期刊
CELL DEATH & DISEASE
卷 9, 期 -, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41419-018-0616-8
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资金
- National Natural Science Foundation of China [81270553, 81300363, 81521004, 81572262]
- Fund of State Key Laboratory of Reproductive Medicine, Nanjing Medical University [SKLRM-K201706]
- Jiangsu Youth Medical Talents [QNRC2016580]
- Natural Science Foundation of Jiangsu Province [BK20131023, BK20151583]
- Six Talents Peak Project of Jiangsu Province [2014-wsw-004, 2013-wsn-032]
- Jiangsu Province's Key Provincial Talents Program [ZDRCA2016028]
- 333 High Class Talented Man Project [BRA2016516]
- Major Program of Science and Technology Innovation Fund of Nanjing Medical University [2017NJMUCX005]
Glucose metabolic reprogramming from oxidative to aerobic glycolysis, referred as the Warburg effect, is a hallmark of tumor cells Accumulating evidence suggests that a subset of microRNAs play pivotal roles in modulating such reprogramming of glucose metabolism in cancer cells miR-3662 has been implicated previously in both pro tumorigenic and anti tumorigenic effects in several types of cancer The expression level of miR -3662 is downregulated in acute myeloid leukemia, whereas increased miR-3662 expression is observed in lung adenocarcinoma. However, the roles and underlying mechanisms of miR-3662 in hepatocellular carcinoma (HCC) metabolic reprogramming remain unclear Our present study revealed that miR-3662 was frequently downregulated in HCC tissues and cell lines The low expression level of miR-3662 was associated with tumor size, tumor multiplicity, Edmondson grade, and tumor node metastasis stage Gain of function and loss of function assays showed that miR -3662 dampened glycolysis by reducing lactate production, glucose consumption, cellular glucose 6 phosphate level, ATP generation, and extracellular acidification rate, and increasing oxygen consumption rate in HCC cells after treatment with the hypoxia mimetic CoCl2 Moreover, miR-3662 suppressed cell growth in vitro and in vivo, and induced G1/S cell cycle arrest miR-3662 inhibited the activation of ERK and JNK signaling pathways in HCC By combined computational and experimental approaches, hypoxia inducible factor la (HIF l alpha) was determined as a direct target of miR -3662 After treatment with the hypoxia mimetic CoCl2, miR-3662 regulated the Warburg effect and HCC progression via decreasing HIF 1-alpha expression Our findings uncover a mechanistic role for miR 3662/HIF 1-1 alpha axis in HCC metabolic reprogramming, providing a potential therapeutic strategy in liver cancer.
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