S100A4 drives non-small cell lung cancer invasion, associates with poor prognosis, and is effectively targeted by the FDA-approved anti-helminthic agent niclosamide.

Rachel L Stewart,Min Chen,Lili Liu,Heidi L Weiss,Eric B Durbin,Teresa Knifley,Tamas S Gal,Chi Wang,Brittany L Carpenter,Dava S West,Kathleen L O’Connor,Susanne M Arnold

doi:10.18632/oncotarget.8969

Abstract

S100A4 (metastasin-1), a metastasis-associated protein and marker of the epithelial to mesenchymal transition, contributes to several hallmarks of cancer and has been implicated in the progression of several types of cancer. However, the impacts of S100A4 signaling in lung cancer progression and its potential use as a target for therapy in lung cancer have not been properly explored. Using established lung cancer cell lines, we demonstrate that S100A4 knockdown reduces cell proliferation, invasion and three-dimensional invasive growth, while overexpression of S100A4 increases invasive potential. In patient-derived tissues, S100A4 is preferentially elevated in lung adenocarcinoma. This elevation is associated with lymphovascular invasion and decreased overall survival. In addition, depletion of S100A4 by shRNA inhibits NF-κB activity and decreases TNFα-induced MMP9 expression. Furthermore, inhibition of the NF-κB/MMP9 axis decreases lung carcinoma invasive potential. Niclosamide, a reported inhibitor of S100A4, blocks expression and function of S100A4 with a reduction in proliferation, invasion and NF-κB-mediated MMP9 expression. Collectively, this study highlights the importance of the S100A4/NF-κB/MMP9 axis in lung cancer invasion and provides a rationale for targeting S100A4 to combat lung cancer.

Highlights

A majority of lung cancer patients present at an advanced stage, which often precludes treatment with surgical resection alone [1]
The majority of patients with advanced Non-small cell lung cancer (NSCLC) die within 18 months of diagnosis, usually as a result of metastatic disease [21, 22]
S100A4 is often overexpressed in NSCLC as well as other tobaccorelated malignancies, making it an excellent therapeutic target for lung and other cancers

Summary

Introduction

A majority of lung cancer patients present at an advanced stage, which often precludes treatment with surgical resection alone [1]. S100A4 can activate NF-κB, stimulating a pathway that promotes proliferation and cell survival in multiple tumor types [10] Through these intracellular and extracellular actions, S100A4 contributes to several hallmarks of cancer, including cell survival and proliferation, angiogenesis, invasion and metastasis, and tumor-promoting inflammation [11, 12]. Through these extensive biological functions, S100A4 expression is associated with tumor progression and is identified as a prognostic indicator in many human malignancies [6]

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Results

Conclusion