Mitochondrial calcium uniporter as a target of microRNA-340 and promoter of metastasis via enhancing the Warburg effect

• Published in: Oncotarget Vol. 8; no. 48; pp. 83831 - 83844
• Main Authors: Yu, Changhui, Wang, Yuhao, Peng, Jiawen, Shen, Qiang, Chen, Mimi, Tang, Wei, Li, Xiumei, Cai, Chunqing, Wang, Bin, Cai, Shaoxi, Meng, Xiaojing, Zou, Fei
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 13-10-2017
• Subjects: Research Paper; mitochondrial calcium uniporter; breast cancer; metastasis; microRNA-340; Warburg effect
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.19747

A shift from oxygen phosphorylation to aerobic glycolysis was known as the Warburg effect and a characteristic of cancer cell metabolism facilitating metastasis. Mitochondrial calcium uniporter (MCU), a key ion channel that mediates Ca
uptake into mitochondria, was found to promote cancer progression and metastasis. However, its explicit role in shifting metabolism of breast cancer cells has not been defined.
We evaluated MCU overexpression or knock-down on migration, invasion and glucose metabolismin breast cancer cells. Mitochondrial Ca
dynamics were monitored with Rhod-2 fluorescence imaging. Luciferase reporter assay was used to confirm the interaction between miR-340 and 3'-untranslated region (3'-UTR) of
gene. Mouse models of lung metastasis were used to determine whether gain-/loss-of-MCU impacts metastasis. MCU expression was assessed in 60 tumor samples from breast cancer patients by immunohistochemistry (IHC).
Knockdown of MCU in MDA-MB-231 cells significantly reduced cell migration and invasion
and lung metastasis
; whereas overexpression of MCU in MCF-7 cells significantly increased migration and invasion
and lung metastasis
. Overexpression of MCU promoted lung metastasis by enhancing glycolysis, whereas suppression of MCU abolished this effect. Moreover, a novel mechanism was identified that MCU was a direct target of microRNA-340, which suppressed breast cancer cell motility by inhibiting glycolysis. Consistently, significantly increased MCU protein was found in metastatic breast cancer patients.
We identified a novel mechanism that upregulated MCU promotes breast cancer metastasis via enhancing glycolysis, and that this process is posttranscriptionally and negatively regulated by microRNA-340.