title: S100A4 drives non-small cell lung cancer invasion, associates with poor prognosis, and is effectively targeted by the FDA-approved anti-helminthic agent niclosamide.
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.
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY 40506, USA.|Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Stewart
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY 40506, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Brittany L
authors.initials: BL
authors.lastname: Carpenter
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Dava S
authors.initials: DS
authors.lastname: West
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Knifley
authors.affiliation: Department of Toxicology, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, Guangdong, 510300, PR China.
authors.forename: Lili
authors.initials: L
authors.lastname: Liu
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY 40506, USA.|Department of Biostatistics, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Chi
authors.initials: C
authors.lastname: Wang
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY 40506, USA.|Department of Biostatistics, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Weiss
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY 40506, USA.|Division of Biomedical Informatics, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Tamas S
authors.initials: TS
authors.lastname: Gal
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY 40506, USA.|Division of Biomedical Informatics, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Durbin
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Arnold
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY 40506, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: O'Connor
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY 40506, USA.|Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Chen
mesh_terms: D000072283:A549 Cells; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009534:Niclosamide / Q000494:pharmacology*; D011379:Prognosis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D000071999:S100 Calcium-Binding Protein A4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D034741:RNA, Small Interfering; D000071999:S100 Calcium-Binding Protein A4; D014409:Tumor Necrosis Factor-alpha; C077591:S100A4 protein, human; D009534:Niclosamide; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: FSP-1; MMP9; NF-κB; NSCLC; metastasin-1