MicroRNA-126 suppresses mesothelioma malignancy by targeting IRS1 and interfering with the mitochondrial function.
OBJECTIVE
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-1α (HIF1α) 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.


CONCLUSIONS
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.
1 Department of Clinical and Molecular Science, Polytechnic University of Marche , Ancona, Italy .
Marco
M
Tomasetti
Linda
L
Nocchi
Sara
S
Staffolani
Nicola
N
Manzella
Monica
M
Amati
Jacob
J
Goodwin
Katarina
K
Kluckova
Maria
M
Nguyen
Elisabetta
E
Strafella
Martina
M
Bajzikova
Martin
M
Peterka
Sandra
S
Lettlova
Jaroslav
J
Truksa
Wan
W
Lee
Lan-Feng
LF
Dong
Lory
L
Santarelli
Jiri
J
Neuzil
D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D008928:Mitochondria / Q000378:metabolism*; D009368:Neoplasm Transplantation; D018384:Oxidative Stress; D010101:Oxygen Consumption; D034622:RNA Interference; D015398:Signal Transduction
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C527111:MIRN126 microRNA, human; D035683:MicroRNAs