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Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Oncotarget 2017 ; 8 (48): 83831-44 Nephropedia Template TP
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Mitochondrial calcium uniporter as a target of microRNA-340 and promoter of metastasis via enhancing the Warburg effect #MMPMID29137386
Yu C; Wang Y; Peng J; Shen Q; Chen M; Tang W; Li X; Cai C; Wang B; Cai S; Meng X; Zou F
Oncotarget 2017[Oct]; 8 (48): 83831-44 PMID29137386show ga
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.