S100A4 drives non-small cell lung cancer invasion, associates with poor prognosis, and is effectively targeted by the FDA-approved anti-helminthic agent niclosamide
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Rachel L. Stewart1,2, Brittany L. Carpenter1,3, Dava S. West2, Teresa Knifley1, Lili Liu4, Chi Wang1,5, Heidi L. Weiss1,5, Tamas S. Gal1,6, Eric B. Durbin1,6, Susanne M. Arnold1, Kathleen L. O’Connor1,3, Min Chen1,7
1Markey Cancer Center, University of Kentucky, Lexington, KY 40506, USA
2Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40506, USA
3Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40506, USA
4Department of Toxicology, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, Guangdong, 510300, PR China
5Department of Biostatistics, University of Kentucky, Lexington, KY 40506, USA
6Division of Biomedical Informatics, University of Kentucky, Lexington, KY 40506, USA
7Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40506, USA
Min Chen, e-mail: [email protected]
Keywords: metastasin-1, NF-κB, MMP9, FSP-1, NSCLC
Received: September 03, 2015 Accepted: April 10, 2016 Published: April 25, 2016
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.
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