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MicroRNA-126 Suppresses Mesothelioma Malignancy by Targeting IRS1 and Interfering with the Mitochondrial Function
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SYSNO ASEP 0437289 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název MicroRNA-126 Suppresses Mesothelioma Malignancy by Targeting IRS1 and Interfering with the Mitochondrial Function Tvůrce(i) Tomasetti, M. (IT)
Nocchi, L. (IT)
Staffolani, S. (IT)
Manzella, N. (IT)
Amati, M. (IT)
Goodwin, J. (IT)
Klučková, Katarína (BTO-N) RID
Nguyen, M. (AU)
Strafella, E. (IT)
Bajziková, Martina (BTO-N) RID
Peterka, Martin (BTO-N)
Lettlová, Sandra (BTO-N)
Truksa, Jaroslav (BTO-N) RID, ORCID
Lee, W. (KR)
Dong, L.-F. (AU)
Santarelli, L. (IT)
Neužil, Jiří (BTO-N) RIDZdroj.dok. Antioxidants & Redox Signaling. - : Mary Ann Liebert - ISSN 1523-0864
Roč. 21, č. 15 (2014), s. 2109-2125Poč.str. 17 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova ATP CITRATE LYASE ; OXIDATIVE STRESS ; PLEURAL MESOTHELIOMA ; CANCER-CELLS Vědní obor RIV EB - Genetika a molekulární biologie CEP GAP301/10/1937 GA ČR - Grantová agentura ČR GAP305/12/1708 GA ČR - Grantová agentura ČR ED1.1.00/02.0109 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Institucionální podpora BTO-N - RVO:86652036 UT WOS 000343982000004 DOI 10.1089/ars.2013.5215 Anotace 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-1 alpha (HIF1 alpha) stabilization.Consequently, MiR126 suppressed the malignancy of MM cells in vitro, a notion corroborated by the failure of H28(MiR126) 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 Pracoviště Biotechnologický ústav Kontakt Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Rok sběru 2015
Počet záznamů: 1