The metastasis associated protein S100A4: role in tumour progression and metastasis

Helfman, David M.; Ej, Kim; Lukanidin, Eugene; Grigorian, Mariam

doi:10.1038/sj.bjc.6602613

Cited by 211 publications

(177 citation statements)

References 33 publications

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“…25 Many in vitro and in vivo studies in rodents have provided evidence that S100A4 is directly involved in tumor progression and metastasis. 25,26 Hence, the prognostic significance of S100A4 expression has been evaluated in various human cancers, and it has been shown to be a prognostic marker in breast, pancreatic, prostate, gallbladder, esophageal, gastric and non-small cell lung cancers. 27 With regard to thyroid cancer, S100A4 was reported to be the most highly expressed gene in a thyroid carcinoma cell line with high metastatic potential, and its overexpression was observed in most advanced thyroid carcinomas including papillary thyroid carcinomas and anaplastic carcinomas.…”

Section: Discussionmentioning

confidence: 99%

S100A4 expression is associated with lymph node metastasis in papillary microcarcinoma of the thyroid

et al. 2008

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The detection of papillary microcarcinomas of the thyroid is increasing due to frequent use of ultrasound and fine-needle aspiration biopsy. Although most of the papillary microcarcinomas remain quiescent and follow an indolent clinical course, some behave aggressively and metastasize early, giving rise to clinically significant disease. There have been few studies concerning factors predictive of lymph node metastasis in papillary microcarcinomas. We analyzed the expression of S100A4, cyclin D1, p27 and MUC1, the presence of the BRAF V600E mutation and the clinicopathological features of the tumors, including patient age, tumor size (Z5 vs o5 mm), extrathyroidal extension, multifocality, histological subtype, sclerosis and encapsulation, in a series of 198 papillary microcarcinomas in relation to lymph node metastasis to determine the predictive factors of lymph node metastasis. On univariate analysis, tumor size of 5 mm or more, extrathyroidal extension, multifocality, sclerosis and the expression of S100A4 and cyclin D1 predicted lymph node metastasis, whereas patient age, expression of p27 and MUC1 and the BRAF V600E mutation did not. Moreover, tumor size 5 mm or more, multifocality and expression of S100A4, especially its strong expression in the invasive fronts, were significantly associated with macrometastasis and lateral node metastasis. On multivariate analysis, multifocality and expression of S100A4 were found to be common independent predictive factors of lymph node metastasis, macrometastasis and lateral node metastasis. In conclusion, S100A4 expression in papillary microcarcinomas may indicate the presence of nodal metastasis. Thus, S100A4 immunohistochemistry may be valuable for predicting metastatic potential in papillary microcarcinomas.

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Section: Discussionmentioning

confidence: 99%

S100A4 expression is associated with lymph node metastasis in papillary microcarcinoma of the thyroid

et al. 2008

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“…These genes were also chosen based on recent studies which suggest the role of S100 proteins in mediating various cellular processes including cell growth, differentiation, cell migration, and cell adhesion (20)(21)(22). Among S100 proteins, S100A4, S100A8, and S100A9 have emerged as potential prognostic markers for poor patient survival and metastasis of a number of cancers (14,(23)(24)(25). S100A8 and S100A9 were shown to be overexpressed in gastric cancer (26,27), prostate cancer (28), breast cancer (29), lung adenocarcinomas (30), pulmonary adenocarcinoma (30), and hepatocellular carcinoma (31).…”

Section: Discussionmentioning

confidence: 99%

“…Because mounting evidence suggested oncogenic activities of S100 proteins in the regulation of cell motility and invasion during human cancer progression and metastasis (14,15), the subsequent study focused on these two proteins. In order to ensure the real-time PCR data of S100A8 and S100A9 obtained by TaqMan assay, the SYBRGreen assay was done on these two genes and the same results were obtained (data not shown).…”

Section: Validation Of Microarray Analysis By Real-time Pcr and Revermentioning

confidence: 99%

Global Gene Expression Profiling Unveils S100A8/A9 as Candidate Markers in H-Ras-Mediated Human Breast Epithelial Cell Invasion

Moon

Hao

Song

et al. 2008

Molecular Cancer Research

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The goal of the present study is to unveil the gene expression profile specific to the biological processes of human breast epithelial cell invasion and migration using an MCF10A model genetically engineered to constitutively activate the H-ras or N-ras signaling pathway. We previously showed that H-Ras, but not N-Ras, induces MCF10A cell invasion/migration, whereas both H-Ras and N-Ras induce cell proliferation and phenotypic transformation. Thus, these cell lines provide an experimental system to separate the gene expression profile associated with cell invasion apart from cell proliferation/transformation. Analysis of whole human genome microarray revealed that 412 genes were differentially expressed among MCF10A, N-Ras MCF10A, and H-Ras MCF10A cells and hierarchical clustering separated 412 genes into four clusters. We then tested whether S100A8 and S100A9, two of the genes which are most highly up-regulated in an H-Ras -specific manner, play a causative role for H-Ras -mediated MCF10A cell invasion and migration. Importantly, small interfering RNA -mediated knockdown of S100A8/A9 expression significantly reduced H-Ras -induced invasion/ migration. Conversely, the induction of S100A8/A9 expression conferred the invasive/migratory phenotype to parental MCF10A cells. Furthermore, we provided evidence of signaling cross-talk between S100A8/A9 and the mitogen-activated protein kinase signaling pathways essential for H-Ras -mediated cell invasion and migration. Taken together, this study revealed S100A8/A9 genes as candidate markers for metastatic potential of breast epithelial cells. Our gene profile data provide useful information which may lead to the identification of additional potential targets for the prognosis and/or therapy of metastatic breast cancer. (Mol Cancer Res 2008;6(10):1544 -53)

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“…S100A4 or metastasin, which is a member of the S100 family of calcium-binding proteins, has been shown to have an important role in breast cancer progression (Helfman et al, 2005;Garrett Regulation of NFAT5 by ddx5/ddx17 S Germann et al et al, 2006). We have recently reported that lipocalin 2 (LCN2), which also plays a role in breast cancer progression (Yang et al, 2009;Leng et al, 2011), is regulated by NFAT transcriptional factors (Fougere et al, 2010).…”

Section: Nfat5 Ddx17mentioning

confidence: 99%

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

et al. 2012

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Ddx5 and ddx17 are two highly related RNA helicases involved in both transcription and splicing. These proteins coactivate transcription factors involved in cancer such as the estrogen receptor alpha, p53 and beta-catenin. Ddx5 and ddx17 are part of the splicing machinery and can modulate alternative splicing, the main mechanism increasing the proteome diversity. Alternative splicing also has a role in gene expression level regulation when it is coupled to the nonsensemediated mRNA decay (NMD) pathway. In this work, we report that ddx5 and ddx17 have a dual role in the control of the pro-migratory NFAT5 transcription factor. First, ddx5 and ddx17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration. Second, at the splicing level, ddx5 and ddx17 increase the inclusion of NFAT5 exon 5. As exon 5 contains a pre-mature translation termination codon, its inclusion leads to the regulation of NFAT5 mRNAs by the NMD pathway and to a decrease in NFAT5 protein level. Therefore, we demonstrated for the first time that a transcriptional coregulator can simultaneously regulate the transcriptional activity and alternative splicing of a transcription factor. This dual regulation, where ddx5 and ddx17 enhance the transcriptional activity of NFAT5 although reducing its protein expression level, suggests a critical role for ddx5 and ddx17 in tumor cell migration through the fine regulation of NFAT5 pathway.

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The metastasis associated protein S100A4: role in tumour progression and metastasis

Cited by 211 publications

References 33 publications

S100A4 expression is associated with lymph node metastasis in papillary microcarcinoma of the thyroid

S100A4 expression is associated with lymph node metastasis in papillary microcarcinoma of the thyroid

Global Gene Expression Profiling Unveils S100A8/A9 as Candidate Markers in H-Ras-Mediated Human Breast Epithelial Cell Invasion

Dual role of the ddx5/ddx17 RNA helicases in the control of the pro-migratory NFAT5 transcription factor

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