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  • MicroRNA-126 suppresses mesothelioma malignancy by targeting IRS1 and interfering with the mitochondrial function

    Author(s)
    Tomasetti, Marco
    Nocchi, Linda
    Staffolani, Sara
    Manzella, Nicola
    Amati, Monica
    Goodwin, Jacob
    Kluckova, Katarina
    Nguyen, Maria
    Strafella, Elisabetta
    Bajzikova, Martina
    Peterka, Martin
    Lettlova, Sandra
    Truksa, Jaroslav
    Lee, Wan
    Dong, Lan-Feng
    Santarelli, Lory
    Neuzil, Jiri
    Griffith University Author(s)
    Neuzil, Jiri
    Year published
    2014
    Metadata
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    Abstract
    Aims: MiR126 was found to be frequently lost in many types of cancer, including malignant mesothelioma (MM), which represents one of the most challenging neoplastic diseases. In this study, we investigated the potential tumor suppressor function of MiR126 in MM cells. The effect of MiR126 was examined in response to oxidative stress, aberrant mitochondrial function induced by inhibition of complex I, mitochondrial DNA (mtDNA) depletion, and hypoxia. Results: MiR126 was up-regulated by oxidative stress in nonmalignant mesothelial (Met5A) and MM (H28) cell lines. In Met5A cells, rotenone inhibited MiR126 expression, but mtDNA ...
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    Aims: MiR126 was found to be frequently lost in many types of cancer, including malignant mesothelioma (MM), which represents one of the most challenging neoplastic diseases. In this study, we investigated the potential tumor suppressor function of MiR126 in MM cells. The effect of MiR126 was examined in response to oxidative stress, aberrant mitochondrial function induced by inhibition of complex I, mitochondrial DNA (mtDNA) depletion, and hypoxia. Results: MiR126 was up-regulated by oxidative stress in nonmalignant mesothelial (Met5A) and MM (H28) cell lines. In Met5A cells, rotenone inhibited MiR126 expression, but mtDNA depletion and hypoxia up-regulated MiR126. However, these various stimuli suppressed the levels of MiR126 in H28 cells. MiR126 affected mitochondrial energy metabolism, reduced mitochondrial respiration, and promoted glycolysis in H28 cells. This metabolic shift, associated with insulin receptor substrate-1 (IRS1)-modulated ATP-citrate lyase deregulation, resulted in higher ATP and citrate production. These changes were linked to the down-regulation of IRS1 by ectopic MiR126, reducing Akt signaling and inhibiting cytosolic sequestration of Forkhead box O1 (FoxO1), which promoted the expression of genes involved in gluconeogenesis and oxidative stress defense. These metabolic changes induced hypoxia-inducible factor-1a (HIF1a) stabilization. Consequently, MiR126 suppressed the malignancy of MM cells in vitro, a notion corroborated by the failure of H28MiR126 cells to form tumors in nude mice. Innovation and Conclusion: MiR126 affects mitochondrial energy metabolism, resulting in MM tumor suppression. Since MM is a fatal neoplastic disease with a few therapeutic options, this finding is of potential translational importance
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    Journal Title
    Antioxidants & Redox Signaling
    Volume
    21
    Issue
    15
    DOI
    https://doi.org/10.1089/ars.2013.5215
    Subject
    Biochemistry and cell biology
    Medical biochemistry and metabolomics
    Cancer cell biology
    Pharmacology and pharmaceutical sciences
    Publication URI
    http://hdl.handle.net/10072/67343
    Collection
    • Journal articles

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