Untitled - Red TemÃ¡tica de investigaciÃ³n cooperativa en cÃ¡ncer

More documents

Recommendations

Info

O-14 ANALYSIS OF NEW GENES DIRECTLY REGULATED BY FOXE1 IN THYROID CELLS FERNÁNDEZ LP 1 , SANTISTEBAN P 1 1 INSTITUTO DE INVESTIGACIONES BIOMÉDICAS “ALBERTO SOLS”, MADRID (RD06/0020/0060) Variations on FOXE1 gene have been extensively associated with several types of cancer susceptibility, including papillary thyroid cancer. FOXE1 was identified as a thyroid-specific transcription factor that has a pioneer role during thyroid development and differentiation, due to its intrinsic capacity to initiate chromatin-opening events. Its function, is essential for thyroid gland development, as well as for the maintenance of the thyroid differentiated state in adults. It is known that FOXE1 recognizes and binds to a DNA sequence present in thyroglobulin (Tg) and thyroperoxidase (Tpo) promoters, two thyroid differentiation genes. However, FOXE1 binding to other DNA sequences different than Tg and Tpo promoters remains almost unexplored. In order to investigate FOXE1 downstream targets in thyroid cells, we performed a genome-wide screening that provided us insights into FOXE1 transcriptional networks in differentiated thyroid cells. For this purpose, we used PCCl3 cells, a continuous line of rat differentiated thyroid follicular cells and we performed whole genome microarray analysis after knocking-down FOXE1. Microarray data analysis, allowed us to obtain 55 differentially regulated genes (17 of them were up-regulated and 38 were down-regulated). O-15 MOLECULAR SUBSETS OF MANTLE CELL LYMPHOMA DEFINED BY THE IGHV MUTATIONAL STA- TUS AND SOX11 EXPRESSION HAVE DISTINCT BIOLOGICAL AND CLINICAL FEATURES NAVARRO A 1 , CLOT G 1 , ROYO C 1 , JARES P 1 , HADZIDIMITRIOU A 2 , AGATHANGELIDIS A 2 , BIKOS V 2 , DARZENTAS N 2 , PAPADAKI T 2 , SALAVERRIA I 3 , PINYOL M 1 , PUIG X 4 , PALOMERO J 1 , VEGLIANTE MC 1 , AMADOR V 1 , MARTÍNEZ A 1 , STEFANCIKOVA L 5 , WIESTNER A 6 , WILSON W 6 , POTT C 7 , CALASANZ MJ 8 , TRIM N 9 , ERBER W 10 , SANDER B 11 , OTT G 12 , ROSENWALD A 13 , COLOMER D 14 , GINÉ E 15 , SIEBERT R 16 , LÓPEZ-GUILLERMO A 15 , STAMATOPOULOS K 2 , BEÀ S 1 , CAMPO E 1 1 PATHOLOGY AND HEMATOLOGY DEPARTMENTS, HOSPITAL CLÍNIC, UNIVERSITY OF BARCELONA, INSTITUTE OF BIOMEDICAL RESEARCH AUGUST PI I SUNYER (IDIBAPS), BARCELONA (RD06/0020/0039) 2 INSTITUTE OF AGROBIOTECHNOLOGY, CENTER FOR RESEARCH AND TECHNOLOGY HELLAS, THESSALONIKI, GREECE 3 INSTITUTE OF BIOMEDICAL RESEARCH AUGUST PI I SUNYER (IDIBAPS), BARCELONA (RD06/0020/0039) 4 DEPARTMENT OF STATISTICS, TECHNICAL UNIVERSITY OF CATALONIA, BARCELONA 5 DEPARTMENT OF EXPERIMENTAL BIOLOGY, FACULTY OF SCIENCES, MASARYK UNIVERSITY, BRNO, CZECH REPUBLIC 6 HEMATHOLOGY BRANCH, NATIONAL HEART, LUNG, AND BLOOD INSTITUTE, BETHESDA, MD, USA 7 DEPARTMENT OF MEDICINE, UNIVERSITY MEDICAL CENTER SCHLESWIG-HOLSTEIN, KIEL, GERMANY 8 DEPARTMENT OF GENETICS, UNIVERSITY OF NAVARRA, PAMPLONA, (RD06/0020/0078) 9 ADDENBROOKE’S HOSPITAL, CAMBRIDGE, UK 10 SCHOOL OF PATHOLOGY AND LABORATORY MEDICINE, THE UNIVERSITY OF WESTERN AUSTRALIA, NEDLANDS, AUSTRALIA 11 DEPARTMENT OF LABORATORY MEDICINE, KAROLINSKA INSTITUTET, STOCKHOLM, SWEDEN 12 DEPARTMENT OF CLINICAL PATHOLOGY, ROBERT-BOSCH-KRANKENHAUS AND DR.MARGARETE FISCHER-BOSCH INSTITUTE OF CLINICAL PHARMACOLOGY, STUTTGART, GERMANY 13 UNIVERSITY OF WÜRZBURG, WÜRZBURG, GERMANY With the aim of investigating new FOXE1 direct targets, we searched for a specific FOXE1 binding sequence in promoter regions of FOXE1 statistically significant regulated genes (+/-1000pb). FOXE1 binding sequence was presented in promoter regions of 26 out of 55 differentially FOXE1 deregulated genes. In five of these promoter sequences, we have performed chromatin inmunoprecipitation analysis (ChIP). From this study we conclude that in vivo, FOXE1 binds to three regulatory regions, located close to two genes involved in thyroid differentiation and consequently, in transformation. They are new direct downstream targets of FOXE1. Furthermore, this study point out the important role of FOXE1 in regulation of a large number of genes in thyroid cells, which need to be evaluated by further studies. 14 PATHOLOGY AND HEMATOLOGY DEPARTMENTS, HOSPITAL CLÍNIC, UNIVERSITY OF BARCELONA, INSTITUTE OF BIOMEDICAL RESEARCH AUGUST PI I SUNYER (IDIBAPS), BARCELONA (RD06/0020/0014) 15 PATHOLOGY AND HEMATOLOGY DEPARTMENTS, HOSPITAL CLÍNIC, UNIVERSITY OF BARCELONA, INSTITUTE OF BIOMEDICAL RESEARCH AUGUST PI I SUNYER (IDIBAPS), BARCELONA (RD06/0020/0051) 16 INSTITUTE OF HUMAN GENETICS, UNIVERSITY KIEL, KIEL, GERMANY Mantle cell lymphoma (MCL) is a heterogeneous disease with most patients following an aggressive clinical course while others have an indolent behavior. We performed an integrative and multidisciplinary analysis of 177 MCL to determine whether the immunogenetic features of the clonotypic B cell receptors may identify different subsets of tumors. ‘Truly unmutated’ (100% identity) IGHV genes were found in 24% cases, 40% were ‘minimally/borderline mutated’ (99.9- 97%), 19% ‘significantly mutated’ (96.9-95%) and 17% ‘hypermutated’ (
O-16 ETV5 AND FOXM1 TRANSCRIPTION FACTORS ARE OVEREXPRESSED IN OVARIAN CANCER AND REGULATE CELLULAR ADHESION AND PROLIFE- RATION CONTRIBUTING TO TUMOR DISSEMINATION LLAURADÓ M 1 , MAJEM B 2 , CASTELLVÍ J 2 , CABRERA S 3 , PÉREZ-BENAVENTE A 3 , COLÁS E 1 , RIGAU M 1 , OLIVÁN M 1 , DOLL A 1 , ABAL M 1 , DOLCET X 4 , MATÍAS-GUIU X 4 , GIL-MORENO A 3 , XERCAVINS J 3 , RUIZ A 1 , REVENTÓS J 1 O-17 COUNTERACTING AUTOPHAGY OVERCOMES RESISTANCE TO EVEROLI- MUS IN MANTLE CELL LYMPHOMA ROSICH L 1 , XARGAY-TORRENT S 1 , G. LÓPEZ-GUERRA M 1 , CAMPO E 2 , COLOMER D 1 , ROUE G 1 1 HOSPITAL CLÍNIC–IDIBAPS, BARCELONA (RD06/0020/0014) 2 HOSPITAL CLÍNIC–IDIBAPS, BARCELONA (RD06/0020/0039) 1 INSTITUT RECERCA VALL HEBRÓN, BARCELONA (RD06/0020/0058) 2 PATOLOGÍA HOSPITAL VALL HEBRÓN, BARCELONA (RD06/0020/0058) 3 GINECOLOGÍA HOSPITAL VALL HEBRÓN BARCELONA (RD06/0020/0058) 4 IRB LLEIDA (RD06/0020/1034) Background and aims: Epithelial ovarian cancer is the most lethal gynecological malignancy and the fifth leading cause of cancer deaths in women in the Western world. ETS transcription factors are known to act as positive or negative regulators of the expression of genes that are involved in various biological processes. We have characterized the upregulation of the ETV5 gene (an ETS transcription factor) in endometrial cancer (Monge M 2005, 2007, 2009; Planagumà J 2011; Colás E 2012). In the present study we have investigated the role of ETV5 in epithelial ovarian cancer. Methods: We analyzed ETV5 expression by quantitative RT-PCR and immunohistochemistry in ovarian tumor samples and controls. We examined the biological effects of modulating ETV5 expression in two different human ovarian cancer cell lines. We analyzed cell adhesion proteins by using immunofluorescence and Western blot, and we performed proliferation, migration, adhesion and apoptosis assays. Moreover, we analyzed by gene expression microarray technology those genes whose expression was altered in an ovarian cancer cell line with a stable downregulation of ETV5. Results: We found ETV5 upregulated in ovarian tumor samples compared to ovarian tissue controls. The in vitro inhibition of ETV5 decreased cell proliferation in serum-deprived conditions, induced EMT and decreased cell adhesion to extracellular matrix components. ETV5 inhibition also decreased cell-cell adhesion and induced apoptosis in anchorage independent conditions. Accordingly, ETV5 upregulation induced the expression of cell adhesion molecules and enhanced cell survival in a spheroid model. The analysis of the genes and signaling pathways under the control of ETV5 in OV90 cells has unraveled new signaling pathways that interact with ETV5, among them the cell cycle progression and the TGFβ signaling pathway. In addition, we found that the down-regulation of ETV5 reduced the expression of the oncogenic transcription factor FOXM1. Consistently, FOXM1 was over-expressed in ovarian tumor samples, and its transcriptional levels increased with ETV5 transcription in ovarian tumor samples. Moreover, FOXM1 expression levels increased with tumor grade, suggesting a role in the progression of ovarian cancer. Conclusions: Our findings suggest that the overexpression of ETV5 detected in ovarian cancer cells may contribute to ovarian tumor progression through the ability of ETV5 to enhance ovarian cancer cell proliferation and ovarian cancer cell dissemination and metastasis into the peritoneal cavity by regulating the expression of cell adhesion molecules as E-cadherin as well as other transcription factors as FOXM1. References: Llauradó et al., Int J Cancer 2011; Llauradó et al., Mol Cancer Res 2012. Mantle cell lymphoma (MCL) is an aggressive B-lymphoid neoplasm with poor response to conventional chemotherapy and short survival. The phosphatidylinositol 3-kinase/Akt/mTOR survival pathway is constitutively activated in MCL cells, thereby making the mTOR inhibition an attractive therapeutic strategy. The first clinical studies of everolimus (RAD001), an mTOR inhibitor, in relapsed MCL patients have reported a significant response. Our aim was to analyze the mechanism related to everolimus resistance/sensitivity in MCL cells. Sensitivity to everolimus was analyzed in MCL cell lines and primary MCL cells. Everolimus mechanism of action was determined by flow cytometry, and western blot. Particularly, autophagy was studied by LC3BI/II expression, autophagolysosomes detection by flow cytometry and fluorescence microscopy, and siRNA-mediated gene silencing. Everolimus exerted antitumoral effect on MCL cells while sparing normal cells. In MCL cell lines this phenomenon was associated to G1 cell-cycle arrest, dephosphorylation of the mTOR downstream targets, 4E-BP1 and S6RP, and rephosphorylation of Akt. A synergistic cytotoxic effect was observed between everolimus and an Akt inhibitor, which overcame the compensatory reactivation within the mTOR signaling pathway. Interestingly, MCL cells with low response to this combination showed high levels of autophagy. Accordingly, selective triple knockdown of the autophagy genes ATG7, ATG5 and ATG3, and pre-treatment with the autophagy inhibitor hydroxychloroquine efficiently overcame the resistance to Akt/mTOR inhibitors, leading to the activation of the mitochondrial apoptotic pathway. These results suggest that autophagy induction protects MCL cells from Akt/mTOR targeting and counteracting autophagy may represent an attractive strategy for sensitizing MCL cells to everolimus-based therapy. This work was supported (in part) by grants from Fondo de Investigación Sanitaria (PI09/0060) (to GR), Ministerio de Ciencia e Innovación (SAF 09/9503) (to DC), Red Temática de Investigación Cooperativa en Cáncer (RTICC), Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness (RED 2006-20-014 to DC and 2006-20-039 to EC) and Generalitat de Catalunya (2009SGR967 to DC). LR and SX-T are recipients of predoctoral fellowships from IDIBAPS and Ministerio Ciencia e Innovación (FPU), respectively. ML-G has a contract from RED 2006-20-014. 32 33
Page 3 and 4: Programa Científico 7 Resumenes de
Page 5 and 6: 10:00 h Recepción de los Participa
Page 7: 11:10 h O-19. “PAPEL DEL CORREPRE
Page 10 and 11: O-02 p21 LOSS INDUCES AN INFLAMMATO
Page 12 and 13: O-06 CCND2 REARRANGEMENTS ARE THE M
Page 14 and 15: O-10 INFLUENCE OF LKB1/STK11 IN GEN
Page 18 and 19: O-18 PIK3CA ALTERATIONS IN BLADDER
Page 20 and 21: P-01 “HOMEOBOX NKX2-3 PROTEIN IND
Page 22 and 23: , 43
Page 24 and 25: P-03 TETRACHLORODIBENZO-P-DIOXIN DI
Page 26 and 27: P-07 DIOXIN RECEPTOR KNOCK-DOWN PRO
Page 28 and 29: P-10 MOLECULAR PATHWAYS REGULATED B
Page 30 and 31: P-14 AICAR INDUCES BAK/BAK-DEPENDEN
Page 32 and 33: P-18 DIFFERENT EXOSOME CARGO FROM P
Page 34 and 35: P-22 ÍNDICE DE RIESGO BASADO EN GE
Page 36 and 37: P-26 SECUENCIACIÓN DE ALTO RENDIMI
Page 38 and 39: P-30 GENETIC VARIANTS IN MIRNAS: NE
Page 40 and 41: P-34 CARACTERIZACIÓN CLÍNICA Y BI
Page 42 and 43: P-37 IDENTIFICATION OF PROTEIN BIOM
Page 44 and 45: P-41 LA FOSFORILACIÓN DE eIF4E AUM
Page 46: P-45 METHODS FOR RNA AND miRNA PURI
Page 49 and 50: Apellidos Nombre E-mail Grupo RTICC

Untitled - Red TemÃ¡tica de investigaciÃ³n cooperativa en cÃ¡ncer

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?