Abstract
Although the causal relationship between chronic inflammation and carcinogenesis has long been discussed, the molecular basis of the relation is poorly understood. In the present study, we focused on reactive oxygen species (ROS) and their signals under inflammatory conditions leading to the carcinogenesis of epithelial cells and found that repeated treatment with a low dose of H(2)O(2) (0.2 mmol/L) for periods of 2 to 4 days caused a phenotypic conversion of mouse NMuMG mammary epithelial cells from epithelial to fibroblast-like as in malignant transformation. The phenotypic conversion included the dissolution of cell-cell contacts, redistribution of E-cadherin in the cytoplasm, and up-regulation of a set of integrin family members (integrin alpha2, alpha6, and beta3) and matrix metalloproteinases (MMPs; MMP-3, -10, and -13), as analyzed using Northern blot analysis and quantitative reverse transcription-PCR. Gelatin zymography indicated post-transcriptional activation of gelatinases, including MMP-2 and -9. In parallel, p38 mitogen-activated protein kinase and extracellular signal-regulated kinase 1/2 were activated, which contributed to the induction of MMP-13, and a glutathione S-transferase pull-down assay showed the activation of a small GTPase, Rac1. Surprisingly, the prolonged oxidative treatment was sufficient to induce all of the aforementioned events. Most importantly, depending on the MMP activities, the epithelial cells exposed to oxidative conditions eventually acquired invasiveness in a reconstituted model system with a Matrigel invasion chamber containing normal fibroblasts at the bottom, providing the first substantial evidence supporting the direct role of ROS signals in the malignant transformation of epithelial cells.
Highlights
The causal relationship between chronic inflammation and carcinogenesis has long been discussed, the molecular basis of the relation is poorly understood
Less well defined than protein tyrosine phosphatases (PTPs), protein tyrosine kinases such as src family members have been noted as targets of reactive oxygen species (ROS), whose activation initiates a flow of downstream signal transduction in which intermediate roles often are carried out by mitogen-activated protein (MAP) kinases [16, 17]
We examined the changes in morphology and in gene expression of mouse NMuMG mammary epithelial cells on long-term exposure to H2O2, mimicking chronic inflammation, and showed that the oxidative conditions induced a cellular phenotypic conversion with striking similarities to malignant transformation, accompanied by the induction of genes associated with cell adhesion and migratory behavior together with activation of the small G protein Rac1 and MAP kinases
Summary
The causal relationship between chronic inflammation and carcinogenesis has long been discussed, the molecular basis of the relation is poorly understood. We examined the changes in morphology and in gene expression of mouse NMuMG mammary epithelial cells on long-term exposure to H2O2, mimicking chronic inflammation, and showed that the oxidative conditions induced a cellular phenotypic conversion with striking similarities to malignant transformation, accompanied by the induction of genes associated with cell adhesion and migratory behavior together with activation of the small G protein Rac1 and MAP kinases.
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