Tumour growth and resistance to gemcitabine of pancreatic cancer cells are decreased by AP-2α overexpression

International audienceBACKGROUND: Activator protein-2alpha (AP-2alpha) is a transcription factor that belongs to the family of AP-2 proteins that have essential roles in tumorigenesis. Indeed, AP-2alpha is considered as a tumour-suppressor gene in different tissues such as colonic, prostatic or breast epithelial cells. Moreover, AP-2alpha also participates in the control of colon and breast cancer cells sensitivity towards chemotherapeutic drugs. Despite its potential interest, very few data are available regarding the roles of AP-2alpha in pancreatic cancer. METHODS: We have developed a stable pancreatic CAPAN-1 cell line overexpressing AP-2alpha. Consequences of overexpression were studied in terms of in vivo cell growth, gene expression, migration capacity and chemosensitivity. RESULTS: In vivo tumour growth of CAPAN-1 cells overexpressing AP-2alpha was significantly decreased by comparison to control cells. An altered expression pattern of cell cycle-controlling factors (CDK-4, CDK-6, cyclin-G1, p27(kip1) and p57(kip2)) was observed in AP-2alpha-overexpressing clones by microarrays and western blot analysis. Promoter activity and ChIP analysis indicated that AP-2alpha induces p27(kip1) protein levels by direct binding to and transactivation of its promoter. Moreover, AP-2alpha overexpression increased the chemosensitivity of CAPAN-1 cells to low doses of gemcitabine and reduced their in vitro migration capacity. CONCLUSION: Our data suggested that AP-2alpha overexpression could be exploited to decrease in vivo tumour growth of pancreatic cancer cells and to increase their sensitivity to gemcitabine

Steppes, savannahs, forests and phytodiversity reservoirs during the Pleistocene in the Iberian Peninsula

A palaeobotanical analysis of the Pleistocene floras and vegetation in the Iberian Peninsula shows the existence of patched landscapes with Pinus woodlands, deciduous and mixed forests, parklands (savannah-like), shrublands, steppes and grasslands. Extinctions of Arctotertiary woody taxa are recorded during the Early and Middle Pleistocene, but glacial refugia facilitated the survival of a number of temperate, Mediterranean and Ibero-North African woody angiosperms. The responses of Iberian vegetation to climatic changes during the Pleistocene have been spatially and temporarily complex, including rapid changes of vegetation in parallel to orbital and suborbital variability, and situations of multi-centennial resilience or accommodation to climatic changes. Regional characteristics emerged as soon as for the Middle Pleistocene, if not earlier: Ericaceae in the Atlantic coast indicating wetter climate, thermo-mediterranean elements in the south as currently, and broad-leaf trees in the northeastern. Overall, steppe landscapes and open Pinus woodlands prevailed over many continental regions during the cold spells of the Late Pleistocene. The maintenance of a high phytodiversity during the glacials was linked to several refuge zones in the coastal shelves of the Mediterranean and intramountainous valleys. Northern Iberia, especially on coastal areas, was also patched with populations of tree species, and this is not only documented by palaeobotanical data (pollen, charcoal) but also postulated by phylogeographical models

A miR-200b/200c/429-Binding Site Polymorphism in the 3′ Untranslated Region of the AP-2α Gene Is Associated with Cisplatin Resistance

The transcription factor AP-2α functions as a tumor suppressor by regulating various genes that are involved in cell proliferation and apoptosis. Chemotherapeutic drugs including cisplatin induce post-transcriptionally endogenous AP-2α, which contributes to chemosensitivity by enhancing therapy-induced apoptosis. microRNAs (miRNAs) miR-200b, miR-200c and miR-429 (miR-200b/200c/429) are up-regulated in endometrial and esophageal cancers, and their overexpression correlates with resistance to cisplatin treatment. Using computational programs, we predicted that the 3′ untranslated region (UTR) of AP-2α gene contains a potential miRNA response element (MRE) for the miR-200b/200c/429 family, and the single nucleotide polymorphism (SNP) site rs1045385 (A or C allele) resided within the predicted MRE. Luciferase assays and Western blot analysis demonstrated that the miR-200b/200c/429 family recognized the MRE in the 3′ UTR of AP-2α gene and negatively regulated the expression of endogenous AP-2α proteins. SNP rs1045385 A>C variation enhanced AP-2α expression by disrupting the binding of the miR-200b/200c/429 family to the 3′ UTR of AP-2α. The effects of the two polymorphic variants on cisplatin sensitivity were determined by clonogenic assay. The overexpression of AP-2α with mutant 3′ UTR (C allele) in the endometrial cancer cell line HEC-1A, which has high levels of endogenous miR-200b/200c/429 and low levels of AP-2α protein, significantly increased cisplatin sensitivity, but overexpression of A allele of AP-2α has no significant effects, compared with mock transfection. We concluded that miR-200b/200c/429 induced cisplatin resistance by repressing AP-2α expression in endometrial cancer cells. The SNP (rs1045385) A>C variation decreased the binding of miR-200b/200c/429 to the 3′ UTR of AP-2α, which upregulated AP-2α protein expression and increased cisplatin sensitivity. Our results suggest that SNP (rs1045385) may be a potential prognostic marker for cisplatin treatment

Low dose cranial irradiation-induced cerebrovascular damage is reversible in mice

BACKGROUND: High-dose radiation-induced blood-brain barrier breakdown contributes to acute radiation toxicity syndrome and delayed brain injury, but there are few data on the effects of low dose cranial irradiation. Our goal was to measure blood-brain barrier changes after low (0.1 Gy), moderate (2 Gy) and high (10 Gy) dose irradiation under in vivo and in vitro conditions. METHODOLOGY: Cranial irradiation was performed on 10-day-old and 10-week-old mice. Blood-brain barrier permeability for Evans blue, body weight and number of peripheral mononuclear and circulating endothelial progenitor cells were evaluated 1, 4 and 26 weeks postirradiation. Barrier properties of primary mouse brain endothelial cells co-cultured with glial cells were determined by measurement of resistance and permeability for marker molecules and staining for interendothelial junctions. Endothelial senescence was determined by senescence associated β-galactosidase staining. PRINCIPLE FINDINGS: Extravasation of Evans blue increased in cerebrum and cerebellum in adult mice 1 week and in infant mice 4 weeks postirradiation at all treatment doses. Head irradiation with 10 Gy decreased body weight. The number of circulating endothelial progenitor cells in blood was decreased 1 day after irradiation with 0.1 and 2 Gy. Increase in the permeability of cultured brain endothelial monolayers for fluorescein and albumin was time- and radiation dose dependent and accompanied by changes in junctional immunostaining for claudin-5, ZO-1 and β-catenin. The number of cultured brain endothelial and glial cells decreased from third day of postirradiation and senescence in endothelial cells increased at 2 and 10 Gy. CONCLUSION: Not only high but low and moderate doses of cranial irradiation increase permeability of cerebral vessels in mice, but this effect is reversible by 6 months. In-vitro experiments suggest that irradiation changes junctional morphology, decreases cell number and causes senescence in brain endothelial cells

A method for climatic reconstruction of the Mediterranean Pliocene using pollen data

International audiencePollen data from numerous sites around the Mediterranean Sea indicate that several important vegetation and climatic changes occurred during the Pliocene. These data are in good agreement with pollen records from northwest Europe and with delta(18)O curves from Mediterranean and Atlantic deep-sea cores. Quantitative palaeoclimatic reconstructions from Pliocene pollen data of the Mediterranean region cannot be based on conventional modem analogue techniques, as individual Pliocene pollen spectra contain taxa representing temperate, warm-temperate and subtropical plants that do not grow together today. instead, we propose a new method that uses a climatic amplitude method modified to take partially into account the relative abundances of the taxa. We applied this method to the Pliocene Garraf 1 palynological sequence from Catalonia, which provides a long continuous record of climatic change from 5.3 Ma to the Early Pleistocene. We estimate that annual temperatures were 1 to 5 degrees C higher than today and the annual precipitation 400 to 1000 mm higher than today prior to the beginning of the late Cenozoic glacial-interglacial cycles. in contrast, temperature and precipitation both fell sharply during the glacial phases of the earliest glacial-interglacial cycles. (C) 1998 Elsevier Science B.V. All rights reserved

Histoire plio-pléistocène des écosystèmes végétaux de Méditerranée sud-occidentale : apport de l'analyse pollinique de deux sondages en mer d'Alboran

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The historical origins of aridity and vegetation degradation in southeastern Spain

6 páginas, 4 figuras.The complex relationships within modern landscapes cannot be understood without the benefit of retrospective studies. We review palaeoenvironmental data for southeastern Spain, a landscape vulnerable to desertification and with antiquity of human pressure on the landscape. A xerophytic component is discernible in the pollen diagrams of the southeastern peninsula ever since the Middle Miocene. During glacial stages of the Pleistocene, mountain grasslands and lowland steppes expanded, but tree vegetation, although episodically contracted, was ever present across the region, explaining part of the modern plant-species diversity. The magnitude of human impacts on vegetation during the Holocene has been highly variable, starting earlier (e.g. after c. 5000 cal years BP) in low-elevation areas and river basins. Forest degradation of the mountains started rather late during the Argaric period, and reached its maximum during the Roman occupation. Over the last millennia, natural and/or human-set fires, combined with overgrazing, probably have pushed forests over a threshold leading to the spread of grassland, thorny scrub, junipers, and nitrophilous communities. The high degree of xerophytization observed today in southeastern Spain results from the long-term determinism of the Mid to Late Holocene climate aridification, and the contingency of historical factors like fire events and changes in prehistoric local economies involving resource exhaustion.This researchhas beenfunded by the projectsCGL-2006-2956-BOS (Ministerio de Educación y Ciencia, Madrid) and Paleodiversitas Network (Fundación Séneca, Murcia). This paper is an ISEM contribution no. 2008–113.Peer reviewe

Vegetation, climate and palaeoaltitude reconstructions of the Eastern Alps during the Miocene based on pollen records from Austria, Central Europe.

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Bioclimatic signification of marker taxa of the Mediterranean Pliocene

International audienceThe climatic reconstruction of the Pliocene, based on pollen data, requires a new method of quantification because of the presence in pollen spectra, of temperate, warm-temperate but also subtropical plants. As no modern pollen spectra contain all these taxa, the best analogues method is inappropriate for this period. So, a new method is proposed: it corresponds to a climatic amplitude method modified to partially take into account some taxa abundances. The first step in this new method is to determine the present-day distribution of a few subtropical plants and some taxa still existing in the Mediterranean region with a good climatic signal. Then, the climatic parameters of the corresponding areas are defined, either by a climatic atlas or by personal knowledge. A test on a few pollen spectra, corresponding to different localities but of almost the same age (about 3.4 Ma) is realised. The first results of climatic estimation confirm an increasing latitudinal gradient for annual temperatures from North to South, which is estimated as today, even if the temperatures were higher (about 2 to 6 degrees C more). We may confirm the same for the precipitations which were more important to the North than to the South of the Mediterranean. These latitudinal gradients are quantified