Tumour Biol
JT  - Tumour biology : the journal of the International Society for Oncodevelopmental
      Biology and Medicine
JID - 8409922
RN  - 0 (Glucose Transporter Type 1)
RN  - 0 (MIRN124 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (SLC2A1 protein, human)
RN  - EC 2.7.1.1 (Hexokinase)
RN  - EC 2.7.11.1 (Oncogene Protein v-akt)
SB  - IM
MH  - A549 Cells
MH  - Carcinoma, Non-Small-Cell Lung/*genetics/metabolism/pathology
MH  - Cell Proliferation/genetics
MH  - Energy Metabolism/genetics
MH  - Gene Expression Regulation, Neoplastic
MH  - Glucose Transporter Type 1/*genetics
MH  - Glycolysis/genetics
MH  - Hexokinase/*genetics
MH  - Humans
MH  - MicroRNAs/*genetics
MH  - Oncogene Protein v-akt/*genetics
OTO - NOTNLM
OT  - AKT1/2
OT  - Non-small cell lung cancer
OT  - glycolysis
OT  - hypoxia-inducible factor 1-alpha/beta
OT  - miR-124
EDAT- 2017/05/11 06:00
MHDA- 2017/06/13 06:00
CRDT- 2017/05/11 06:00
AID - 10.1177/1010428317706215 [doi]
PST - ppublish
SO  - Tumour Biol. 2017 May;39(5):1010428317706215. doi: 10.1177/1010428317706215.