Cancer predisposition in mice deficient for the metastasis-associated Mts1(S100A4) gene

El-Naaman, Christina; Grum-Schwensen, Birgitte; Mansouri, Ahmed; Grigorian, Mariam; Santoni-Rugiu, Eric; Hansen, Thomas Folkmann; Kriajevska, Marina; Schäfer, Beat W.; Heizmann, Claus W.; Lukanidin, Eugene; Ambartsumian, Noona

doi:10.1038/sj.onc.1207420

Cited by 61 publications

(44 citation statements)

References 69 publications

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“…Interestingly, mice with a germline inactivation of the S100A4 gene have been found to develop spontaneous tumours as a result of destabilisation of the apoptosis-promoting function of p53 tumour suppressor gene. However, tumours developed in these mice were nonmetastatic (EL Naaman et al, 2004).…”

Section: Analysis Of Thyroid Tumour Specimens For S100a4 Gene Expressmentioning

confidence: 99%

“…Although it is not clear what leads to the focal overexpression of S100A4, it may be resulted from local demethylation or hypomethylation, one of the early events in tumour development. Overexpression of S100A4 induced by this epigenetic event may contribute to abrogation of apoptosis and tumorigenesis (EL Naaman et al, 2004). It may also be an early sign of malignant transformation resulting from genetic mutations leading to oncogene activation and/or inactivation of tumour suppressor genes.…”

Section: Analysis Of Thyroid Tumour Specimens For S100a4 Gene Expressmentioning

confidence: 99%

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S100A4 (Mts1) gene overexpression is associated with invasion and metastasis of papillary thyroid carcinoma

et al. 2005

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Tumour cell invasion and metastasis are the hallmark of malignant neoplasm. S100A4 is a member of small calcium-binding protein family and is involved in the cell proliferation and cancer progression. S100A4 is capable of inducing metastasis in animal models and is associated with aggressive phenotype of human tumours. We previously identified S100A4 as a candidate gene involved in anaplastic thyroid cancer metastasis by microarray analysis. To further determine whether S100A4 overexpression is associated with thyroid tumour invasion and metastasis, in the present study, we examined S100A4 gene expression in six benign multinodular goitres (MNG) and 28 matched samples of adjacent normal thyroid tissue (N), primary (T) and metastatic (M) papillary thyroid carcinomas (PTC) by immunohistochemistry and real-time reverse transcription -polymerase chain reaction (RT-PCR) analysis. This gave us the advantage of directly comparing levels of S100A4 expression within the same genetic background. 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. No S100A4 staining was observed in normal thyroid tissues and simple MNG. However, in MNG coexistent with PTC, moderate focal staining could be found in 11 of 15 MNG adjacent to PTC. The S100A4 was stained more intensely in invading fronts than in central portions of both T and M. Real-time RT -PCR analysis of primary tumours and their matched lymph node metastasis demonstrated that significantly higher S100A4 transcripts were present in metastatic tumours as compared to the primary tumours (Po0.01). These data suggest that overexpression of S100A4 is associated with thyroid tumour invasion and metastasis and it may be a potential target for therapeutic intervention.

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Section: Analysis Of Thyroid Tumour Specimens For S100a4 Gene Expressmentioning

confidence: 99%

Section: Analysis Of Thyroid Tumour Specimens For S100a4 Gene Expressmentioning

confidence: 99%

S100A4 (Mts1) gene overexpression is associated with invasion and metastasis of papillary thyroid carcinoma

et al. 2005

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“…Similarly, S100A4 was only detected in the injured animals in WM and blood cells at the lesion site (Fig. 1b,c, S100A4-specific antibodies characterized in El Naaman et al 26 and Supplementary Fig. S1a,b).…”

Section: S100a4 Is Upregulated In Brain Injury and Protects Neuronsmentioning

confidence: 99%

“…Cross-linking was terminated by adding 50 mM Tris-Cl (pH 7.5, 15 min). The cells were lysed in the thiol-free lysis buffer, and the cross-linked proteins were resolved by SDS-PAGE followed by immunoblotting using antibodies against S100A4 (1:2,000) 26 and anti-Myc (1:1,000, OriGene) and IRDye secondary antibodies (Odyssey, Lincoln, Nebraska, USA). The bands were visualized using Odyssey CLX Infrared Imaging System (Odyssey).…”

Section: 3mentioning

confidence: 99%

“…Immunohistochemistry was performed on 7 mm coronal sections (three per animal) as described in Klementiev et al 24 We used the following primary antibodies: anti-GAP-43 (1:400; Chemicon), anti-GFAP (1:500; DakoCytomation), anti-human S100A4 (1:200) 14 , anti-mouse S100A4 (1:1,000) 16,26 , anti-MTI þ II (1:250, DakoCytomation), anti-8-oxoguanine (1:1,000, Millipore), anti-NF-200 (1:1,000, Sigma), anti-tau1 (1:4,000, Millipore) and anti-NeuN (1:250, Chemicon), followed by biotin-conjugated (Sigma) or Alexa Fluor-conjugated (Invitrogen) secondary antibodies. Negative controls were prepared identically, but the primary antibody was omitted.…”

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confidence: 99%

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The metastasis-promoting S100A4 protein confers neuroprotection in brain injury

Dmytriyeva¹,

Pankratova²,

Owczarek³

et al. 2012

Nat Commun

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117

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Identification of novel pro-survival factors in the brain is paramount for developing neuroprotective therapies. The multifunctional S100 family proteins have important roles in many human diseases and are also upregulated by brain injury. However, S100 functions in the nervous system remain unclear. Here we show that the S100A4 protein, mostly studied in cancer, is overexpressed in the damaged human and rodent brain and released from stressed astrocytes. Genetic deletion of S100A4 exacerbates neuronal loss after brain trauma or excitotoxicity, increasing oxidative cell damage and downregulating the neuroprotective protein metallothionein I þ II. We identify two neurotrophic motifs in S100A4 and show that these motifs are neuroprotective in animal models of brain trauma. Finally, we find that S100A4 rescues neurons via the Janus kinase/STAT pathway and, partially, the interleukin-10 receptor. Our data introduce S100A4 as a therapeutic target in neurodegeneration, and raise the entire S100 family as a potentially important factor in central nervous system injury.

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Up‐regulation of metastasis‐promoting S100A4 (Mts‐1) in rheumatoid arthritis: Putative involvement in the pathogenesis of rheumatoid arthritis

Klingelhöfer¹,

Šenolt²,

Baslund³

et al. 2007

Arthritis & Rheumatism

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107

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Objective. To examine the involvement of the metastasis-inducing protein S100A4 (Mts-1) in the pathogenesis of rheumatoid arthritis (RA).Methods. Synovial tissue, synovial fluid, and plasma were obtained from RA and osteoarthritis (OA) patients who were undergoing joint surgery. Immunohistochemical and immunofluorescence analyses and enzyme-linked immunosorbent assays were used to determine the locations and concentrations of S100A4. The conformational structure of S100A4 in plasma and synovial fluid was determined after fractionation by size-exclusion chromatography, protein separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and Western blot analysis. Expression of various S100 proteins in RA synovium was determined by immunofluorescence and double-staining using specific anti-S100 antibodies.Results. We found an up-regulation of S100A4 in cells infiltrating RA synovial tissue. Most cell types identified by cell-specific markers (fibroblasts, immune cells, and vascular cells) contributed to the production of S100A4 in RA synovial tissue. The pattern of S100A4 expression differed significantly from that of the proinflammatory proteins S100A9 and S100A12, which were restricted to phagocytes and granulocytes. The upregulation of S100A4 in RA synovial tissue was consistent with the high concentrations of the protein in RA versus OA plasma (mean 1,100 versus 211 ng/ml) and synovial fluid (mean 1,980 versus 247 ng/ml). Moreover, we found that S100A4 in RA plasma and synovial fluid was present in bioactive multimeric (M-S100A4) conformations, whereas in OA, the majority of extracellular S100A4 was detected as the less active dimeric form. Consistent with our observations in tumor models, extracellular S100A4 stabilized the p53 tumor suppressor in RA synovial fibroblast-like cells and affected the regulation of p53 target genes, including Bcl-2, p21 WAF , and Hdm-2, as well as matrix metalloproteinases.Conclusion. Overexpression of S100A4 in RA synovial tissue and its release as M-S100A4 can influence p53 function and modulate the expression of several genes that are potentially implicated in the disease process. Thus, S100A4 might play an important role in the pathogenesis of RA and might represent a new target for the treatment of RA.

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Cancer predisposition in mice deficient for the metastasis-associated Mts1(S100A4) gene

Cited by 61 publications

References 69 publications

S100A4 (Mts1) gene overexpression is associated with invasion and metastasis of papillary thyroid carcinoma

S100A4 (Mts1) gene overexpression is associated with invasion and metastasis of papillary thyroid carcinoma

The metastasis-promoting S100A4 protein confers neuroprotection in brain injury

Up‐regulation of metastasis‐promoting S100A4 (Mts‐1) in rheumatoid arthritis: Putative involvement in the pathogenesis of rheumatoid arthritis

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