MicroRNA-210 Regulates Mitochondrial Free Radical Response to Hypoxia and Krebs Cycle in Cancer Cells by Targeting Iron Sulfur Cluster Protein ISCU

被引：257

作者：

Favaro, Elena ^{[1
,2
]}

Ramachandran, Anassuya ^{[2
]}

McCormick, Robert ^{[2
]}

Gee, Harriet ^{[2
]}

Blancher, Christine ^{[1
]}

Crosby, Meredith ^{[3
]}

Devlin, Cecilia ^{[4
]}

Blick, Christopher ^{[2
]}

Buffa, Francesca ^{[2
]}

Li, Ji-Liang ^{[2
]}

Vojnovic, Borivoj ^{[5
]}

das Neves, Ricardo Pires ^{[2
]}

Glazer, Peter ^{[3
]}

Iborra, Francisco ^{[2
]}

Ivan, Mircea ^{[4
]}

Ragoussis, Jiannis ^{[1
]}

Harris, Adrian L. ^{[2
]}

机构：

[1] Univ Oxford, Genom Grp, Wellcome Trust Ctr Human Genet, Oxford, England

[2] Univ Oxford, John Radcliffe Hosp, Mol Oncol Labs, Weatherall Inst Mol Med, Oxford OX3 9DU, England

[3] Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06510 USA

[4] Indiana Univ, Indianapolis, IN 46204 USA

[5] Univ Oxford, Gray Inst Radiat Oncol & Biol, Oxford, England

来源：

PLOS ONE | 2010年 / 5卷 / 04期

基金：

英国惠康基金;

关键词：

GENE-EXPRESSION; BREAST-CANCER; INDUCIBLE FACTOR; MUTATION; HEAD; DEHYDROGENASE; RESPIRATION; BIOGENESIS; SIGNATURE; HELICASES;

D O I：

10.1371/journal.pone.0010345

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Background: Hypoxia in cancers results in the upregulation of hypoxia inducible factor 1 (HIF-1) and a microRNA, hsa-miR-210 (miR-210) which is associated with a poor prognosis. Methods and Findings: In human cancer cell lines and tumours, we found that miR-210 targets the mitochondrial iron sulfur scaffold protein ISCU, required for assembly of iron-sulfur clusters, cofactors for key enzymes involved in the Krebs cycle, electron transport, and iron metabolism. Down regulation of ISCU was the major cause of induction of reactive oxygen species (ROS) in hypoxia. ISCU suppression reduced mitochondrial complex 1 activity and aconitase activity, caused a shift to glycolysis in normoxia and enhanced cell survival. Cancers with low ISCU had a worse prognosis. Conclusions: Induction of these major hallmarks of cancer show that a single microRNA, miR-210, mediates a new mechanism of adaptation to hypoxia, by regulating mitochondrial function via iron-sulfur cluster metabolism and free radical generation.

引用

页数：11

共 44 条

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