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Cancer Biology, Immunology, Cytokines |
Section of Radiation Biology, Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157 [J. A. M.]; the Centers for Immunology and Microbial Disease [K. K. N., A. C. R., J. M., J. A. B.], and Cell Biology and Cancer Research [K. M. P., K. P.], Albany Medical College, Albany, New York 12208; Division of Genetic Disorders, Wadsworth Center, New York State Department of Health, Albany, New York 12201 [A. M. R.]; and National Cancer Institute, NIH, DCEG/LPG, Bethesda, Maryland 20892-5060 [J. L. R.]
Purpose: Elevated manganese superoxide dismutase (Sod2) levels have been reported to be associated with an increasedfrequency of tumor invasion and metastasis in certain cancers, and the aim of this study is to examine the molecular mechanisms by which this occurs.
Experimental Design: Sod2 and catalase overexpressing HT-1080 fibrosarcoma cell lines were used to evaluate the H2O2-dependent regulation of matrix metalloproteinase (MMP)-1 promoter activity, mitogen-activated protein (MAP) kinase signaling, DNA-binding activity, and MMP mRNA levels. The invasive and metastatic potential of Sod2 overexpressing cells was characterized using subrenal capsular implantation or tail vein injection of tumor cells into nude mice, respectively.
Results: Our data reveal that Sod2 overexpression increases the DNA-binding activity of transcription factors critical for MMP expression but also enhances MMP-1 promoter activity via the Ras//MAP/extracellular signal-regulated kinase (MEK) signaling cascade. A single nucleotide polymorphism that creates an Ets site at position -1607 bp confers Sod2-dependent MMP-1 promoter activity. Sod2 overexpression also increases the mRNA levels of MMPs-2, -3, -7, -10, -9, -11 and enhances the metastatic potential of fibrosarcoma cells when implanted in immunodeficient mice. The Sod2-dependent increases in AP-1 and SP-1 DNA-binding activity, MMP-1 promoter activity, general MMP expression, and collagen degradation can be reversed by the hydrogen peroxide-detoxifying enzyme, catalase.
Conclusion: MMPs play a critical role in the process of stromal invasion and metastasis, and these findings suggest that the association between increased Sod2 and poor prognosis in certain cancers may be attributed to elevated MMP production.
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