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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This work was supported by the National Institutes of Health T32 CA160003 (RLS), T32 CA165990 (BLC), American Cancer Society Institutional Research Grant IRG-85-001-25 (MC), the National Center for Advancing Translational Sciences, National Institutes of Health UL1TR000117 (MC), the Dr. Joseph F. Pulliam Pilot Award (MC and RLS), and the National Institutes of Health R01 CA109136 (KLO). The Markey Biospecimen and Tissue Procurement, Biostatistics and Bioinformatics and Cancer Research Informatics Shared Resource Facilities assisted with the construction of tissue microarrays and clinical annotations, and are supported by National Institutes of Health P30 CA177558.
Stewart, Rachel L.; Carpenter, Brittany L.; West, Dava S.; Knifley, Teresa; Liu, Lili; Wang, Chi; Weiss, Heidi L.; Gal, Tamas S.; Durbin, Eric B.; Arnold, Susanne M.; O'Connor, Kathleen L.; and Chen, Min, "S100A4 Drives Non-Small Cell Lung Cancer Invasion, Associates with Poor Prognosis, and is Effectively Targeted by the FDA-Approved Anti-Helminthic Agent Niclosamide" (2016). Markey Cancer Center Faculty Publications. 66.