The extracellular matrix is a component of physiological microenvironment and a regulator of cellular processes such as migration and proliferation. Secreted
Protein Acidic and Rich in
Cysteine (SPARC/
osteonectin) is an extracellular matrix-associated
glycoprotein involved in the regulation of cell proliferation and cell migration in several types of
cancers. However, the role of SPARC in
lung cancer is paradoxical and details of the regulatory mechanism are not well-known. In this study, we investigated novel SPARC-mediated signaling pathways. Treatment of SPARC increased cell proliferation, migration, and mesenchymal phenotype in two
non-small cell lung cancer cell lines, CL1-5 and H1299. We found that these phenotypes were not regulated by
focal adhesion kinase and
Src kinase, but were mediated by with no
lysine (K)
kinase 1 (WNK1). Suppression of WNK1 expression decreased the expression of SPARC-induced
N-cadherin and smooth muscle actin. Moreover, Snail, an important
transcription factor for regulating epithelial-mesenchymal transition, is also involved in SPARC/WNK1 pathway. In a murine
tumor model, SPARC treatment significantly induced phosphorylation of Akt and WNK1 in lung
tumor nodules when compared to control mice. In conclusion, these data suggest that WNK1 is a novel molecule in SPARC-mediated mesenchymal signaling pathway in
non-small cell lung cancer.