Journal Article

Oxidative phosphorylation dysfunction modulates expression of extracellular matrix—remodeling genes and invasion

Corina van Waveren, Yubo Sun, Herman S. Cheung and Carlos T. Moraes

in Carcinogenesis

Volume 27, issue 3, pages 409-418
Published in print March 2006 | ISSN: 0143-3334
Published online October 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi242
Oxidative phosphorylation dysfunction modulates expression of extracellular matrix—remodeling genes and invasion

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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.

Keywords: CCN, members of the cysteine-rich 61 connective tissue growth factor and nephroblastoma-overexpressed gene/protein family; CPI, calpain inhibitor; CTGF, connective tissue growth factor; CYR61, cysteine-rich angiogenic inducer 61; ECM, extracellular matrix; HEK, human embryonic kidney; HIF, hypoxia inducing factor; IVT, in vitro transcription; MMP, matrix metalloproteinases; MERRF, myoclonus epilepsy and ragged-red fibers; mtDNA, mitochondrial DNA; OXPHOS, oxidative phosphorylation; PAI1, plasminogen-activator inhibitor I; ROS, reactive oxygen species; SOD2, superoxide dismutase 2; TIMP, tissue inhibitor of metalloproteinase; uPA, urokinase plasminogen activator

Journal Article.  6250 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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