Vitamin D and the Epithelial to Mesenchymal Transition

Altres ajuts: Comunidad de Madrid to Alberto Muñoz and Antonio García de Herreros (S2010/BMD-2344 Colomics2).Several studies support reciprocal regulation between the active vitamin D derivative 1 α,25-dihydroxyvitamin D (1,25(OH)D) and the epithelial to mesenchymal transition (EMT). Thus, 1,25(OH)D inhibits EMT via the induction of a variety of target genes that encode cell adhesion and polarity proteins responsible for the epithelial phenotype and through the repression of key EMT inducers. Both direct and indirect regulatory mechanisms mediate these effects. Conversely, certain master EMT inducers inhibit 1,25(OH)D action by repressing the transcription of VDR gene encoding the high affinity vitamin D receptor that mediates 1,25(OH)D effects. Consequently, the balance between the strength of 1,25(OH)D signaling and the induction of EMT defines the cellular phenotype in each context. Here we review the current understanding of the genes and mechanisms involved in the interplay between 1,25(OH)D and EMT

Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription: implications for the epithelial-mesenchymal transition

We report that the activity of glycogen synthase kinase-3 (GSK-3) is necessary for the maintenance of the epithelial architecture. Pharmacological inhibition of its activity or reducing its expression using small interfering RNAs in normal breast and skin epithelial cells results in a reduction of E-cadherin expression and a more mesenchymal morphology, both of which are features associated with an epithelial-mesenchymal transition (EMT). Importantly, GSK-3 inhibition also stimulates the transcription of Snail, a repressor of E-cadherin and an inducer of the EMT. We identify NFkappaB as a transcription factor inhibited by GSK-3 in epithelial cells that is relevant for Snail expression. These findings indicate that epithelial cells must sustain activation of a specific kinase to impede a mesenchymal transition

Arranjos produtivos locais no estado do Pará: localização espacial das atividades florestal e de madeira e mobiliário

At the present time, the State of Pará is the third in the ranking of exports and concentrates 75% of the extracted wood from the nation’s native forests. Of the extracted wood from the Legal Amazon, 64% is directed to the national market while 36% is directed to export markets. The objective of this study was identify and to map, using the Normalized Index of Concentration (NIC), during the 1998 to 2004 period, the municipalities which are specialized in the forest, wood and furniture activities and that show significant potential to be transformed in local clusters. The results showed the existence of nine municipalities specialized, simultaneously, in the two activities, indicating the possibility of implementing public policies directed to influence the local sustainable development from those clusters with forest tradition.Forest economics, Concetration indexes, Local development, Industrial Organization,

Snail1 transcription factor controls telomere transcription and integrity

Besides controlling epithelial-to-mesenchymal transition (EMT) and cell invasion, the Snail1 transcriptional factor also provides cells with cancer stem cell features. Since telomere maintenance is essential for stemness, we have examined the control of telomere integrity by Snail1. Fluorescence in situ hybridization (FISH) analysis indicates that Snail1-depleted mouse mesenchymal stem cells (MSC) have both a dramatic increase of telomere alterations and shorter telomeres. Remarkably, Snail1-deficient MSC present higher levels of both telomerase activity and the long non-coding RNA called telomeric repeat-containing RNA (TERRA), an RNA that controls telomere integrity. Accordingly, Snail1 expression downregulates expression of the telomerase gene (TERT) as well as of TERRA 2q, 11q and 18q. TERRA and TERT are transiently downregulated during TGF-induced EMT in NMuMG cells, correlating with Snail1 expression. Global transcriptome analysis indicates that ectopic expression of TERRA affects the transcription of some genes induced during EMT, such as fibronectin, whereas that of TERT does not modify those genes. We propose that Snail1 repression of TERRA is required not only for telomere maintenance but also for the expression of a subset of mesenchymal genes

Snail1 protein in the stroma as a new putative prognosis marker for colon tumours

Peer reviewe

Mesenchymal cells reactivate Snail1 expression to drive three-dimensional invasion programs

Epithelial–mesenchymal transition (EMT) is required for mesodermal differentiation during development. The zinc-finger transcription factor, Snail1, can trigger EMT and is sufficient to transcriptionally reprogram epithelial cells toward a mesenchymal phenotype during neoplasia and fibrosis. Whether Snail1 also regulates the behavior of terminally differentiated mesenchymal cells remains unexplored. Using a Snai1 conditional knockout model, we now identify Snail1 as a regulator of normal mesenchymal cell function. Snail1 expression in normal fibroblasts can be induced by agonists known to promote proliferation and invasion in vivo. When challenged within a tissue-like, three-dimensional extracellular matrix, Snail1-deficient fibroblasts exhibit global alterations in gene expression, which include defects in membrane type-1 matrix metalloproteinase (MT1-MMP)-dependent invasive activity. Snail1-deficient fibroblasts explanted atop the live chick chorioallantoic membrane lack tissue-invasive potential and fail to induce angiogenesis. These findings establish key functions for the EMT regulator Snail1 after terminal differentiation of mesenchymal cells

TWIST1 Is Expressed in Colorectal Carcinomas and Predicts Patient Survival

TWIST1 is a transcription factor that belongs to the family of basic helix-loop-helix proteins involved in epithelial-to-mesenchymal transition and invasion processes. The TWIST1 protein possesses oncogenic, drug-resistant, angiogenic and invasive properties, and has been related with several human tumors and other pathologies. Colorectal cancer is one of the tumors in which TWIST1 is over-expressed, but its involvement in the clinical outcome of the disease is still unclear. We tested, by RT-PCR, the expression levels of TWIST1 in normal and tumor paired-sample tissues from a series of 151 colorectal cancer patients, in order to investigate its prognostic value as a tumor marker. TWIST1 expression was restricted to tumor tissues (86.1%) and correlated with lymph node metastasis (LNM). Adjusted analysis showed that the expression levels of TWIST1 correlated with overall survival (OS) and disease-free survival (DFS). Importantly, TWIST1 expression levels predicted OS specifically at stages I and II. Moreover, patients with stage II tumors and high TWIST1 levels showed even shorter survival than patients with stage III tumors. These results suggest that TWIST1 expression levels could be a tumor indicator in stage II patients and help select patients at greater risk of poor prognosis who might benefit from adjuvant chemotherapy