Hypoxia-responsive miR-210 promotes self-renewal capacity of colon tumor-initiating cells by repressing ISCU and by inducing lactate production

Ullmann, Pit; Qureshi-Baig, Komal; Rodriguez, Fabien; Ginolhac, Aurélien; Nonnenmacher, Yannic; Ternes, Dominik; Weiler, Jil; Gäbler, Karoline; Bahlawane, Christelle; Hiller, Karsten; Haan, Serge; Letellier, Elisabeth

doi:10.18632/oncotarget.11772

Cited by 52 publications

(58 citation statements)

References 81 publications

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“…In vitro self-renewal and clonogenic capacity were tested with sphere and colony formation assays, as described previously (23,24). Limiting dilution assays were performed in SC conditions with different cell densities (ranging from 1 to 1,000).…”

Section: Sphere and Colony Formation Assaysmentioning

confidence: 99%

The miR-371∼373 Cluster Represses Colon Cancer Initiation and Metastatic Colonization by Inhibiting the TGFBR2/ID1 Signaling Axis

et al. 2018

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The vast majority of colorectal cancer-related deaths can be attributed to metastatic spreading of the disease. Therefore, deciphering molecular mechanisms of metastatic dissemination is a key prerequisite to improve future treatment options. With this aim, we took advantage of different colorectal cancer cell lines and recently established primary cultures enriched in colon cancer stem cells, also known as tumor-initiating cells (TIC), to identify genes and miRNAs with regulatory functions in colorectal cancer progression. We show here that metastasis-derived TICs display increased capacity for self-renewal, TGFβ signaling activity, and reduced expression of the miR-371∼373 cluster compared with nonmetastatic cultures. TGFβ receptor 2 () and aldehyde dehydrogenase A1 () were identified as important target genes of the miR-371∼373 cluster. In addition, TGFBR2 repression, either by direct knockdown or indirectly via overexpression of the entire miR-371∼373 cluster, decreased tumor-initiating potential of TICs. We observed significantly reduced self-renewal activity as well as lowered tumor initiation and metastatic outgrowth capacity following stable overexpression of the miR-371∼373 cluster in different colon TIC cultures. Inhibitor of DNA binding 1 (ID1) was affected by both TGFBR2 and miR-371∼373 cluster alterations. Functional sphere and tumor formation as well as metastatic dissemination assays validated the link between miR-371∼373 and ID1. Altogether, our results establish the miR-371∼373/TGFBR2/ID1 signaling axis as a novel regulatory mechanism of TIC self-renewal and metastatic colonization. These findings establish the miR-371∼373/TGFBR2/ID1 signaling axis as a novel mechanism regulating self-renewal of tumor-initiating cell and metastatic colonization, potentially opening new concepts for therapeutic targeting of cancer metastasis. http://cancerres.aacrjournals.org/content/canres/78/14/3793/F1.large.jpg .

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Section: Sphere and Colony Formation Assaysmentioning

confidence: 99%

The miR-371∼373 Cluster Represses Colon Cancer Initiation and Metastatic Colonization by Inhibiting the TGFBR2/ID1 Signaling Axis

et al. 2018

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“…Most studies have used a hypoxia-induced oxidative stress model to explore the effect of miR-210 on the energy metabolism shift [8, 10, 11, 29], but this study used H 2 O 2 to simulate oxidative stress and found that it also induced an energy metabolism shift. The highest expression of lactate (the end product of the glycolysis pathway) was observed after 1 h of 1 mM H 2 O 2 treatment, indicating that this is the point at which the energy metabolism shift is the most significant and the rate of glycolysis is the highest under the above conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown a repressive effect of microRNA-210 (miR-210) on ISCU, whose 3´untranslated region (UTR) is predicted to contain a highly conserved binding site for miR-210 [8, 11-13]. MiR-210 is a member of the microRNA (miR) family.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-210 Modulates the Cellular Energy Metabolism Shift During H2O2-Induced Oxidative Stress by Repressing ISCU in H9c2 Cardiomyocytes

Sun

Zhao

Song

et al. 2017

Cell Physiol Biochem

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Background/Aims: The myocardial energy metabolism shift is one of the most important pathological features of ischemic heart disease (IHD). Although several microRNAs (miRs) are involved in the regulation of myocardial energy metabolism, their exact effects and underlying mechanisms remain unclear. The aim of this study was to investigate whether microRNA(miR-210) regulates the energy metabolism shift during oxidative stress in H9c2 cardiomyocytes. Methods: Cell survival was analyzed via CCK assay. The energy metabolism shift was detected by lactate assay, ATP assay and RT² profiler glucose metabolism PCR array. Protein and mRNA expression levels were determined by western blot and qPCR. We also used kits to detect the activity of Complex I, Sirt3 and the NAD⁺/NADH ratio. Results: We determined that miR-210 promoted the energy metabolism shift. The iron-sulfur cluster assembly protein (ISCU) was a target of miR-210. Additionally, we detected the activity of complex I and found that miR-210 inhibits mitochondrial respiration. Interestingly, miR-210 may also indirectly regulate SIRT3 by regulating ISCU. Conclusion: Our results confirm that miR-210 is essential and sufficient for modulating the cellular energy metabolism shift during H₂O₂-induced oxidative stress in H9c2 cardiomyocytes by targeting ISCU.

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“…Indeed, miR-210 has been linked to poor patient prognosis for different epithelial cancer types, including CRC (Ivan & Huang, 2014). ISCU and miR-210 are known to influence the metabolism of cells by regulating mitochondrial activity, lactate production and self-renewal activity of tumor-initiating cells (TICs) as well as their clinical relevance for CRC patients (Gao, Sun, He, Cao, & Zhang, 2012 can be reversed by blocking lactate production, again highlighting the central role of this miRNA in the regulation of hypoxia-induced TIC activity (Ullmann et al, 2016). It potentially indicates that the combined expression of hypoxia-induced miR-210 and its target gene ISCU may be preferentially used for prognostic assessment of CRC patients.…”

Section: Micrornas (Mirnas) Mediated the Glycolytic Pathway And Lacmentioning

confidence: 99%

New strategies for targeting glucose metabolism–mediated acidosis for colorectal cancer therapy

Wang

Yin

et al. 2018

Journal Cellular Physiology

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Colorectal cancer (CRC) is a heterogeneous group of diseases that are the result of abnormal glucose metabolism alterations with high lactate production by pyruvate to lactate conversion, which remodels acidosis and offers an evolutional advantage for tumor cells, even enhancing their aggressive phenotype. This review summarizes recent findings that involve multiple genes, molecules, and downstream signaling in the dysregulated glycolytic pathway, which can allow a tumor to initiate acid byproducts and to progress, thereby resulting in acidosis commonly found in the tumor microenvironment of CRC. Moreover, the relationship between CRC cells and the tumor acidic microenvironment, especially for regulating lactate production and lactate dehydrogenase A levels, is also discussed, as well as comprehensively defining different aspects of glycolytic pathways that affect cancer cell proliferation, invasion, and migration. Furthermore, this review concentrates on glucose metabolism-mediated transduction factors in CRC, which include acid-sensing ion channels, triosephosphate isomerase and key glycolysis-related enzymes that regulate glycolytic metabolites, coupled with the effect on tumor cell glycolysis as well as signaling pathways. In conclusion, glucose metabolism mediated by glycolytic pathways that are integral to tumor acidosis in CRC is demonstrated. Therefore, selective metabolic inhibitors or agents against these targets in glucose metabolism through glycolytic pathways may be clinically useful to regulate the tumor's acidic microenvironment for CRC treatment and to identify specific targets that regulate tumor acidosis through a cancer patient-personalized approach. Furthermore, strategies for modifying the metabolic processes that effectively inhibit cancer cell growth and tumor progression and activate potent anticancer effects may provide more effective antitumor prospects for CRC therapy.

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Hypoxia-responsive miR-210 promotes self-renewal capacity of colon tumor-initiating cells by repressing ISCU and by inducing lactate production

Cited by 52 publications

References 81 publications

The miR-371∼373 Cluster Represses Colon Cancer Initiation and Metastatic Colonization by Inhibiting the TGFBR2/ID1 Signaling Axis

The miR-371∼373 Cluster Represses Colon Cancer Initiation and Metastatic Colonization by Inhibiting the TGFBR2/ID1 Signaling Axis

MicroRNA-210 Modulates the Cellular Energy Metabolism Shift During H2O2-Induced Oxidative Stress by Repressing ISCU in H9c2 Cardiomyocytes

New strategies for targeting glucose metabolism–mediated acidosis for colorectal cancer therapy

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