The S100A4 Metastasis Factor Regulates Cellular Motility via a Direct Interaction with Myosin-IIA

Li, Zhong Hua; Bresnick, Anne R.

doi:10.1158/0008-5472.can-05-3087

Cited by 175 publications

(183 citation statements)

References 40 publications

(48 reference statements)

Supporting

Mentioning

167

Contrasting

Unclassified

Order By: Relevance

“…Indeed, it has been shown that, in breast cancer, intracellular S100A4 can induce cell motility in part through its ability to interact with myosin-IIA and extracellular S100A4 can stimulate MMP-13 activity, possibly contributing to tumor invasion (Garrett et al, 2006;Li and Bresnick, 2006). Therefore, S100A4 can promote metastasis and crossing mice that overexpress S100A4 in the mammary epithelium with mouse models of metastasis dramatically increases the incidence of metastasis (Davies et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2012

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Coupled to this is a myosin II-mediated contraction at the cell rear, which disconnects the cell from its ECM attachments. This mechanism requires that myosin II be rapidly transported through the dense actin network in the lamellipodium-a process facilitated by mts1, which depolymerizes myosin IIA (Li and Bresnick, 2006). By contrast, if myosin II is specifically required to squeeze a stiff nucleus through small pores, and if the brain environment prevents lamellipodium formation, then rapid redistribution of myosin II might not be required, and mts1 might be unnecessary.…”

Section: Molecular Biology Of the Cell 3364mentioning

confidence: 99%

The Role of Myosin II in Glioma Invasion of the Brain

Beadle

Assanah

Monzo

et al. 2008

MBoC

292

334

View full text Add to dashboard Cite

The ability of gliomas to invade the brain limits the efficacy of standard therapies. In this study, we have examined glioma migration in living brain tissue by using two novel in vivo model systems. Within the brain, glioma cells migrate like nontransformed, neural progenitor cells-extending a prominent leading cytoplasmic process followed by a burst of forward movement by the cell body that requires myosin II. In contrast, on a two-dimensional surface, glioma cells migrate more like fibroblasts, and they do not require myosin II to move. To explain this phenomenon, we studied glioma migration through a series of synthetic membranes with defined pore sizes. Our results demonstrate that the A and B isoforms of myosin II are specifically required when a glioma cell has to squeeze through pores smaller than its nuclear diameter. They support a model in which the neural progenitor-like mode of glioma invasion and the requirement for myosin II represent an adaptation needed to move within the brain, which has a submicrometer effective pore size. Furthermore, the absolute requirement for myosin II in brain invasion underscores the importance of this molecular motor as a potential target for new anti-invasive therapies to treat malignant brain tumors. INTRODUCTIONMalignant gliomas are a group of primary brain tumors that have remained resistant to therapy and that have a dismal prognosis (Buckner et al., 2007;Stupp et al., 2007). Part of the reason for this state of affairs is that although gliomas rarely metastasize outside the CNS, they are capable of spreading long distances within the brain (Sherer, 1940;Burger and Kleihues, 1989;Hoelzinger et al., 2007). This invasive behavior limits the effectiveness of local therapies and contributes to the high mortality rate seen in these tumors (Lim et al., 2007). Preventing glioma invasion therefore has the potential to convert this highly malignant tumor into a focal disease, which could then be effectively treated with focal therapies, such as radiation and surgery. Realizing this outcome, however, will require a detailed understanding how gliomas invade normal brain.Gliomas typically invade the brain by migrating long distances through white matter tracts and by infiltrating cortex and subcortical gray matter structures. Brain parenchyma (neuropil) is composed of tightly packed neuronal and glial processes, and it is characterized by extracellular spaces that are in the submicrometer range (Thorne and Nicholson, 2006). This environment therefore represents a particular mechanical challenge to motile cells, such as gliomas, that need to insinuate themselves through a highly constraining brain matrix to migrate. Unfortunately, there is very little information about how glioma cells accomplish this process in vivo. Some insight is provided by studies of embryonic and early postnatal brain, where neural progenitor cells migrate along radial glial cells, and to some extent through the white matter and cortex before stopping and differentiating into mature neurons and glia. Ti...

show abstract

“…Intracellular S100A4 interacts with proteins of the cytoskeleton, such as actin filaments, nonmuscle tropomyosin, and nonmuscle myosin II, thereby directly increasing cell motility. [13][14][15] S100A4 also induces a migratory phenotype by affecting cell adhesion via binding to liprin ␤1. 16 Moreover, S100A4 binds to the tumor suppressor p53 and modulates its transcriptional activity.…”

mentioning

confidence: 99%

Diagnostic and Prognostic Value of Metastasis Inducer S100A4 Transcripts in Plasma of Colon, Rectal, and Gastric Cancer Patients

Stein

Burock

Herrmann

et al. 2011

The Journal of Molecular Diagnostics

View full text Add to dashboard Cite

Early detection of tumors and metastases is critical for improving treatment strategies and patient outcomes.The development of molecular markers and simple tests that are clinically applicable for detection, prognostication, and therapy monitoring is strongly needed. The gene S100A4 has long been known to act as a metastasis inducer. High S100A4 levels in the primary tumor are prognostic for metachronous metastasis and correlate with reduced patient survival. We provide, for the first time, a plasma-based assay for transcript quantification of S100A4 in gastrointestinal patients' plasma. We conducted a study to define the diagnostic and prognostic power of S100A4 transcripts using 466 plasma samples from colon, rectal, and gastric cancer patients. Plasma was separated, RNA was isolated, and S100A4 mRNA was determined by quantitative RT-PCR. S100A4 transcripts were increased in cancer patients of each entity (P < 0.0001) and all disease stages (P < 0.05), compared with tumor-free volunteers (sensitivities of 96%, 74%, and 90% and specificities of 59%, 82%, and 71%, for colon, rectal, and gastric cancer patients, respectively). Prospectively analyzed follow-up patients who later experienced metastasis showed higher S100A4 levels than follow-up patients without metastasis. Disease-free survival was decreased in high S100A4-expressing follow-up colorectal cancer patients (P ‫؍‬ 0.013). In summary, we developed a method for quantitative S100A4 transcript determination in plasma that allows clinical application routinely. We demonstrated the diagnostic and prognostic potential of this method for early defining cancer staging and patients' risk for metastasis. Gastrointestinal cancers, such as colon, rectal, and gastric cancers, belong to the malignancies with the highest incidences and mortalities worldwide. Approximately 90% of all cancer deaths arise from the metastatic dissemination of primary tumors. 1,2 To date, primary colorectal carcinomas cannot be sufficiently distinguished with respect to clinical outcome parameters, such as local recurrence and metastasis, by means of conventional clinical and histopathological/immunhistochemical examination. The tumor-node-metastasis (TNM) classification represents the main tool for identifying prognostic differences among patients with early-stage colorectal cancer. 3 This is also true for gastric cancer, currently evaluated by histological staging as well. 4 Therefore, early detection of tumors and metastasis is critical for improving treatment strategies and patient outcomes. There is a clear need for development of molecular markers and of simple tests that can clinically be used for detection, prognostication, and therapy monitoring of cancer. A noninvasive blood test for the early identification of high-risk cancer patients is therefore of special interest. Circulating nucleic acids and, in particular, cell-free mRNA can be detected in plasma and permit plasma-based expression profiling. 5-9 It was recently reported that extracellular plasma RNA from colon cancer pa...

show abstract

The S100A4 Metastasis Factor Regulates Cellular Motility via a Direct Interaction with Myosin-IIA

Cited by 175 publications

References 40 publications

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

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

The Role of Myosin II in Glioma Invasion of the Brain

Diagnostic and Prognostic Value of Metastasis Inducer S100A4 Transcripts in Plasma of Colon, Rectal, and Gastric Cancer Patients

Contact Info

Product

Resources

About