Secreted protein acidic and rich in cysteine (SPARC) induces cell migration and epithelial mesenchymal transition through WNK1/snail in non-small cell lung cancer.

Jen-Yu Hung,Wei-An Chang,Kuan-Ting Liu,Cheng-Ying Wu,Inn-Wen Chong,Po-Lin Kuo,Shu-Fang Jian,Ya-Ling Hsu,Meng-Chi Yen

doi:10.18632/oncotarget.19475

Abstract

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.

Highlights

Lung cancer is the most common cancer worldwide, and the most common cause of cancer related deaths globally [1]
SPARC treatment promotes migration and epithelial-mesenchymal transition (EMT) phenotype in non-small cell lung cancer cells
These results indicate that exogenous SPARC plays an oncogenic role in highly metastatic lung cancer cells

Summary

Introduction

Lung cancer is the most common cancer worldwide, and the most common cause of cancer related deaths globally [1]. In the United States, lung cancer has been the leading cause of cancer related deaths for several decades, even though it is not the most common cancer [2]. Lung cancer is usually diagnosed at www.impactjournals.com/oncotarget a late stage, and the overall survival rate for those patients of an advanced stage is poor, even with chemotherapy [3]. TKIs) or EML4-ALK inhibitors, extends the survival of those patients with driver gene mutation [4]. Since 2015, three agents of immunotherapy, either PD-1 or PD-L1 antibodies, have been approved by the FDA to be used in www.impactjournals.com/oncotarget the treatment of lung cancer patients, for they all showed some effect in prolonging the survival rates of lung cancer patients with or without driver gene mutation [5,6,7,8,9]. Identifying details of the tumorigenic signaling pathways and novel therapeutic targets is still an emerging issue

Methods

Results

Conclusion