TY - JOUR
T1 - Key contribution of CPEB4mediated translational control to cancer progression
AU - Ortiz-Zapater, Elena
AU - Pineda, David
AU - Martínez-Bosch, Neus
AU - Fernández-Miranda, Gonzalo
AU - Iglesias, Mar
AU - Alameda, Francesc
AU - Moreno, Mireia
AU - Eliscovich, Carolina
AU - Eyras, Eduardo
AU - Real, Francisco X.
AU - Méndez, Raúl
AU - Navarro, Pilar
N1 - Funding Information:
The authors acknowledge F. Gebauer, S. AznarBenitah, A. García de Herreros and J. Valcárcel for critical comments on the manuscript and for other valuable contributions. We also thank S. Hahn (Department of Molecular GIOncology, University of Bochum, Germany) and M. Buchholz (Department of Gastroenterology, Endocrinology and Metabolism, PhilippsUniversity of Marburg, Marburg, Germany) for providing normal pancreas RNA, O. Casanovas (Translational Research Laboratory, Catalan Institute of Oncology (ICO)–Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Spain) for his help with the T98G nude mice injections, J.R. GonzálezVallinas (Computational Genomics Group, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona (PRBB)) for assistance with Gene Ontology tools and E. Castillo from the Ultrasequencing Unit (Centre for Genomic Regulation, PRBB), S. Mojal from the Statistics Unit (IMIM, PRBB) and T. Lobato from the Histopathological Unit (IMIM, PRBB) for technical assistance. This work was funded by the research grants Instituto de Salud Carlos–Fondos Europeos de Desarrollo Regional (FEDER) (PI080421) from the Ministerio de Ciencia e Innovación (MICINN) and grants from Fundació La MaratóTV3 (051110), the American Institute for Cancer Research (AICR) (110086) and Generalitat de Catalunya (2009SGR1409) to P.N.; grants BFU200802373 and Consolider RNAREG CSD200900080 from the MICINN and grants from Fundació La MaratóTV3 (051110), AICR (110086) and Generalitat de Catalunya (2009SGR1436) to R.M.; grant SAF200760860 and Consolider ONCOBIO from the MICINN and a grant from the VI EU Framework Programme MolDiagPaCa project to F.X.R.; grants Consolider RNAREG CSD200900080 and BIO200801091 from the MICINN to E.E.; and grants from the Instituto de Salud Carlos III FEDER (RD09/0076/00036) and the Xarxa de Bancs de tumors sponsored by the Pla Director d’Oncologia de Catalunya to the MARBiobanc. P.N. is supported by the Instituto de Salud Carlos III and the Departament de Sanitat de la Generalitat de Catalunya. D.P. holds a Juan de la Cierva grant from the MICINN. N.M.B. holds a grant from the Fundación Ramón Areces. C.E. was supported by a fellowship from the DURSI (Generalitat de Catalunya) and Fons Social Europeu (ESF).
PY - 2012/1
Y1 - 2012/1
N2 - Malignant transformation, invasion and angiogenesis rely on the coordinated reprogramming of gene expression in the cells from which the tumor originated. Although deregulated gene expression has been extensively studied at genomic and epigenetic scales, the contribution of the regulation of mRNA-specific translation to this reprogramming is not well understood. Here we show that cytoplasmic polyadenylation element binding protein 4 (CPEB4), an RNA binding protein that mediates meiotic mRNA cytoplasmic polyadenylation and translation, is overexpressed in pancreatic ductal adenocarcinomas and glioblastomas, where it supports tumor growth, vascularization and invasion. We also show that, in pancreatic tumors, the pro-oncogenic functions of CPEB4 originate in the translational activation of mRNAs that are silenced in normal tissue, including the mRNA of tissue plasminogen activator, a key contributor to pancreatic ductal adenocarcinoma malignancy. Taken together, our results document a key role for post-transcriptional gene regulation in tumor development and describe a detailed mechanism for gene expression reprogramming underlying malignant tumor progression.
AB - Malignant transformation, invasion and angiogenesis rely on the coordinated reprogramming of gene expression in the cells from which the tumor originated. Although deregulated gene expression has been extensively studied at genomic and epigenetic scales, the contribution of the regulation of mRNA-specific translation to this reprogramming is not well understood. Here we show that cytoplasmic polyadenylation element binding protein 4 (CPEB4), an RNA binding protein that mediates meiotic mRNA cytoplasmic polyadenylation and translation, is overexpressed in pancreatic ductal adenocarcinomas and glioblastomas, where it supports tumor growth, vascularization and invasion. We also show that, in pancreatic tumors, the pro-oncogenic functions of CPEB4 originate in the translational activation of mRNAs that are silenced in normal tissue, including the mRNA of tissue plasminogen activator, a key contributor to pancreatic ductal adenocarcinoma malignancy. Taken together, our results document a key role for post-transcriptional gene regulation in tumor development and describe a detailed mechanism for gene expression reprogramming underlying malignant tumor progression.
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U2 - 10.1038/nm.2540
DO - 10.1038/nm.2540
M3 - Article
C2 - 22138752
AN - SCOPUS:84855540060
SN - 1078-8956
VL - 18
SP - 83
EP - 90
JO - Nature Medicine
JF - Nature Medicine
IS - 1
ER -