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Mitochondrial calcium uniporter as a target of microRNA-340 and promoter of metastasis via enhancing the Warburg effect
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 Ca(2+) uptake into mitochondria, was found to promote c...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663558/ https://www.ncbi.nlm.nih.gov/pubmed/29137386 http://dx.doi.org/10.18632/oncotarget.19747 |
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author | Yu, Changhui Wang, Yuhao Peng, Jiawen Shen, Qiang Chen, Mimi Tang, Wei Li, Xiumei Cai, Chunqing Wang, Bin Cai, Shaoxi Meng, Xiaojing Zou, Fei |
author_facet | Yu, Changhui Wang, Yuhao Peng, Jiawen Shen, Qiang Chen, Mimi Tang, Wei Li, Xiumei Cai, Chunqing Wang, Bin Cai, Shaoxi Meng, Xiaojing Zou, Fei |
author_sort | Yu, Changhui |
collection | PubMed |
description | 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 Ca(2+) 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 Ca(2+) 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. |
format | Online Article Text |
id | pubmed-5663558 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-56635582017-11-13 Mitochondrial calcium uniporter as a target of microRNA-340 and promoter of metastasis via enhancing the Warburg effect Yu, Changhui Wang, Yuhao Peng, Jiawen Shen, Qiang Chen, Mimi Tang, Wei Li, Xiumei Cai, Chunqing Wang, Bin Cai, Shaoxi Meng, Xiaojing Zou, Fei Oncotarget Research Paper 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 Ca(2+) 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 Ca(2+) 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. Impact Journals LLC 2017-07-31 /pmc/articles/PMC5663558/ /pubmed/29137386 http://dx.doi.org/10.18632/oncotarget.19747 Text en Copyright: © 2017 Yu et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Yu, Changhui Wang, Yuhao Peng, Jiawen Shen, Qiang Chen, Mimi Tang, Wei Li, Xiumei Cai, Chunqing Wang, Bin Cai, Shaoxi Meng, Xiaojing Zou, Fei Mitochondrial calcium uniporter as a target of microRNA-340 and promoter of metastasis via enhancing the Warburg effect |
title | Mitochondrial calcium uniporter as a target of microRNA-340 and promoter of metastasis via enhancing the Warburg effect |
title_full | Mitochondrial calcium uniporter as a target of microRNA-340 and promoter of metastasis via enhancing the Warburg effect |
title_fullStr | Mitochondrial calcium uniporter as a target of microRNA-340 and promoter of metastasis via enhancing the Warburg effect |
title_full_unstemmed | Mitochondrial calcium uniporter as a target of microRNA-340 and promoter of metastasis via enhancing the Warburg effect |
title_short | Mitochondrial calcium uniporter as a target of microRNA-340 and promoter of metastasis via enhancing the Warburg effect |
title_sort | mitochondrial calcium uniporter as a target of microrna-340 and promoter of metastasis via enhancing the warburg effect |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663558/ https://www.ncbi.nlm.nih.gov/pubmed/29137386 http://dx.doi.org/10.18632/oncotarget.19747 |
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