MicroRNA-126 Suppresses Mesothelioma Malignancy by Targeting IRS1 and Interfering with the Mitochondrial Function

0437289 - BTÚ 2015 RIV US eng J - Journal Article
Tomasetti, M. - Nocchi, L. - Staffolani, S. - Manzella, N. - Amati, M. - Goodwin, J. - Klučková, Katarína - Nguyen, M. - Strafella, E. - Bajziková, Martina - Peterka, Martin - Lettlová, Sandra - Truksa, Jaroslav - Lee, W. - Dong, L.-F. - Santarelli, L. - Neužil, Jiří
MicroRNA-126 Suppresses Mesothelioma Malignancy by Targeting IRS1 and Interfering with the Mitochondrial Function.
Antioxidants & Redox Signaling. Roč. 21, č. 15 (2014), s. 2109-2125. ISSN 1523-0864. E-ISSN 1557-7716
R&D Projects: GA ČR(CZ) GAP301/10/1937; GA ČR GAP305/12/1708; GA MŠMT(CZ) ED1.1.00/02.0109
Institutional support: RVO:86652036
Keywords : ATP CITRATE LYASE * OXIDATIVE STRESS * PLEURAL MESOTHELIOMA * CANCER-CELLS
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 7.407, year: 2014

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
Permanent Link: http://hdl.handle.net/11104/0240865