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

Abstract

BackgroundA 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.MethodsWe 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).ResultsKnockdown 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.ConclusionsWe 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.

Comparative mitochondrial proteomic analysis of human large cell lung cancer cell lines with different metastasis potential

“…We also demonstrated that transfection of wild type nm23‐H1 complementary DNA (cDNA) into human high‐metastatic large cell lung cancer cells (which exhibit loss of heterozygosity [LOH] of nm23‐H1 ), can regulate the expression of metastatic relative genes and reverse the metastatic phenotype of lung cancer cell lines . Our findings and other reports have provided sufficient evidence to indicate that nm23‐H1 is a metastasis suppressor gene in many tumors . Our studies have also proven that the nm23‐H1 gene is a key and upstream regulative gene in the “lung cancer metastatic suppressive cascade.” However, the exact molecular mechanism by which nm23‐H1 suppresses or reverses lung cancer metastasis is unclear.…”

“…[23][24][25][26][27][28][29][30] Our findings and other reports have provided sufficient evidence to indicate that nm23-H1 is a metastasis suppressor gene in many tumors. [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] Our studies have also proven that the nm23-H1 gene is a key and upstream regulative gene in the "lung cancer metastatic suppressive cascade." [23][24][25][26][27][28][29][30][31][32][33] However, the exact molecular mechanism by which nm23-H1 suppresses or reverses lung cancer metastasis is unclear.…”

“…Lung cancer metastasis is not only the malignant marker but is the main cause of treatment failure . Metastasis is a complex biological behavior that is correlated with many factors, genes, signal pathways, and biological processes . Therefore, exploration of changes to molecular genetics and cell signal transduction related to invasion and metastasis in lung cancer will not only illuminate the molecular mechanisms of tumor invasion and metastasis, but also provide a new targeting molecule and route for blocking signal transduction and reversing the metastatic phenotype of lung cancer .…”

“…[16][17][18][19][20] Metastasis is a complex biological behavior that is correlated with many factors, genes, signal pathways, and biological processes. [21][22][23][24][25][26] Therefore, exploration of changes to molecular genetics and cell signal transduction related to invasion and metastasis in lung cancer will not only illuminate the molecular mechanisms of tumor invasion and metastasis, but also provide a new targeting molecule and route for blocking signal transduction and reversing the metastatic phenotype of lung cancer. [27][28][29][30][31][32] Our previous studies showed that low expression and hetero-deletion of tumor metastasis suppressor gene nm23-H1 are closely correlated with high metastatic ability and poor prognosis in lung cancer patients.…”

Progress in understanding mitochondrial calcium uniporter complex‐mediated calcium signalling: A potential target for cancer treatment

“…Certain MCU-dependent pro-oncogenic events are thought to be more sensitive to mitoxantrone, such as the increased metastatic abilities of MCF-7 cells and HCC cells, as well as the MCU-dependent chemotherapy resistance in multiple myeloma cells (Arduino et al, 2017;Ren et al, 2017;Song et al, 2013;Yu et al, 2017). Certain MCU-dependent pro-oncogenic events are thought to be more sensitive to mitoxantrone, such as the increased metastatic abilities of MCF-7 cells and HCC cells, as well as the MCU-dependent chemotherapy resistance in multiple myeloma cells (Arduino et al, 2017;Ren et al, 2017;Song et al, 2013;Yu et al, 2017).…”