Haiying Shen , Junjie Nie , Xiaojun Wang , Guangqing Li , Liwei Zhao , Yuji Jin , Lianhai Jin
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引用次数: 0
Abstract
Background
Mitochondrial ORF of the 12S rRNA type-c (MOTS-c) as an AMPK agonist can regulate the expression of adaptive nuclear genes to promote cell homeostasis. However, the investigation of MOTS-c in hepatocellular carcinoma (HCC) is insufficient. This study aims to reveal the role of MOTS-c on HCC cell apoptosis.
Methods
Huh7 and HCCLM3 cells were incubated with MOTS-c under a hypoxic condition. MOTS-c levels were quantified by enzyme-linked immunosorbent assay in the peripheral blood of HCC patients and healthy controls. Cell viability was detected by 3-(4,5-Dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell apoptosis was investigated by flow cytometry and Tunel assay. Protein expression was detected by western blotting or immunohistochemistry assay. Dual-luciferase reporter assay and chromatin immunoprecipitation assay were performed to identify the association among myocyte enhancer factor 2A (MEF2A), death receptor 4 (DR4) and DR5. A tumor-bearing nude mouse model was conducted to assess the effect of MOTS-c on HCC tumor formation in vivo.
Results
MOTS-c levels in the peripheral blood of HCC patients were significantly lower compared to healthy individuals. MOTS-c promoted HCC cell apoptosis under hypoxia conditions. Hypoxia stimulation decreased the protein expression of MEF2A, DR4, DR5, fas-associating via death domain (FADD) and caspase-8, while these effects were attenuated after MOTS-c treatment. MOTS-c induced TRAIL-induced apoptosis of HCC cells by activating MEF2A through the phosphorylation of AMPK under hypoxia treatment. In addition, MEF2A transcriptionally up-regulated DR4 and DR5. MOTS-c activated MEF2A to regulate DR4 and DR5 expression, further mediating TRAIL-induced apoptosis. Further, MOTS-c treatment relieved hypoxia-induced tumor growth in vivo.
Conclusion
MOTS-c relieved hypoxia-induced HCC cell resistance to TRAIL-caused apoptosis by activating MEF2A.
期刊介绍：
Our scope includes but is not limited to areas such as: Chromosome biology; Chromatin and epigenetics; DNA repair; Gene regulation; Nuclear import-export; RNA processing; Non-coding RNAs; Organelle biology; The cytoskeleton; Intracellular trafficking; Cell-cell and cell-matrix interactions; Cell motility and migration; Cell proliferation; Cellular differentiation; Signal transduction; Programmed cell death.
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