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Key contribution of CPEB4-mediated translational control to cancer progression

Nature Medicine volume 18, pages 83–90 (2012)Cite this article

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Abstract

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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Figure 1: CPEB4 is overexpressed in PDA cell lines and tumor tissues.
Figure 2: In vitro characterization of the effects of CPEB4 knockdown in RWP-1 cells.
Figure 3: Effects of CPEB4 knockdown in vivo on tumorigenicity in nude mice.
Figure 4: Effects of CPEB4 knockdown on proliferation, vessel density and stroma in xenograft tumors.
Figure 5: Illumina Solexa sequencing analysis of mRNAs bound to CPEB4 in RWP-1 cells.
Figure 6: tPA expression is regulated at the translational level by CPEB4 in normal and tumoral pancreatic tissues.

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Acknowledgements

The authors acknowledge F. Gebauer, S. Aznar-Benitah, 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 GI-Oncology, University of Bochum, Germany) and M. Buchholz (Department of Gastroenterology, Endocrinology and Metabolism, Philipps-University 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. González-Vallinas (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) (11-0086) and Generalitat de Catalunya (2009SGR1409) to P.N.; grants BFU2008-02373 and Consolider RNAREG CSD2009-00080 from the MICINN and grants from Fundació La MaratóTV3 (051110), AICR (11-0086) and Generalitat de Catalunya (2009SGR1436) to R.M.; grant SAF2007-60860 and Consolider ONCOBIO from the MICINN and a grant from the VI EU Framework Programme MolDiag-PaCa project to F.X.R.; grants Consolider RNAREG CSD2009-00080 and BIO2008-01091 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).

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  1. Eduardo Eyras & Raúl Méndez

    Present address: Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. Present addresses: Richard Dimbleby Department of Cancer Research, King's College London, London, UK (E.O.-Z.) and Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York, USA (C.E.).,

Authors and Affiliations

  1. Cancer Research Programme, Hospital del Mar Research Institute (IMIM), Barcelona, Spain

    Elena Ortiz-Zapater, David Pineda, Neus Martínez-Bosch, Mar Iglesias, Mireia Moreno, Francisco X Real & Pilar Navarro

  2. Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    Elena Ortiz-Zapater & Francisco X Real

  3. Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain

    Elena Ortiz-Zapater & Francisco X Real

  4. Center for Genomic Regulation (CRG), Barcelona, Spain

    David Pineda, Carolina Eliscovich & Raúl Méndez

  5. Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain

    Gonzalo Fernández-Miranda & Raúl Méndez

  6. Department of Pathology, Hospital del Mar, Parc de Salut Mar, Universitat Autónoma de Barcelona (UAB), Barcelona, Spain

    Mar Iglesias & Francesc Alameda

  7. Computational Genomics Group, Universitat Pompeu Fabra (UPF), Barcelona, Spain

    Eduardo Eyras

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Contributions

E.O.-Z. performed the experiments shown in Figures 1,2,3,4,5,6 and in Supplementary Figures 1, 3, 4 and 6–10, prepared the figures for the manuscript (except Fig. 5b) and contributed to the experimental design of the study and the preparation of the manuscript. D.P. generated the majority of the plasmids used in the study, designed the primers for the RIP validation experiments, helped with the frog surgery, injection of the oocytes, reporter analyses and in vivo experiments and prepared Figures 5b, 6d and 6f and Supplementary Figure 2. N.M.-B. established the RWP-1 LUC cell line, helped with the in vivo experiments, performed immunohistochemistry analyses of the Capan-1 xenografts and performed all the statistical analyses. D.P. and N.M.-B. prepared Figure 3 and Supplementary Figure 5 and made useful contributions to the experimental design and the interpretation of the data. G.F.-M. generated Capan-1 shCtrl and shCPEB4 cells and contributed to the interpretation of the data. M.I. supplied all the human pancreatic samples used in the study and helped with the histopathological analyses of all the immunohistochemistries performed in samples from both mice and humans. F.A. supplied human glioblastoma samples and helped with the histopathological and immunohistochemistries analyses in tumors from both mice and humans. M.M. helped with the in vivo experiments. C.E. generated the data shown at the bottom of Figure 6b. E.E. performed the analysis of the data generated in the Illumina Solexa sequencing, performed the motif analysis of the 3′ UTR sequences shown in Figure 5a, generated the data shown in Supplementary Figures 6 and 7 and contributed to the preparation of the manuscript. F.X.R. contributed to the study design, data analysis and manuscript preparation. P.N. and R.M. directed the study and wrote the manuscript, which all authors approved.

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Correspondence to Raúl Méndez or Pilar Navarro.

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Ortiz-Zapater, E., Pineda, D., Martínez-Bosch, N. et al. Key contribution of CPEB4-mediated translational control to cancer progression. Nat Med 18, 83–90 (2012). https://doi.org/10.1038/nm.2540

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