S100A2 Induces Metastasis in Non–Small Cell Lung Cancer

Abstract

Purpose: S100 proteins are implicated in metastasis development in several cancers. In this study, we analyzed the prognostic role of mRNA levels of all S100 proteins in early stage non^small cell lung cancer (NSCLC) patients as well as the pathogenetic of S100A2 in the development of metastasis in NSCLC. Experimental Design: Microarray data from a large NSCLC patient cohort was analyzed for the prognostic role of S100 proteins for survival in surgically resected NSCLC. Metastatic potential of the S100A2 gene was analyzed in vitro and in a lung cancer mouse model in vivo. Overexpression and RNAi approaches were used for analysis of the biological functions of S100A2. Results: High mRNA expression levels of several S100 proteins and especially S100A2 were associated with poor survival in surgically resected NSCLC patients. Upon stable transfection into NSCLC cell lines, S100A2 did not alter proliferation. However, S100A2 enhanced transwell migration as well as transendothelial migration in vitro. NOD/SCID mice injected s.c. with NSCLC cells overexpressing S100A2 developed significantly more distant metastasis (64%) than mice with control vector transfected tumor cells (17%; P < 0.05). When mice with S100A2 expressing tumors were treated i.v. with shRNA against S100A2, these mice developed significantly fewer lung metastasis than mice treated with control shRNA (P = 0.021). Conclusions: These findings identify S100A2 as a strong metastasis inducer in vivo. S100A2 might be a potential biomarker as well as a novel therapeutic target in NSCLC metastasis.

Impact of somatic copy number alterations on the glioblastoma miRNome: miR‐4484 is a genomically deleted tumour suppressor

“…It is noteworthy that most of these genes play a significant role in gliomagenesis in particular as well as in other cancers in general. S100A2 has been reported to be hypomethylated in GBM (Etcheverry et al ., 2010; Martinez and Schackert, 2007) and functions as an inducer of metastasis in vivo in non‐small‐cell lung cancer (Bulk et al ., 2009). Overexpression of S100A2 also induced epithelial‐to‐mesenchymal transformation followed by enhanced invasion and increased AKT phosphorylation in A549 lung cancer cells (Naz et al ., 2014).…”

Involvement of S100A14 Protein in Cell Invasion by Affecting Expression and Function of Matrix Metalloproteinase (MMP)-2 via p53-dependent Transcriptional Regulation

“…Among them, S100A4 has been identified as a well known metastasis marker (9). In addition, S100A2 has also been reported as a strong metastasis inducer in non-small cell lung cancer (41). S100A8/ S100A9 has been implicated in both myeloid cell recruitment and tumor cell invasion in lung cancer (10).…”

S100A2 (S100 calcium binding protein A2)

“…High expression of S100A2 is associated with metastasis and predicts survival in early stages of NSCLC. These findings are supported by studies in a mouse model of non-small cell lung cancer (NSCLC) where NOD/SCID mice xenografted with NSCLC cells overexpressing S100A2 demonstrated significantly more metastases than vector alone transfected cells (Heighway et al, 2002;Diederichs et al, 2004;Smith et al, 2004;Wang et al, 2005;Zech et al, 2006;Bartling et al, 2007;Bulk et al, 2009;Strazisar et al, 2009a;Strazisar et al, 2009b).…”