Abstract A15: Snail upregulation of SPARC leads to increased invasion in models of both early-and late-stage NSCLC

Abstract

Abstract The zinc-finger protein Snail is upregulated in human non-small cell lung cancer (NSCLC) tissues and is associated with poor patient prognosis. We have shown that Snail upregulation in lung cancer cell lines leads to morphologic changes indicative of epithelial-mesenchymal transition (EMT) in vitro and tumor progression in vivo. Snail overexpression is associated with differential gene expression related to diverse aspects of lung cancer progression. One gene upregulated by Snail in both NSCLC and histologically normal human bronchial epithelial cell lines is secreted protein, acidic and rich in cysteine (SPARC). Expression of SPARC modulates reversible interactions between cells and their extracellular matrix and is known to play an important role in the wound healing process of normal epithelial cells. Its upregulation in several cancer types is associated with increased migration, invasion, and poor patient prognosis. Here, we show that overexpression of Snail leads to increased invasion in a modified Boyden chamber assay in models of both early and late stage NSCLC. Knockdown of SPARC by shRNA leads to a reversal of invasion, indicating that SPARC is at least partially responsible for the effect of Snail on invasion. Computational analysis indicates that Snail does not directly enhance the transcription of SPARC; therefore, we have investigated the indirect mechanism for this relationship. Both ERK1/2 and the chaperone protein HSP27 have emerged as potential components of the pathway. Snail overexpression also leads to activation of ERK1/2, and chemical inhibition of this pathway leads to a decrease in SPARC protein. Snail-overexpressing cell lines show increased transcription of HSP27 mRNA. As Snail has been shown to be overexpressed in the inflammatory microenvironment of premalignancy and in established tumors, SPARC-driven invasion supports both the parallel and linear models of tumor progression. Delineating pathways involved in Snail-dependent and SPARC-mediated tumor progression may yield new targets for lung cancer prevention and treatment.