Expression of S100A4, ephrin-A1 and osteopontin in non-small cell lung cancer

Abstract

BackgroundThe metastasis-promoting protein S100A4 induces expression of ephrin-A1 and osteopontin in osteosarcoma cell lines. The aim of this study was to investigate S100A4-mediated stimulation of ephrin-A1 and osteopontin in non-small cell lung cancer (NSCLC) cell lines, and to characterize the expression of these biomarkers in primary tumor tissue from NSCLC patients.MethodsFour NSCLC cell lines were treated with extracellular S100A4, and ephrin-A1 and osteopontin expression was analyzed by real time RT-PCR and Western blotting. Immunohistochemical staining for S100A4, ephrin-A1 and osteopontin was performed on tissue microarrays containing primary tumor samples from a cohort of 217 prospectively recruited NSCLC patients, and associations with clinicopathological parameters were investigated.ResultsS100A4 induced ephrin-A1 mRNA and protein expression in adenocarcinoma, but not in squamous carcinoma cell lines, whereas the level of osteopontin was unaffected by S100A4 treatment. In primary tumors, moderate or strong immunoreactivity was observed in 57% of cases for cytoplasmic S100A4, 46% for nuclear S100A4, 86% for ephrin-A1 and 77% for osteopontin. Interestingly, S100A4 expression was associated with ephrin-A1 also in vivo, but there was no association between S100A4 and osteopontin. Expression levels of S100A4 and ephrin-A1 were significantly higher in adenocarcinomas compared to other histological subtypes, and S100A4-positive tumors were smaller and more differentiated than tumors without expression.ConclusionsOur findings suggest that S100A4, ephrin-A1 and osteopontin are involved in the biology of NSCLC, and further investigation of their potential use as biomarkers in NSCLC is warranted.

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

“…S100A4 is often overexpressed in NSCLC as well as other tobacco-related malignancies, making it an excellent therapeutic target for lung and other cancers. As published in other reports [23, 24], we found that S100A4 expression was elevated in lung adenocarcinoma. However, due to the small sample size and lack of non-smokers in our population, we could not confirm an association between S100A4 expression and tobacco exposure.…”

LIM and SH3 Protein 1 Induces TGFβ-Mediated Epithelial–Mesenchymal Transition in Human Colorectal Cancer by Regulating S100A4 Expression

“…Among them, S100A4, a member of the S100 family, was positively regulated by LASP1 in colorectal cancer cells. S100A4 was overexpressed in several kinds of tumor, including gastric (23), hepatocellular (24), colorectal (25), lung (26), and breast carcinoma (27). This was recognized as colorectal cancer metastasis-associated protein and represented as a highly significant prognostic marker in colorectal cancer (28)(29)(30)(31).…”

Role of osteopontin in osteosarcoma

“…Up-regulated OPN induces increased expression of GLUT1 and GLUT3 resulting in enhanced glucose uptake into hypoxic OS cells via the avb3 integrin which is responsible for the OS cell proliferation and drug resistance [25]. OPN is a downstream effector of S100A4 (the metastasis-promoting protein) which induces a variety of cellular effects including stimulation of angiogenesis, regulation of cell death, increased cell motility, invasion and metastasis [37,38]. Extracellular S100A4 is reported to stimulate the secretion of OPN, and increased level of OPN induces up-regulation of the components of the plasminogen activator system (uPA and its receptor uPAR) as well as matrix metalloproteinases (MMPs) by activating the transcription factor NF-kappaB in OS cell lines through induction of phosphorylation and subsequent degradation of the NF-kappaB inhibitor, IjBa.…”