Stress-Induced MicroRNA-708 Impairs Beta-Cell Function and Growth

Title on article: Stress-Induced MicroRNA-708 Impairs β-Cell Function and Growt

Translational reprogramming in tumour cells can generate oncoselectivity in viral therapies

Systemic treatment of cancer requires tumour-selective therapies that eliminate cancer cells yet preserve healthy tissues from undesired damage. Tumoral transformation is associated with profound effects in translational reprogramming of gene expression, such that tumour-specific translational regulation presents an attractive possibility for generating oncoselective therapies. We recently discovered that mRNA translational control by cytoplasmic polyadenylation element-binding proteins (CPEBs) is reactivated in cancer. Here we present a novel approach to restrict genetic-engineered therapies to malignant tissues based on CPEB translational regulation of target mRNAs. We demonstrate that tumour reprogramming of CPEB-mediated mRNA stability and translational regulation modulates tumour-specific expression of viral proteins. For oncolytic adenoviruses, insertion of CPE regulatory sequences in the 3'-untranslated region of the E1A gene provides oncoselectivity, with full potency in cancer cells but attenuated in normal tissues. Our results demonstrate the potential of this strategy to improve oncolytic virus design and provide a framework for exploiting CPE-regulated transgenes for therapy.This work was supported by grants to C.F. from the Spanish Ministry of Economia y Competitividad BIO2011-30299-C02-01/02 and BIO2014-57716-C2-2-R, and receives partial support from the Generalitat de Catalunya SGR14/248. CIBER de Enfermedades Raras is an initiative of the ISCIII. The C.F. group is partially financed by the Instituto de Salud Carlos III (IIS10/00014) and cofi-nanced by Fondo Europeo de Desarrollo Regional (FEDER) and also acknowledges the support of COST Action BM1204 EUPancreas and the Spanish Adenovirus Network (AdenoNet, BIO2015-68990-REDT). R.M. received support for this work from the Fundacio´n Botı´n and the Banco Santander, through its Santander Universities Global Division, from the Asociación Española Contra el Cancer (AECC) from the Worldwide Cancer Research Foundation and from the Spanish Ministerio de Economia y Competitividad (BFU2011-30121, BFU2014-54122-P and Consolider RNAREG CSD2009-00080). This work was also supported by grants to P.N. from the Spanish Ministerio de Economía y Competitividad/ISCIII-FEDER (PI14/00125), RETIC Cancer RD12/0036/0051/FEDER and the ‘Generalitat de Catalunya’ (2014/SGR/143). We also acknowledge the support of CERCA Programme/Generalitat de Catalunya. E.V. received a fellowship from the Gobierno Vasco, Spain. This work was developed at the Centro Esther Koplowitz, Barcelona, Spain