Down-regulation of a mitochondrial micropeptide MPM promotes hepatoma metastasis by enhancing mitochondrial complex Ⅰ activity
Down-regulation of a mitochondrial micropeptide MPM promotes hepatoma metastasis by enhancing mitochondrial complex Ⅰ activity
复制标题
线粒体微肽 MPM 的下调通过增强线粒体复合物 I 活性促进肝癌转移
DOI：
10.1016/j.ymthe.2021.08.032
复制
发表时间：
2022
影响因子：
12.4
通讯作者：
Fang Jian-Hong（共同通讯）
中科院分区：
文献类型：
--
作者：
Xiao Man-Huan;Lin Yi-Fang;Xie Peng-Peng;Chen Hua-Xing;Deng Jun-Wen;Zhang Wei;Zhao Na;Xie Chen;Meng Yu;Liu Xingguo;Zhuang Shi-Mei（共同通讯）;Zhu Ying（共同通讯）;Fang Jian-Hong（共同通讯）
我们和其他人已经表明，MPM（线粒体中的微肽）调节肌细胞分化和肌肉发育。然而，MPM在癌症发展中的作用仍然未知。我们发现MPM在人肝细胞癌（HCC）组织中显著下调，其下调与转移潜能增加和HCC复发相关。功能获得和丧失的研究表明，肝癌细胞的体外迁移/侵袭和体内肝/肺转移通过恢复MPM表达而受到抑制，而通过沉默MPM而增加。机制研究表明，MPM与NDUFA 7相互作用。线粒体复合物I的活性被抑制过表达MPM和siMPM增强，并通过敲低NDUFA 7减弱siMPM的这种作用。NAD+/NADH比值由复合物I调节，MPM降低，而siMPM增加。用NAD+前体烟酰胺处理废除了MPM对肝癌细胞迁移的抑制作用。进一步的研究表明，miR-17- 5 p与MPM结合并抑制MPM的表达。在HCC组织中，miR-17- 5 p上调与MPM下调相关。这些发现表明MPM表达的减少可能通过增加线粒体复合物I活性和NAD+/NADH比率来促进肝癌转移。
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 thatin vitromigration/invasion andin vivoliver/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.