SPROUTY-2 represses the epithelial phenotype of colon carcinoma cells via upregulation of ZEB1 mediated by ETS1 and miR-200/miR-150

SPROUTY-2 (SPRY2) is a modulator of tyrosine kinase receptor signaling with receptor- and cell type-dependent inhibitory or enhancing effects. Studies on the action of SPRY2 in major cancers are conflicting and its role remains unclear. Here we have dissected SPRY2 action in human colon cancer. Global transcriptomic analyses show that SPRY2 downregulates genes encoding tight junction proteins such as claudin-7 and occludin and other cell-to-cell and cell-to-matrix adhesion molecules in human SW480- ADH colon carcinoma cells. Moreover, SPRY2 represses LLGLL2/HUGL2, PATJ1/INADL and ST14, main regulators of the polarized epithelial phenotype, and ESRP1, an epithelial-to-mesenchymal transition (EMT) inhibitor. A key action of SPRY2 is the upregulation of the major EMT inducer ZEB1, as these effects are reversed by ZEB1 knock-down by means of RNA interference. Consistently, we found an inverse correlation between the expression level of claudin-7 and those of SPRY2 and ZEB1 in human colon tumors. Mechanistically, ZEB1 upregulation by SPRY2 results from the combined induction of ETS1 transcription factor and the repression of microRNAs (miR-200 family, miR-150) that target ZEB1 RNA. Moreover, SPRY2 increased AKT activation by epidermal growth factor (EGF) whereas AKT and also Src inhibition reduced the induction of ZEB1. Altogether, these data suggest that AKT and Src are implicated in SPRY2 action. Collectively, these results show a tumorigenic role of SPRY2 in colon cancer that is based on the dysregulation of tight junction and epithelial polarity master genes via upregulation of ZEB1. The dissection of the mechanism of action of SPRY2 in colon cancer cells is important to understand the upregulation of this gene in a subset of patients with this neoplasia that have poor prognosis.This study was supported by the Ministerio de Economía y Competitividad of Spain and Fondo Europeo de Desarrollo Regional (FEDER) (grant SAF2013-43468-R to A.M., SAF2011-29530 to F.X.R.); FEDERInstituto de Salud Carlos III (RD12/0036/0021 to A.M. and J.M.R., RD12/0036/0034 to F.X.R., RD12/0036/0016 to M.S., RD12/0036/0012 to H.G.P., RD06/0020/0003, PS09/00562 and PI13/00703 to J.M.R.); Comunidad de Madrid (S2010/BMD-2344 Colomics2 to A.M.); Fundación Científica de la Asociación Española contra el Cáncer (to J.M.R.); U.S. Department of Defense (CA093471 and CA110602 to E.H.); National Institutes of Health/National Cancer Institute (1R01CA155234-01 to E.H.); National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (1R21AR062239-01 to E.H.); and the Melanoma Research Alliance (to E. H.)

Synthesizing plausible futures for biodiversity and ecosystem services in europe and central asia using scenario archetypes

Scenarios are a useful tool to explore possible futures of social-ecological systems. The number of scenarios has increased dramatically over recent decades, with a large diversity in temporal and spatial scales, purposes, themes, development methods, and content. Scenario archetypes generically describe future developments and can be useful in meaningfully classifying scenarios, structuring and summarizing the overwhelming amount of information, and enabling scientific outputs to more effectively interface with decision-making frameworks. The Intergovernmental Platform for Biodiversity and Ecosystem Services (IPBES) faced this challenge and used scenario archetypes in its assessment of future interactions between nature and society. We describe the use of scenario archetypes in the IPBES Regional Assessment of Europe and Central Asia. Six scenario archetypes for the region are described in terms of their driver assumptions and impacts on nature (including biodiversity) and its contributions to people (including ecosystem services): Business-as-usual, economic optimism, regional competition, regional sustainability, global sustainable development, and inequality. The analysis shows that trade-offs between nature’s contributions to people are projected under different scenario archetypes. However, the means of resolving these trade-offs depend on differing political and societal value judgements within each scenario archetype. Scenarios that include proactive decision making on environmental issues, environmental management approaches that support multifunctionality, and mainstreaming environmental issues across sectors, are generally more successful in mitigating tradeoffs than isolated environmental policies. Furthermore, those scenario archetypes that focus on achieving a balanced supply of nature’s contributions to people and that incorporate a diversity of values are estimated to achieve more policy goals and targets, such as the UN Sustainable Development Goals and the Convention on Biological Diversity Aichi targets. The scenario archetypes approach is shown to be helpful in supporting science-policy dialogue for proactive decision making that anticipates change, mitigates undesirable trade-offs, and fosters societal transformation in pursuit of sustainable development. © 2019 by the author(s)

β-catenin negatively regulates expression of the prostaglandin transporter PGT in the normal intestinal epithelium and colorectal tumour cells: A role in the chemopreventive efficacy of aspirin

Background: Levels of the pro-tumorigenic prostaglandin PGE 2 are increased in colorectal cancer, previously attributed to increased synthesis through COX-2 upregulation and, more recently, to decreased catabolism. The functionally linked genes 15-prostaglandin dehydrogenase (15-PGDH) and the prostaglandin transporter PGT co-operate in prostaglandin degradation and are downregulated in colorectal cancer. We previously reported repression of 15-PGDH expression by the Wnt/β-catenin pathway, commonly deregulated during early colorectal neoplasia. Here we asked whether β-catenin also regulates PGT expression. Methods: The effect of β-catenin deletion in vivo was addressed by PGT immunostaining of β-catenin/lox-villin-cre-ERT2 mouse tissue. The effect of siRNA-mediated β-catenin knockdown and dnTCF4 induction in vitro was addressed by semi-quantitative and quantitative real-time RT-PCR and immunoblotting. Results: This study shows for the first time that deletion of β-catenin in murine intestinal epithelium in vivo upregulates PGT protein, especially in the crypt epithelium. Furthermore, β-catenin knockdown in vitro increases PGT expression in both colorectal adenoma-and carcinoma-derived cell lines, as does dnTCF4 induction in LS174T cells.Conclusions:These data suggest that β-catenin employs a two-pronged approach to inhibiting prostaglandin turnover during colorectal neoplasia by repressing PGT expression in addition to 15-PGDH. Furthermore, our data highlight a potential mechanism that may contribute to the non-selective NSAID aspirins chemopreventive efficacy. © 2012 Cancer Research UK All rights reserved

The use of scenarios and models to evaluate the future of nature values and ecosystem services in Mediterranean forests

Science and society are increasingly interested in predicting the effects of global change and socio-economic development on natural systems, to ensure maintenance of both ecosystems and human well-being. The Intergovernmental Platform on Biodiversity and Ecosystem Services has identified the combination of ecological modelling and scenario forecasting as key to improving our understanding of those effects, by evaluating the relationships and feedbacks between direct and indirect drivers of change, biodiversity, and ecosystem services. Using as case study the forests of the Mediterranean basin (complex socio-ecological systems of high social and conservation value), we reviewed the literature to assess (1) what are the modelling approaches most commonly used to predict the condition and trends of biodiversity and ecosystem services under future scenarios of global change, (2) what are the drivers of change considered in future scenarios and at what scales, and (3) what are the nature and ecosystem service indicators most commonly evaluated. Our review shows that forecasting studies make relatively little use of modelling approaches accounting for actual ecological processes and feedbacks between different socio-ecological sectors; predictions are generally made on the basis of a single (mainly climate) or a few drivers of change. In general, there is a bias in the set of nature and ecosystem service indicators assessed. In particular, cultural services and human well-being are greatly underrepresented in the literature. We argue that these shortfalls hamper our capacity to make the best use of predictive tools to inform decision-making in the context of global change.This work was supported by the Spanish Government through the INMODES project (grant number CGL2017-89999-C2-2-R), the ERA-NET FORESTERRA project INFORMED (grant number 29183), and the project Boscos Sans per a una Societat Saludable funded by Obra Social la Caixa (https://obrasociallacaixa.org/). AMO and AA were supported by Spanish Government through the “Juan de la Cierva” fellowship program (IJCI-2016-30349 and IJCI-2016-30049, respectively). JVRD was supported by the Government of Asturias and the FP7-Marie Curie-COFUND program of the European Commission (Grant “Clarín” ACA17-02)

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Dissecting tumor anatomy: Intratumoral cell heterogeneity defines response to target-directed therapies

Resumen del trabajo presentado al XXXIV Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Barcelona del 5 al 8 de septiembre de 2011.-- et al.Accumulated evidences indicate that most solid tumors are not homogeneous but built of cancer cell populations with divers biological properties. They follow a hierarchical organization in which self-renewing cancer stem cells (CSC) are in the apex of a differentiation process within the cancerous tissue. CSC can also compose the small reservoir of drug-resistant cells responsible for tumor relapse or can give rise to metastasis. Our laboratory is exploring such heterogeneity and describing novel populations of cancer cells within colon carcinomas responsible for drugresistance, relapse or metastasis, all clinical determinants of patients' survival. Blocking signaling pathways that drive CSC distinctive properties is a new strategy being recently explored in clinical oncology by the use of novel targetdirected drugs. Wnt/β-catenin and PI3K/AKT are two of these pathways playing a central role in CSC homeostasis. We have described the function of their corresponding effectors - β-catenin and FOXO3a - cooperating in colon cancer. Their activation promotes cell scatteringand metastasis regulating a set of common target genes. Unexpectedly, the anti-tumoral AKT inhibitor API-2 promotes nuclear FOXO3a accumulation and metastasis from cells with high nuclear β-catenin. β-catenin confers resistance to FOXO3a-induced apoptosis promoted by PI3K and AKT inhibitors in patient-derived cells enriched in CSC, that is reverted by Wnt/β-catenin inhibitor XAV-939. Our findings could have a serious impact on therapy since we demonstrate that nuclear β-catenin heterogeneity compromises the response of different cancer cell populations to anti-tumoral drugs currently in clinical trials and directed against PI3K/AKT oncogenic signal.Peer Reviewe

SPROUTY2 is a β-catenin and FOXO3a target gene indicative of poor prognosis in colon cancer

SPROUTY2 (SPRY2) is an intracellular regulator of receptor tyrosine kinase signaling involved in cell growth, differentiation and tumorigenesis. Here, we show that SPRY2 is a target gene of the Wnt/β-catenin pathway that is abnormally activated in more than 90% of colon carcinomas. In human colon cancer cells, SPRY2 expression is induced by β-catenin in co-operation with the transcription factor FOXO3a instead of lymphoid enhancer factor/T-cell factor proteins. We found binding of β-catenin to the SPRY2 promoter at FOXO3a response elements. In vivo, cells marked by nuclear β-catenin and FOXO3a express SPRY2 in proliferative epithelial tissues, such as intestinal mucosa and epidermis. Consistently, inducible β-catenin deletion in mice reduced Spry2 expression in the small intestine. Moreover, SPRY2 protein expression correlated with nuclear β-catenin and FOXO3a colocalization in human colon carcinomas. Importantly, the amount of SPRY2 protein correlated with shorter overall survival of colon cancer patients. Our data reveal SPRY2 as a novel Wnt/β-catenin and FOXO3a target gene indicative of poor prognosis in colon cancer

Data from: Patterns and drivers of aquatic invertebrate diversity across an arid biome

Managing and restoring faunal diversity across large areas requires an understanding of the roles of connectivity and dispersal in driving community patterns. We sought to determine the influence of connectivity, water regime, water source, geographical location, and dispersal traits on patterns of aquatic invertebrate diversity across a continent-wide arid biome. We compiled data on freshwater invertebrate assemblages from sites spanning the breadth of arid Australia. Univariate analyses (analysis of variance and rarefaction) revealed that alpha and gamma diversity across sites decreased as latitude increased. Multivariate analyses (ordination and analysis of similarity) revealed that community composition had considerable fidelity to geographic regions. Hydrological connectivity was strongly associated with riverine community composition although water rarely flowed (often less than annually). Hydrologically isolated sites (springs and rockholes) supported communities that were markedly dissimilar to hydrologically connected sites, and to each other. We investigated the influence of dispersal on diversity patterns by examining Distance Decay Relationships for each of four dispersal trait groups (obligate aquatic and passive, weak, and strong aerial dispersers) on the basis of geodesic (shortest path) distances between pairs of sites and Mantel tests. We did not detect clear differences between dispersal traits and distance decay relationships at the continental scale, even for the two groups with the lowest dispersal ability (obligate aquatics and passive dispersers.) Our results suggest that the loss of hydrological connectivity from water developments in arid lands (for example, the impoundment of intermittent rivers) is likely to affect macroinvertebrates. However, the exact flow mechanisms underlying such changes remain to be determined