(540f) Carbon Nanotubes Induce Invasion of Human Mesothelial Cells Through Matrix Metalloproteinase-2

Carbon nanotubes (CNT) have increasingly been used in a wide variety of applications.  However, because of their needle-shape morphology, biopersistence and mode of exposure similar to those of asbestos which is a known carcinogen causing lung mesothelioma, there has been a great concern about their potential carcinogenicity.  In this study, we investigated the effect of long-term exposure of CNT on proliferative and invasive properties of human pleural mesothelial cells.  We found that sub-chronic exposure of human mesothelial MeT5A cells to low-dose non-cytotoxic concentration of single- and multi-walled CNT (0.02 µg/cm² for 6 months) in culture induced malignant transformation of the cells as indicated by their increased cell invasion and migration.  An up-regulation of several key genes known to be important in cell invasion, notably matrix metalloproteinase-2 (MMP-2), was observed in the exposed mesothelial cells as determined by real-time PCR.  Western blot analysis of protein expression confirmed the up-regulation of MMP-2 in the exposed cells.  Whole genome microarray analysis further indicated the importance of MMP-2 in the invasion gene signaling network of the cells.  Knockdown of MMP-2 in the CNT-transformed cells by short-hairpin (sh)RNA stable transfection effectively inhibited MMP-2 activity and expression in these cells as well as their invasive and migratory activities.  Preliminary animal studies demonstrated colonization of CNT-transformed cells in the lungs of mice which was absent in mice receiving shMMP-2 knockdown cells.  These results indicate MMP-2 as a key regulator of the aggressive phenotype of CNT-transformed cells.  This study fortifies the carcinogenic potential of CNT and reveals a novel mechanism that may be important in CNT-induced mesothelioma.

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