Matrix metalloproteinase-9, -10, and -12, MDM2 and p53 expression in mouse liver during dimethylnitrosamine-induced oxidative stress and genomic injury


Treatment during early tumor development has greater success because tissue growth remains largely confined to its original locus. At later stages, malignant cells migrate from their original location, invade surrounding normal areas, and can disseminate widely throughout the body. Remodeling of the extracellular matrix (ECM) serves as a key facilitator of this dissemination. Proteolytic enzymes including plasmin and matrix metalloproteinases (MMPs) play an integral role in degrading the surrounding ECM proteins and clearing a path for tumor cell migration. Specific MMPs are highly expressed late during malignant tumor invasion. It is not understood whether early changes in MMPs influence apoptotic and necrotic cell death, processes known to govern the early stages of carcinogenesis. Similarly, the interaction between MDM2 and p53 is tightly controlled by a complex array of post-translational modifications, which in turn dictates the stability and activity of both p53 and MDM2. The present studies examine the hypothesis that model hepatotoxin dimethylnitrosamine (DMN), which is also a model carcinogen, will induce the MMP family of proteins after administration in hepatotoxic doses. Doses of 25, 50, and 100 mg/kg DMN were administered i.p. to male C3H mice. Changes in parameters associated with apoptotic and necrotic cell death, DNA damage, cell proliferation, and extracellular proteinases were examined in liver at 24 h. Serum ALT activity, oxidative stress [malondialdehyde], and caspase-activated DNAse mediated DNA laddering increased in a dose-dependent manner, as did the level of MDM2 protein. MMP-9, -10 and -12 (gelatinase-B, stromelysin-2, macrophage elastase), and p53 protein levels increased following 25 mg/kg DMN, but were successively decreased after higher DMN doses. The results of this study demonstrate changes in MDM2 and MMPs during DMN-induced acute liver injury and provide a plausible linkage between DMN-induced oxidative stress-mediated genomic injury and its likely involvement in setting the stage for initiating subsequent metastatic disease at later circumstances.

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This study was supported by the Division of Pharmaceutical Sciences, AMS College of Pharmacy and Health Sciences, NY. Assistance provided by Ms. Dottie Young during the preparation of this manuscript is gratefully acknowledged. Animals used in this study was a generous gift by the Dean Dr. David Taft. This work was presented at the Annual meeting of the Society of Toxicology, 2007.

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Correspondence to Sidhartha D. Ray.

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Syed, I., Rathod, J., Parmar, M. et al. Matrix metalloproteinase-9, -10, and -12, MDM2 and p53 expression in mouse liver during dimethylnitrosamine-induced oxidative stress and genomic injury. Mol Cell Biochem 365, 351–361 (2012).

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  • Oxidative stress
  • Apoptosis
  • Necrosis
  • Dimethylnitrosamine
  • Extracellular matrix
  • Matrix metalloproteinases
  • MDM2
  • Hepatotoxicity
  • PCNA
  • P53