Research Papers:
Mitochondrial calcium uniporter as a target of microRNA-340 and promoter of metastasis via enhancing the Warburg effect
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Abstract
Changhui Yu1,2, Yuhao Wang1, Jiawen Peng1, Qiang Shen3, Mimi Chen1, Wei Tang1, Xiumei Li4, Chunqing Cai1, Bin Wang1, Shaoxi Cai2, Xiaojing Meng1 and Fei Zou1
1Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
2Department of Respiratory and Critical Care Medicine, Chronic Airways Diseases Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou, China
3Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, U.S.A
4Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
Correspondence to:
Xiaojing Meng, email: [email protected]
Fei Zou, email: [email protected]
Keywords: breast cancer, metastasis, Warburg effect, mitochondrial calcium uniporter, microRNA-340
Received: March 26, 2017 Accepted: June 19, 2017 Published: July 31, 2017
ABSTRACT
Background: 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 Ca2+ 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.
Methods: We evaluated MCU overexpression or knock-down on migration, invasion and glucose metabolismin breast cancer cells. Mitochondrial Ca2+ 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 MCU 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).
Results: Knockdown of MCU in MDA-MB-231 cells significantly reduced cell migration and invasion in vitro and lung metastasis in vivo; whereas overexpression of MCU in MCF-7 cells significantly increased migration and invasion in vitro and lung metastasis in vivo. 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.
Conclusions: 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.
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