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  • MicroRNA-126 induces autophagy by altering cell metabolism in malignant mesothelioma

    Author(s)
    Tomasetti, Marco
    Monaco, Federica
    Manzella, Nicola
    Rohlena, Jakub
    Rohlenova, Katerina
    Staffolani, Sara
    Gaetani, Simona
    Ciarapica, Veronica
    Amati, Monica
    Bracci, Massimo
    Valentino, Matteo
    Goodwin, Jacob
    Maria, Nguyen
    Truksa, Jaroslav
    Sobol, Margaryta
    Hozak, Pavel
    Dong, Lan-Feng
    Santarelli, Lory
    Neuzil, Jiri
    Griffith University Author(s)
    Neuzil, Jiri
    Year published
    2016
    Metadata
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    Abstract
    Autophagy favors both cell survival and cancer suppression, and increasing evidence reveals that microRNAs (MIRs) regulate autophagy. Previously we reported that MIR126 is downregulated in malignant mesothelioma (MM). Therefore, we investigated the role of MIR126 in the regulation of cell metabolism and autophagy in MM models. We report that MIR126 induces autophagic flux in MM cells by downregulating insulin receptor substrate-1 (IRS1) and disrupting the IRS1 signaling pathway. This was specific to MM cells, and was not observed in non-malignant cells of mesothelial origin or in MM cells expressing MIR126-insensitive IRS1 ...
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    Autophagy favors both cell survival and cancer suppression, and increasing evidence reveals that microRNAs (MIRs) regulate autophagy. Previously we reported that MIR126 is downregulated in malignant mesothelioma (MM). Therefore, we investigated the role of MIR126 in the regulation of cell metabolism and autophagy in MM models. We report that MIR126 induces autophagic flux in MM cells by downregulating insulin receptor substrate-1 (IRS1) and disrupting the IRS1 signaling pathway. This was specific to MM cells, and was not observed in non-malignant cells of mesothelial origin or in MM cells expressing MIR126-insensitive IRS1 transcript. The MIR126 effect on autophagy in MM cells was recapitulated by IRS1 silencing, and antagonized by IRS1 overexpression or antisense MIR126 treatment. The MIR126-induced loss of IRS1 suppressed glucose uptake, leading to energy deprivation and AMPK-dependent phosphorylation of ULK1. In addition, MIR126 stimulated lipid droplet accumulation in a hypoxia-inducible factor-1α (HIF1α)-dependent manner. MIR126 also reduced pyruvate dehydrogenase kinase (PDK) and acetyl-CoA-citrate lyase (ACL) expression, leading to the accumulation of cytosolic citrate and paradoxical inhibition of pyruvate dehydrogenase (PDH) activity. Simultaneous pharmacological and genetic intervention with PDK and ACL activity phenocopied the effects of MIR126. This suggests that in MM MIR126 initiates a metabolic program leading to high autophagic flux and HIF1α stabilization, incompatible with tumor progression of MM. Consistently, MIR126-expressing MM cells injected into immunocompromised mice failed to progress beyond the initial stage of tumor formation, showing that increased autophagy has a protective role in MM.
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    Journal Title
    Oncotarget
    Volume
    7
    Issue
    24
    DOI
    https://doi.org/10.18632/oncotarget.8916
    Subject
    Oncology and carcinogenesis
    Oncology and carcinogenesis not elsewhere classified
    Publication URI
    http://hdl.handle.net/10072/142502
    Collection
    • Journal articles

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