Prelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion

Jorge de la Rosa, José M.P. Freije, Rubén Cabanillas, Fernando G. Osorio, Mario F. Fraga, M. Soledad Fernández-García, Roland Rad, Víctor Fanjul, Alejandro P. Ugalde, Qi Liang, Haydn M. Prosser, Allan Bradley, Juan Cadiñanos () and Carlos López-Otín
Additional contact information
Jorge de la Rosa: Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA)
José M.P. Freije: Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo
Rubén Cabanillas: Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA)
Fernando G. Osorio: Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo
Mario F. Fraga: Unidad de Epigenética del Cáncer, IUOPA, Universidad de Oviedo
M. Soledad Fernández-García: Unidad de Histopatología Molecular, IUOPA, Universidad de Oviedo
Roland Rad: Klinikum Rechts der Isar; Technische Universität München
Víctor Fanjul: Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo
Alejandro P. Ugalde: Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo
Qi Liang: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK
Haydn M. Prosser: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK
Allan Bradley: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK
Juan Cadiñanos: Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA)
Carlos López-Otín: Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo

Nature Communications, 2013, vol. 4, issue 1, 1-9

Abstract: Abstract Defining the relationship between ageing and cancer is a crucial but challenging task. Mice deficient in Zmpste24, a metalloproteinase mutated in human progeria and involved in nuclear prelamin A maturation, recapitulate multiple features of ageing. However, their short lifespan and serious cell-intrinsic and cell-extrinsic alterations restrict the application and interpretation of carcinogenesis protocols. Here we present Zmpste24 mosaic mice that lack these limitations. Zmpste24 mosaic mice develop normally and keep similar proportions of Zmpste24-deficient (prelamin A-accumulating) and Zmpste24-proficient (mature lamin A-containing) cells throughout life, revealing that cell-extrinsic mechanisms are preeminent for progeria development. Moreover, prelamin A accumulation does not impair tumour initiation and growth, but it decreases the incidence of infiltrating oral carcinomas. Accordingly, silencing of ZMPSTE24 reduces human cancer cell invasiveness. Our results support the potential of cell-based and systemic therapies for progeria and highlight ZMPSTE24 as a new anticancer target.

Date: 2013
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DOI: 10.1038/ncomms3268

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