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

Authors: 
Rojanasakul, Y., West Virginia University
Lohcharoenkal, W., West Virginia University
Dinu, C. Z., West Virginia University
Stueckle, T., National Institute for Occupational Safety and Health
Wang, L., National Institute for Occupational Safety and Health



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.

Disclaimer: The findings and conclusions in this abstract are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health.

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