Here, we found that S100 calcium-binding protein A4 (S100A4), a major metastasis-promoting protein, confers metabolic plasticity to drive tumor invasion and metastasis of non-small cell lung cancer cells.
Our data demonstrate that the S100A4 gene controls the invasive potential of human CaP cells through regulation of MMP-9 and that this association may contribute to metastasis of CaP cells.
Using immunohistochemistry, we found that high levels of S100A4 were detected in 24 of 28 (86%) PTC specimens and their local regional lymph node or distant metastases.
Mutations of the cell cycle regulatory genes p16INK4A and p21WAF1 and the metastasis-inducing gene S100A4 are infrequent and unrelated to p53 tumour suppressor gene status and data on survival in oropharyngeal squamous cell carcinomas.
The structure of the active form of S100A4 provides insight into its interactions with its binding partners and a better understanding of its role in metastasis.
Further multivariate analysis suggested that depth of invasion, lymph node and distant metastases, tumor-node-metastasis (TNM) stage, and upregulation of S100A4 were independent prognostic indicators for the disease.
The consequences are intriguing, connecting the metastasis-promoting protein S100A4 to the large set of important p53-mediated functions, with broad potential importance in cancer development and metastasis.
These results identify the amino acids of S100A4 that are involved in metastasis induction and show that the C-terminal region of S100A4 is a possible target for inhibitors of its metastatic action.
Furthermore, S100A4 levels were determined because recent reports have suggested a possible association between MMPs, TIMPs, and the metastasis-associated gene S100A4.
High levels of S100A4 were found to significantly correlate with histological grade (P=0.030) and loss of oestrogen receptor (P=0.046), but not to the time interval between surgery and development of distant metastasis (P=0.51) or to patient survival (P=0.89).
We then knocked down of S100A4 expression by RNA interference (S100A4 siRNA) and investigated its effects on growth and metastasis in two human ATC cell lines 8505C (BRAFV600E) and Cal-62 (BRAFwt) in vitro and in vivo.
To investigate whether S100A4 plays an important role in the invasion and metastasis of gastric cancers, we examined the gene mutations in the coding regions and expression patterns of the S100A4 in gastric adenocarcinoma in Korea.
OPN is, as S100A4, known to result in a variety of cellular effects potentially leading to increased angiogenesis and metastasis, and several of the activated signaling pathways are common for the two proteins.
In metastatic breast cancers, NFAT5 promotes epithelial-mesenchymal transition (EMT) and invasion of cells by switching on the expression of the calcium binding protein S100A4, and facilitates the angiogenesis of breast epithelial cells and thus the development of metastases by transcriptionally activating vascular endothelial growth factor C (VEGF-C).
The functional importance of stromal Tenascin-C and S100A4(+) fibroblast-derived VEGF-A in metastasis was established by examining Tenascin-C null mice and transgenic mice expressing Cre recombinase under control of the S100A4 promoter crossed with mice carrying VEGF-A alleles flanked by loxP sites, which exhibited a significant decrease in metastatic colonization without effects on primary tumor growth.
In addition, the expression of the metastasis-associated gene 18A2/mts1 as well as the tissue inhibitor of metalloproteinases-2 (TIMP-2) was analysed in each of the glioma-derived cell lines.