S100A4 regulates membrane induced activation of matrix metalloproteinase-2 in osteosarcoma cells

Mathisen, Berit; Lindstad, Rune I.; Hansen, Janne; El-Gewely, Sara Ann; Mælandsmo, Gunhild Mari; Hovig, Eivind; Fodstad, Øystein; Loennechen, Thrina; Winberg, Jan

doi:10.1023/b:clin.0000006819.21361.03

Cited by 58 publications

(45 citation statements)

References 53 publications

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“…Down-regulation of S100A4 with ribozyme reduced the activity of several MMPs, including MMP2, as well as cell motility and invasiveness (55,56). On the other hand, treatment of tumor or endothelial cells with S100A4 increased their proteolytic activity, in particular, the activity of MMP13, and invasive growth (24,27).…”

Section: Discussionmentioning

confidence: 99%

Metastasis-associated Protein S100A4 Induces Angiogenesis through Interaction with Annexin II and Accelerated Plasmin Formation

Semov

Moreno

Onichtchenko

et al. 2005

Journal of Biological Chemistry

211

193

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Many advanced tumors overexpress and secrete the S100A4 protein that is known to promote angiogenesis and metastasis development. The mechanisms of this effect and the endothelial receptor for S100A4 are both still unknown. Here we report that extracellular S100A4 interacts with annexin II, an endothelial plasminogen co-receptor. Co-localization and direct binding of S100A4 and annexin II were demonstrated, and the binding site was identified in the N-terminal region of annexin II. S100A4 alone or in a complex with annexin II accelerated tissue plasminogen activator-mediated plasminogen activation in solution and on the endothelial cell surface through interaction of the S100A4 Cterminal lysines with the lysine-binding domains of plasminogen. A synthetic peptide corresponding to the N terminus of annexin II prevented S100A4-induced plasmin formation in the endothelial cell culture. Local plasmin formation induced by circulating S100A4 could contribute to tumor-induced angiogenesis and metastasis formation that makes this protein an attractive target for new anti-cancer and anti-angiogenic therapies.

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Section: Discussionmentioning

confidence: 99%

Metastasis-associated Protein S100A4 Induces Angiogenesis through Interaction with Annexin II and Accelerated Plasmin Formation

Semov

Moreno

Onichtchenko

et al. 2005

Journal of Biological Chemistry

211

193

View full text Add to dashboard Cite

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“…(35) Noviskaya et al reported that S100A4 stimulation was involved in the activation of both phospholipase C and protein kinase C. (16) A possible relationship between S100A4, matrix metalloproteinases, and invasive capacity has also been reported. (36,37) Extracellular function of S100A4 might also include angiogenesis. (17,38) Thus, further research is needed to clarify the intercellular and extracellular mechanisms of S100A4 involvement in the progression of ovarian carcinomas.…”

Section: Discussionmentioning

confidence: 99%

Nuclear expression of S100A4 is associated with aggressive behavior of epithelial ovarian carcinoma: An important autocrine/paracrine factor in tumor progression

Kikuchi

Horiuchi²,

Osada

et al. 2006

Cancer Science

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Although S100A4 expression has reportedly been associated with metastasis of various malignancies, little is known about its biological significance in ovarian carcinomas. In this study, we investigated expression and secretion of S100A4 and its extracellular function in ovarian carcinoma cells. We first used immunohistochemistry to examine the expression and localization of S100A4 in 113 epithelial ovarian neoplasms (24 benign, 20 borderline, and 69 malignant tumors) and analyzed its prognostic significance in patients with ovarian carcinoma. Then we investigated the expression, subcellular localization, and secretion of S100A4 in four ovarian carcinoma cell lines. Finally, we examined the effect of S100A4 treatment on the cell proliferation and invasiveness of ovarian carcinoma cells, along with activation of small GTPase, RhoA. Both cytoplasmic and nuclear expressions of S100A4 were significantly stronger in carcinomas than those in benign and borderline tumors. Ovarian carcinoma patients with strong nuclear S100A4 expression showed a significantly shorter survival than those without (P = 0.0045). This was not the case for cytoplasmic S100A4 expression. Ovarian carcinoma cell lines were shown to express S100A4, and secrete S100A4 into the culture media. Treatment with recombinant S100A4 resulted in the upregulation of S100A4 expression, translocation of S100A4 into the nucleus, and enhancement of invasiveness, which was associated with the upregulation of small GTPase, RhoA. These findings suggest that the nuclear expression of S100A4 is involved in the aggressive behavior of ovarian carcinoma and S100A4 is an autocrine/paracrine factor that plays an important role in the aggressiveness of ovarian carcinoma cells. (Cancer Sci 2006; 97: 1061-1069) E pithelial ovarian carcinoma is the leading cause of death in female genital malignancies, and more than half of the patients are diagnosed at the advanced stage of disease.(1) The poor prognosis in patients with ovarian carcinoma is most likely related to the degree of peritoneal dissemination of cancer cells. The process of peritoneal dissemination is reportedly affected by a variety of gene products.(2-8) However, little is known about the molecular aspects of the migration and invasion of ovarian carcinoma cells. Recent attention has focused on the intracellular molecules involved in the enhancement of motility and invasiveness of cancer cells, and we previously showed that upregulation and activation of a small GTPase, RhoA, plays an important role in the tumor progression of ovarian carcinoma in vivo and in vitro. The S100A4 (also known as mts-l/metastasin/pEL98/p9ka) protein belongs to the S100 protein family, which consists of 21 small, acidic, calcium-binding proteins with two common EFhand structure motifs.(10) S100A4 has been identified so far as a cytoplasmic protein that cosediments with cytoskeletal proteins such as actin, non-muscle myosin, and non-muscle tropomyosin, implying a possible role in cell motility and invasion.(11) Its relevance to the inv...

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“…The S100A4 gene is reported to confer invasive characteristics to various cancer cells; however, its role in the invasion and metastasis of CaP is yet unknown (11). Next, we analyzed the effect of S100A4 gene suppression on the invasive capability of highly invasive and metastatic CaP cells PC-3 by employing an in vitro chemoinvasion assay.…”

Section: Effect Of S100a4 Gene Knockdown On Invasive Capability Of Pcmentioning

confidence: 99%

S100A4 accelerates tumorigenesis and invasion of human prostate cancer through the transcriptional regulation of matrix metalloproteinase 9

Saleem

Kweon

Johnson

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

172

139

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We previously showed that the calcium-binding protein S100A4 is overexpressed during the progression of prostate cancer (CaP) in humans and in the TRAMP (transgenic adenocarcinoma of the mouse prostate) mouse model. We tested a hypothesis that the S100A4 gene plays a role in the invasiveness of human CaP and may be associated with its metastatic spread. We observed that siRNAmediated suppression of the S100A4 gene significantly reduced the proliferative and invasive capability of the highly invasive CaP cells PC-3. We evaluated the mechanism through which the S100A4 gene controls invasiveness of cells by using a macroarray containing 96 well characterized metastatic genes. We found that matrix metalloproteinase 9 (MMP-9) and its tissue inhibitor (TIMP-1) were highly responsive to S100A4 gene suppression. Furthermore, S100A4 suppression significantly reduced the expression and proteolytic activity of MMP-9. By employing an MMP-9-promoter reporter, we observed a significant reduction in the transcriptional activation of the MMP-9 gene in S100A4-siRNA-transfected cells. Cells overexpressing the S100A4 gene (when transfected with pcDNA3.1-S100A4 plasmid) also significantly expressed MMP-9 and TIMP-1 genes with increased proteolytic activity of MMP-9 concomitant to increased transcriptional activation of the MMP-9 gene. S100A4-siRNA-transfected cells exhibited a reduced rate of tumor growth under in vivo conditions. 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. We suggest that S100A4 could be used as a biomarker for CaP progression and a novel therapeutic or chemopreventive target for human CaP treatment. extracellular matrix ͉ metastasis ͉ biomarker A pproximately 27,350 prostate cancer (CaP)-related deaths are predicted during this year alone in the United States, and despite recent improvements in diagnostic and therapeutic techniques, the survival rate of CaP patients is poor because of the posttreatment recurrence of disease (1, 2). The lack of effective therapies for advanced CaP is related to a large extent to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis (3). Thus, the identification of new predictive biomarkers, especially those that are indicative of invasiveness of the disease, which could serve as targets for establishing effectiveness of therapeutic and chemopreventive interventions, will improve clinical management of CaP. S100A4 (also known as mts1), a calcium-binding protein associated with invasion and metastasis of cancer cells, has been reported to be frequently overexpressed in metastatic tumors, normal cells with uninhibited movement (such as macrophages), and transformed cells, and in various cancer types such as breast, ovary, thyroid, lung, esophageal squamous cell carcinoma, gastric, and colon (4-6). Studies have shown that breast cancers expressing high levels of S100A4 have a sign...

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S100A4 regulates membrane induced activation of matrix metalloproteinase-2 in osteosarcoma cells

Cited by 58 publications

References 53 publications

Metastasis-associated Protein S100A4 Induces Angiogenesis through Interaction with Annexin II and Accelerated Plasmin Formation

Metastasis-associated Protein S100A4 Induces Angiogenesis through Interaction with Annexin II and Accelerated Plasmin Formation

Nuclear expression of S100A4 is associated with aggressive behavior of epithelial ovarian carcinoma: An important autocrine/paracrine factor in tumor progression

S100A4 accelerates tumorigenesis and invasion of human prostate cancer through the transcriptional regulation of matrix metalloproteinase 9

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