1. Downregulation of a mitochondrial micropeptide, MPM, promotes hepatoma metastasis by enhancing mitochondrial complex I activity
- Author
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Xingguo Liu, Peng-Peng Xie, Hua-Xing Chen, Jian-Hong Fang, Shi-Mei Zhuang, Yi-Fang Lin, Yu Meng, Jun-Wen Deng, Chen Xie, Na Zhao, M. Xiao, Wei Zhang, and Ying Zhu
- Subjects
Carcinoma, Hepatocellular ,Down-Regulation ,Mitochondrion ,Metastasis ,chemistry.chemical_compound ,Downregulation and upregulation ,Cell Movement ,Cell Line, Tumor ,Drug Discovery ,Genetics ,medicine ,Humans ,Gene silencing ,Neoplasm Metastasis ,Molecular Biology ,Cell Proliferation ,Pharmacology ,Nicotinamide ,Chemistry ,Liver Neoplasms ,medicine.disease ,Mitochondria ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Hepatocellular carcinoma ,Cancer research ,Molecular Medicine ,Original Article ,NAD+ kinase ,Mitochondrial Complex I - Abstract
We and others have shown that MPM (micropeptide in mitochondria) regulates myogenic differentiation and muscle development. However, the roles of MPM in cancer development remain unknown. Here we revealed that MPM was downregulated significantly in human hepatocellular carcinoma (HCC) tissues and its decrease was associated with increased metastasis potential and HCC recurrence. Gain- and loss-of-function investigations disclosed that in vitro migration/invasion and in vivo liver/lung metastasis of hepatoma cells were repressed by restoring MPM expression and increased by silencing MPM. Mechanism investigations revealed that MPM interacted with NDUFA7. Mitochondrial complex I activity was inhibited by overexpressing MPM and enhanced by siMPM, and this effect of siMPM was attenuated by knocking down NDUFA7. The NAD(+)/NADH ratio, which was regulated by complex I, was reduced by MPM but increased by siMPM. Treatment with the NAD(+) precursor nicotinamide abrogated the inhibitory effect of MPM on hepatoma cell migration. Further investigations showed that miR-17-5p bound to MPM and inhibited MPM expression. miR-17-5p upregulation was associated with MPM downregulation in HCC tissues. These findings indicate that a decrease in MPM expression may promote hepatoma metastasis by increasing mitochondrial complex I activity and the NAD(+)/NADH ratio.
- Published
- 2022