Induction of miR-21-PDCD4 Signaling and Transformation by Freshly Fractured Crystalline Silica in JB6 or BEAS-2B Cells

Abstract

Background: Crystalline silica particles are fibrogenic agents and established carcinogens, but the mechanisms for disease initiation and progression are not well understood. Previous studies demonstrate that the tumor suppressor gene, programmed cell death 4 (PDCD4), and its upstream regulator, microRNA 21 (miR-21), may be oncogenes for novel cancer prevention or anticancer therapies. Methods: This study examined the alterations of miR-21-PDCD4 signaling in mouse epidermal JB6 cells after exposure to freshly fractured silica particles. Results: The results demonstrate that exposure to crystalline silica caused PDCD4 inhibition in JB6 cells and a significant increase in miR-21 expression. Inhibition of phosphorylated extracellular signal-regulated kinases (ERKs) or phosphorylated p38 with U0126 or SB 203580 reversed silica-induced PDCD4 inhibition. Reactive oxygen species (ROS) scavengers and N-acetyl-l-cysteine also reversed the inhibitory effect of silica on PDCD4 expression. Human lung epithelial BEAS-2B or JB6 cells chronically exposed to low-dose silica resulted in neoplastic transformation as assayed by soft agar. Discussion: These findings demonstrate that freshly fractured silica particles may induce miR-21 expression and PDCD4 inhibition, which may be mediated through ROS and ERK pathways. Unraveling the complex mechanisms associated with these events may provide insights into the initiation and progression of silica-induced carcinogenesis.