Carcinogenesis Advance Access originally published online on October 12, 2005
Carcinogenesis 2006 27(3):409-418; doi:10.1093/carcin/bgi242
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Carcinogenesis vol.27 no.3 © Oxford University Press 2005; all rights reserved.
Oxidative phosphorylation dysfunction modulates expression of extracellular matrix—remodeling genes and invasion
1 Department of Cell Biology and Anatomy, 2 Department of Medicine and 3 Department of Neurology, University of Miami School of Medicine, Miami, FL 33136, USA
* To whom correspondence should be addressed at: Department of Cell Biology and Anatomy, University of Miami School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA. Tel: +1 305 243 5858; Fax: +1 305 243 3914; Email: cmoraes{at}med.miami.edu
A number of recent studies suggest that mitochondrial function is a player in tumor development and progression. In this study, we have used gene expression arrays to examine transcriptional differences between oxidative phosphorylation (OXPHOS)-competent and OXPHOS-impaired human osteosarcoma cells. Genes associated with extracellular matrix remodeling, including members of the matrix metalloproteinases (MMPs) and tissue inhibitors of the MMP (TIMP) family, urokinase plasminogen activator and its inhibitor plasminogen-activator inhibitor-1 (PAI1), and CTGF and CYR61 (members of the Cysteine-rich 61, Connective Tissue Growth Factor and Nephroblastoma-overexpressed (CCN) gene family of growth regulators), were among the ones significantly altered in the OXPHOS-deficient cells. These changes were confirmed by RT–PCR and promoter reporter assays. Alterations at the protein level for some of these factors were also observed, though at a lower magnitude, with the exception of TIMP1, where a marked change in steady-state levels of the protein was observed after induction of OXPHOS dysfunction. Repopulation of mitochondrial DNA (mtDNA)-less cells with wild-type mtDNA reduced matrigel invasion, whereas repopulation with a mutated mtDNA did not. Taken together our data suggests that OXPHOS dysfunction modulates the invasive phenotype by transcriptional regulation of genes coding for members of the MMP/TIMP system, urokinase plasminogen activator/plasminogen-activator inhibitor I and CCN proteins.
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