Abstract 2275: S100A4/metastasin-1 promotes lung cancer cell invasion and associates with decreased overall survival among patients with adenocarcinoma
Authors: Stewart Rachel L. , Carpenter Brittany L. , West Dava S. , Knifley Teresa , Wang Chi , Weiss Heidi L. , Gal Tamas S. , O'Connor Kathleen L. , Chen Min 
Published: August 2015

Abstract
The metastatic nature of advanced non-small cell lung cancer (NSCLC) is associated with therapeutic resistance, quick time to progression, and poor prognosis. This dismal outcome remains until we gain a better understanding of the crucial drivers of the metastatic process and the power to effectively target them. S100A4 (metastasin-1) is a tumor metastasis associated protein and an epithelial to mesenchymal transition (EMT) marker. S100A4 contributes to several hallmarks of cancer such as anti-apoptosis, proliferation, and therapeutic resistance. This protein has been implicated in the progression of different types of cancer, including breast, colon and pancreas. However, the impacts of S100A4 signaling in lung cancer progression and its potential use as a target for therapy have not been properly explored. Here, using established lung cancer cell lines, we demonstrate that S100A4 is overexpressed in about 45% of lung cancer cell lines tested, both at the mRNA and protein levels. To address the biological action of S100A4 overexpression in lung cancer cells, loss-of function and gain-of function experiments were performed. We found that inhibition of S100A4 by shRNA in A549 and H460 lung cancer cell lines reduced cell proliferation and invasion and decreased 3D invasive growth, while exogenous overexpression of S100A4 in H1299 cells increased invasive potential. In order to examine S100A4 expression in patient-derived tissues, we constructed a lung cancer tissue microarray (TMAs, N = 212) and analyzed it using immunohistochemistry. We found that S100A4 is preferentially overexpressed in lung adenocarcinoma (P = 0.0007) when compared to squamous cell carcinoma, which was confirmed using publicly available gene expression datasets (TCGA). Furthermore, we found that S100A4 overexpression is associated with the presence of lymphovascular invasion (P = 0.0189) and with decreased overall survival (Hazard ratio 2.14, 95% confidence interval 1.08-4.22, P = 0.0243) among patients with lung adenocarcinoma. To elucidate the mechanisms by which S100A4 promotes lung cancer invasive capacity, we focused on the NF-κB pathway. We observed that depletion of S100A4 by shRNA inhibited NF-κB activity and decreased TNFα-induced MMP9 expression. Furthermore, inhibition of the NF-κB/MMP9 axis decreased lung cancer cell invasive potential. Collectively, this study highlights the importance of the S100A4/NF-κB/MMP9 axis in lung cancer invasion and metastasis and provides rationale for targeting S100A4 to combat lung cancer.
Citation Format: Rachel L. Stewart, Brittany L. Carpenter, Dava S. West, Teresa Knifley, Chi Wang, Heidi L. Weiss, Tamas S. Gal, Kathleen L. O'Connor, Min Chen. S100A4/metastasin-1 promotes lung cancer cell invasion and associates with decreased overall survival among patients with adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2275. doi:10.1158/1538-7445.AM2015-2275