Role Of Slug Research Articles

Role of the epithelial-mesenchymal transition regulator Slug in primary human cancers

Epithelial-mesenchymal-transition (EMT) is a crucial process during morphogenesis of multi-cellular organisms. EMT not only is a normal developmental process but also plays a role in tumor invasion and metastasis. Indeed, molecules involved in EMT, such as the transcription factor and E-cadherin repressor Slug (SNAI2), have recently been demonstrated to be important for cancer cells to down-regulate epithelial markers and up-regulate mesenchymal markers in order to become motile and invasive. Here we summarize major studies focusing on Slug expression in human tumor samples. We review a total of 13 studies involving 1150 cases from 9 different types of tumors. It is becoming clear that this transcription factor plays a role in the progression of some tumor types, including breast and gastric cancer. Interestingly, Slug expression is not always associated with down-regulation of E-cadherin. The mode of action, the signaling pathways involved in its regulation, and the interplay with other EMT regulators need to be addressed in future studies in order to fully understand Slug's role in tumor progression.

The role of slug in neural crest

Neural crest (NC) cells are multipotent progenitor cells that migrate throughout the vertebrate embryo and give rise to diverse derivatives. The Snail family of transcription factors plays key roles during NC development and are important mediators of metastasis in epithelial-derived tumors. Snail family factors are among the earliest regulators expressed in newly formed NC cells and play multiple roles in their development. However, the transcriptional targets of Snail family factors in NC cells and how the activity of these factors is controlled such that correct targets are regulated at the right time remain poorly understood.We show that one mechanism which the activity of Snail family factors is controlled during NC development is at the level of protein turnover. Snail and Slug are targeted to the ubiquitin–proteasome system by an E3 ubiquitin ligase, Partner of Paired, and loss of this regulation leads to premature neural crest migration, suggesting that threshold levels of Snail/Slug protein regulate distinct targets. In order to elucidate other mechanisms via which the activity of reiterative transcription factors such as Snail and Slug can be directed to the correct developmental targets we explore the contributions that distinct protein domains play in processes regulated by these factors, including NC precursor formation, migration and the regulation of apoptosis. We dissect the role that SNAG, Slug and a C-terminal Binding Protein motif play in these processes. Also, we examine the role of apoptosis in neural crest formation. We suggest that cell death is not as prevalent in this region as previously reported and that Slug-mediated control of apoptosis may not play a major role in NC precursor cell formation.

Microarray Analysis Demonstrates a Role for Slug in Epidermal Homeostasis

Slug (Snail2) is a member of the Snail family of zinc-finger transcription factors with regulatory functions in development, tissue morphogenesis, and tumor progression. Little is known about Slug in normal adult tissue; however, a role for Slug in the skin was suggested by our previous observations of Slug expression in normal murine keratinocytes and Slug induction at wound margins. To study the impact of Slug in the skin, we compared patterns of gene expression in epidermis from Slug-null and wild-type mice. A total of 139 genes had significantly increased, and 109 genes had significantly decreased expression in Slug knockout epidermis. Altered expression of selected genes in Slug knockout epidermis was validated by real-time PCR and immunohistochemistry. Previously reported Slug targets were identified, in addition to novel genes, including cytokeratins, adhesion molecules, and extracellular matrix components. Functional classification of altered gene expression was consistent with a role for Slug in keratinocyte development and differentiation, proliferation, apoptosis, adhesion, motility, as well as angiogenesis and response to environmental stimuli. These results highlight the utility of genetic models to study the in vivo impact of regulatory factors in unperturbed skin and suggest that Slug has significant activities in the adult epidermis.

New Doctorial Cancer Research:Role of Slug in Gastric Carcinoma—From Tissue Expression to Functional Analysis Using an In Vitro Model

New Doctorial Cancer Research:Role of Slug in Gastric Carcinoma—From Tissue Expression to Functional Analysis Using an In Vitro Model

Role of slug in TGF-β1 mediated MMP-9 expression in human oral squamous cell cancer

21000 Background: Oral squamous cell cancer (OSCC) causes significant morbidity and mortality as a result of loco-regional invasion and distant metastasis. Invasive OSCC tumors demonstrate increased expression of matrix metalloproteinases (MMPs), including MMP-9. TGF-β1, which promotes MMP-dependent invasion, is also frequently overexpressed in OSCC. Recent reports indicate that TGF-β1 can signal through Snail family of transcription factors, including Slug, which are key regulators of epithelial to mesenchymal transition. Methods: To examine the relationship between TGF-β1 and MMP-9 in human OSCC tumors, phospho-Smad2 and MMP-9 expression was quantified in an oral cancer tissue microarray, and then the relationship determined using Pearson correlation coefficient. To understand the role of Slug in TGF-β1-mediated MMP-9 expression, premalignant oral keratinocyte cell lines (OKF4 and OKF6) and malignant OSCC lines (SCC25 and UMSCC1) were treated with TGF-β1 (10 ng/ml) and analyzed for Slug and MMP-9 expression at the message and protein levels. The specific role of Slug was determined by transfecting OSCC cells with Slug specific siRNA or control siRNA, treating with TGF-β1 for 24h, and determining the effect on MMP-9 expression. Results: There was a statistically significant correlation between phospho-Smad2 and MMP- 9 expression in human OSCC samples, with a Pearson correlation coefficient of 0.4392 (p=0.0007). In vitro, treatment of premalignant and OSCC cells with TGF-β1 induced both Slug and MMP-9 expression at the message and protein level. Interestingly, transfection of Slug siRNA in OKF4 and OKF6 cells increased both basal and TGF-β1-mediated MMP-9 expression, while transfection of Slug siRNA in SCC25 and UMSCC1 cells decreased basal and TGF-β1-mediated MMP-9 expression. Conclusions: Overall, our data indicate that TGF-β1 may regulate MMP-9 expression in human oral squamous cell cancer. Additionally, our data indicate a role for Slug in TGF-β1-mediated MMP-9 expression in oral cancer cells. Future experiments will examine the mechanism by which Slug differentially regulates MMP-9 expression in premalignant and malignant OSCC cells. No significant financial relationships to disclose.

Role of Slug in Head and Neck Squamous Cell Carcinoma

Role of Slug in Head and Neck Squamous Cell Carcinoma

Transcription RepressorSlugPromotes Carcinoma Invasion and Predicts Outcome of Patients with Lung Adenocarcinoma

In a previous genome-wide gene expression profiling analysis using an invasion cancer cell lines model, we have identified Slug as selectively overexpressed in the highly invasive cancer cells. Here, we investigated the clinical significance of Slug in lung adenocarcinoma and the role of Slug in the process of cancer cell invasion and metastasis. Real-time quantitative reverse transcription-PCR was used to investigate Slug mRNA in surgically resected lung adenocarcinoma of 54 patients and its correlation with survival. We overexpressed Slug in a lung adenocarcinoma cell line with very low Slug levels and investigated the in vitro and in vivo effects of Slug expression. High expression of Slug mRNA in lung cancer tissue was significantly associated with postoperative relapse (P = 0.03) and shorter patient survival (P < 0.001). The overexpression of Slug enhanced xenograft tumor growth and increased microvessel counts in angiogenesis assay. Both inducible and constitutive overexpression of Slug suppressed the expression of E-cadherin and increased the in vitro invasive ability. Zymography revealed increased matrix metalloproteinase-2 activity in Slug overexpressed cells. ELISA, reverse transcription-PCR, and immunohistochemistry confirmed the increase of matrix metalloproteinase-2 proteins and mRNA in Slug overexpressed cells and xenograft tumors. Slug expression can predict the clinical outcome of lung adenocarcinoma patients. Slug is a novel invasion-promoting gene in lung adenocarcinoma.

Slug Is a Mediator of Epithelial–Mesenchymal Cell Transformation in the Developing Chicken Heart

An epithelial–mesenchymal cell transformation occurs during the development of the endocardial cushions in the atrioventricular (AV) canal of the heart. We hypothesized that the transcription factor Slug is required for this epithelial–mesenchymal cell transformation since Slug is required for similar transformations during gastrulation and neural crest differentiation in chicken embryos. We found by RT-PCR and immunostaining that the temporal and spatial localization of Slug in the embryonic chicken heart is consistent with a role for Slug in endocardial cushion formation. Moreover, we found that Slug expression by AV canal endothelial cells is induced by a signal provided by AV canal myocardium. Slug appears to be required for epithelial–mesenchymal cell transformation in the chicken heart since treatment of AV canal explants with antisense Slug oligodeoxynucleotides inhibited mesenchymal cell formation in vitro. Antisense Slug oligodeoxynucleotides prevented endothelial cell–cell separation, suggesting that Slug acts early in the transformation pathway.

The Role of Slugs in Dispersal of the Asexual Propagules of Dicranum flagellare

Dicranum flagellare Hedw. depends primarily on the dispersal ofasexual brood branch- es to colonize disturbance gaps on decaying logs. Forest slugs appear to be a significant dispersal vector. Propagules became entrapped in the slug secretions and were deposited in the slime trail. Field and laboratory trials demonstrated that slugs can detach and transport brood bodies at least 23 cm from the colony, although the mean dispersal distance was only 3.7 cm. The presence of slug secretions did not affect propagule germination rate, but did significantly increase adherence to the substrate.

The possible role of slugs (Agriolimax spp.) in the transmission of infective larvae of Cooperia oncophora.

The possible role of slugs (Agriolimax spp.) in the transmission of infective larvae of Cooperia oncophora.

Possible role of slugs as vectors of the chestnut blight fungus

AbstractSlugs (Lchmannia marginata Müller) were observed moving and feeding on chestnut blight cankers in woods. Preliminary laboratory tests support the hypothesis that slugs are important vectors in the natural spreading of the blight, complementary to other physical and biological factors.

Litter decomposition by slugs in mixed deciduous woodland

For the one year period considered, it is calculated that 683.5 g m‐2 plant litter entered the study area site. Of the six slugs studied, Arion intermedius Normand, the smallest species, had the highest overall consumption rate on the nine test foods (29.1 ± 0.9 mg dry wt g live wt‐1 d‐1) and the highest overall mean assimilation efficiency (72.0 + 0.9%). The mean faecal production for each of the six slug species was very similar, ranging from 8.4 to 9.9 mg dry wt g live wt‐1 d‐1. Using regression equations of food consumed on faeces produced, it is estimated that the slug fauna each year consumes 8.4% of the leaf litter input and 6.5% of the total available plant litter. Of the plant material consumed, 13.8 g dry wt m‐2 are deposited annually as faeces. The role of slugs in decomposition processes is discussed and compared with that of other soil organisms.

Quantitative Study of Feeding in Woodland by the Slug Arion ater

The results of gravimetric experiments on ingestion and assimilation rates of the slug Arion ater L. in mixed deciduous woodland are reported. In laboratory experiments on seven plant foods, mature slugs maintained at 10'C had a mean ingestion rate of 4.65 ? 0.32 mg dry wt/g live wt d-l with a mean assimilation efficiency of 69.96 + 0.94 %. Immature A. ater fed with three plant foods had a mean ingestion rate of 15.53 ? 1.22 mg dry wt/g live wt d-1 and a mean assimilation efficiency of 71.93 i 0.97 %. Extrapolation of laboratory measurements of egestion rates to field data suggested that mature slugs ingested a mean of 9.34 mg dry wt/g live wt d-1, while immature slugs ingested 20.15 mg dry wt/g live wtd-1. The experiments were spread over a period of five months from July to November 1973. In the study area, Arion ater made up approximately 29 % of the total slug biomass, with a mean live weight of 1.517 ? 0.414 g m-2. It is estimated that A. ater ingests approximately 8.17 g dry wtm-2 yr-1, which represents 1.54 % of the total leaf litter input. The role of slugs in plant decomposition processes is discussed.

Food of Slugs in Mixed Deciduous Woodland

The palatability of food to 8 species of slug characteristic of lowland woodland on boulder clay soils, is discussed. Faecal analyses show that all 8 species feed largely on plant material but seasonal variations are important and reflect changing food availability. Food palatability experiments suggest that there is a low specificity in the choice of 6 of the slug species but this, together with feeding zone separation, may be sufficient to explain niche separation. The role of slugs as detritivores in woodlands is discussed.

The role of slugs and snails in the maintenance of the cyanogenesis polymorphisms of Lotus corniculatus and Trifolium repens

The role of slugs and snails in the maintenance of the cyanogenesis polymorphisms of Lotus corniculatus and Trifolium repens

Snail populations, beech litter production, and the role of snails in litter decomposition.

The population densities of snails living in beech litter were studied form March 1968 to April 1969. Litter production over one year was measured and the role of snails in litter disappearance assessed.Snails were extracted from litter using a modified Vágvölgyi (1952) flotation method, extraction efficiencies being 84%. The mean annual population density of the twenty-one species of snail recorded on the main sampling site was estimated at 489/m2. Carychium tridentatum was the most numerous species, with a mean density of 200/m2. Acanthinula aculeata, Punctum pygmaeum and Vitrea contracta also had fairly high mean densities. The mean annual biomass was 699 mg dry wt./m2 or 278 mg ash-free dry wt./m2. Hygromia striolata and Oxychilus cellarius/alliarius were the most important species in terms of biomass on the main site. Within the limits of accuracy imposed by the sampling regime the population densities of four out of five of the species (C. tridentatum, A. aculeata, V. contracta, Retinella pura) studied remained unchanged throughout the year, whereas P. pygmaeum had a significantly higher autumn population. C. tridentatum populations were highly aggregated at all times of the year, most markedly so in June. Other species were aggregated at certain times of the year only. Samples taken from other sites showed total population densities of snails ranging from 185-1082 snails/m2.A total tree litter production of 652 g/m2/annum was recorded of which 584g/m2/annum was of beech material. 72% fell in the October-December period. 58% of the beech litter-fall was leaves, 5.2% bud-scales, 27% fruits and 10% twigs and bark. Summation of appropriate field layer peak standing crops amounted to 23.3 g/m2. This was considered as potential litter and was equivalent to 3.4% of the total litter input. The litter standing on the woodland floor in Septermber 1968 was 2,700 g/m2, hence, assuming a steady state, litter turnover time was estimated as 4.5 years.It was calculated that the total snail population ingested 0.35-0.43% of the annual litter input, of which 49% was assimilated. The role of the individual species is examined in relation to concepts of "key species" in ecosystem functioning. The possible role of slugs in decomposition processes is also discussed.