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An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells

Oncogene volume 29, pages 6522–6532 (2010)Cite this article

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Abstract

In this study, we demonstrate that the expression in tumorigenic epidermal cells of a catalytically inactive form of CYLD (CYLDC/S) that mimics the identified mutations of cyld in human tumors and competes with the endogenous CYLD results in enhanced cell proliferation and inhibition of apoptosis; it also stimulates cell migration and induces the expression of angiogenic factors, including vascular endothelial growth factor-A. Altogether, these characteristics indicate an increased oncogenicity of the tumorigenic epidermal CYLDC/S mutant cells in vitro. Moreover, we show the increase in malignancy of epidermal squamous cell carcinomas that express the CYLDC/S transgene in an in vivo xenograft model. Tumors carrying the mutated CYLDC/S exhibit a fast growth, are poorly differentiated and present a robust angiogenesis. CYLDC/S tumors are also characterized by their elevated proliferation rate and decreased apoptosis. In contrast with previous studies showing the development of benign tumors by mutations in the CYLD gene, here we provide evidence that the occurrence of mutations in the CYLD gene in tumorigenic epidermal cells (carrying previous mutations) increases the aggressiveness of carcinomas, mainly through enhancement of the expression of angiogenic factors, having therefore a key role in epidermal cancer malignancy.

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Abbreviations

NMSC:

non-melanoma skin cancer

HA:

hemagglutinin-A

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Acknowledgements

We thank Dr R Bernards for providing the CYLDC/S cDNA; M Isabel de los Santos and Federico Sánchez-Sierra for invaluable assistance in the histological and immunohistochemical analyses; Juan Manuel Luque and Soledad Moreno for technical assistance; and Jesús Martínez, Edilia Almeida and the personnel of the CIEMAT Animal Unit for care of the mice used. This work was funded by grant from the Ministerio de Sanidad (PI061233, PI060655) to MLC and AR respectively and a grant from the Ministerio de Educación y Ciencia (PSE-010000-2008-7).

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  1. J P Alameda and R Moreno-Maldonado: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Epithelial Biomedicine, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain

    J P Alameda, R Moreno-Maldonado, M Navarro, A Ramírez, A Page, J L Jorcano & M L Casanova

  2. Department of Veterinary Clinical Sciences, Veterinary Faculty, University of Santiago de Compostela, Lugo, Spain

    A Bravo

  3. Department of Pathology, Fundación Jiménez Díaz, Madrid, Spain

    M J Fernández-Aceñero

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  1. J P Alameda
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Correspondence to M L Casanova.

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Alameda, J., Moreno-Maldonado, R., Navarro, M. et al. An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells. Oncogene 29, 6522–6532 (2010). https://doi.org/10.1038/onc.2010.378

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