期刊
NATURE
卷 490, 期 7421, 页码 547-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature11452
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- MEXT
- Japan Society for the Promotion of Science for Young Scientists
- Japan Science and Technology Agency
- G-COE program for Global Center for Education and Research in Integrative Membrane Biology
- Fumi Yamamura Memorial Foundation for Female Natural Scientists
- Tomizawa Jun-ichi & Keiko Fund of the Molecular Biology Society of Japan for Young Scientists
- Takeda Science Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Kanae Foundation for the Promotion of Medical Science
- Senri Life Science Foundation
- Human Frontier Science Program Career Development Award
- Grants-in-Aid for Scientific Research [23650596] Funding Source: KAKEN
Mitochondrial respiratory function is frequently impaired in human cancers(1-4). However, the mechanisms by which mitochondrial dysfunction contributes to tumour progression remain elusive. Here we show in Drosophila imaginal epithelium that defects in mitochondrial function potently induce tumour progression of surrounding tissue in conjunction with oncogenic Ras. Our data show that Ras activation and mitochondrial dysfunction cooperatively stimulate production of reactive oxygen species, which causes activation of c-Jun amino (N)-terminal kinase (JNK) signalling. JNK cooperates with oncogenic Ras to inactivate the Hippo pathway, leading to upregulation of its targets Unpaired (an interleukin-6 homologue) and Wingless (a Wnt homologue). Mitochondrial dysfunction in Ras-activated cells further cooperates with Ras signalling in neighbouring cells with normal mitochondrial function, causing benign tumours to exhibit metastatic behaviour. Our findings provide a mechanistic basis for interclonal tumour progression driven by mitochondrial dysfunction and oncogenic Ras.
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