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The orphan receptor GPR55 drives skin carcinogenesis and is upregulated in human squamous cell carcinomas

Oncogene volume 32, pages 2534–2542 (2013)Cite this article

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Abstract

G protein-coupled receptors (GPCRs) control crucial physiological processes and their dysfunction contributes to various human diseases, including cancer. The orphan GPCR GPR55 was identified and cloned more than a decade ago, but very little is known about its physio-pathological relevance. It has been recently shown that GPR55 controls the behavior of human cancer cell lines in culture and xenografts. However, the assessment of the actual role of this receptor in malignant transformation in vivo is hampered by the lack of studies on its functional impact in clinically-relevant models of cancer. Here we demonstrate that GPR55 drives mouse skin tumor development. Thus, GPR55-deficient mice were more resistant to DMBA/TPA-induced papilloma and carcinoma formation than their wild-type littermates. GPR55 exerted this pro-tumor effect primarily by conferring a proliferative advantage on cancer cells. In addition, GPR55 enhanced skin cancer cell anchorage-independent growth, invasiveness and tumorigenicity in vivo, suggesting that it promotes not only tumor development but also tumor aggressiveness. Finally, we observed that GPR55 is upregulated in human skin tumors and other human squamous cell carcinomas compared with the corresponding healthy tissues. Altogether, these findings reveal the pivotal importance of GPR55 in skin tumor development, and suggest that this receptor may be used as a new biomarker and therapeutic target in squamous cell carcinomas.

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Acknowledgements

We are indebted to the members of our laboratories and to Dr MM Caffarel for critical discussion on this work. We thank Dr Manuel M Morente, Head of the CNIO Tumor Bank Core Unit, for kindly provided us with human tumor samples. This work was supported by grants from Fondo de Investigaciones Sanitarias (PI080253 to CS), Fundación Mutua Madrileña (to CS), GW Pharmaceuticals/Otsuka Pharmaceuticals (to CS), Comunidad de Madrid (S2010/BMD-2038 to MG) and Spanish Ministry of Science and Innovation (SAF2010-19152 to MQ and SAF2008-00121 and SAF2011-26122-C02-01 to JMP). EPG and CA were the recipients of a Postdoctoral Research Contract from Fundación Científica Asociación Española Contra el Cáncer (AECC) and a PFIS PhD studentship from the Spanish Ministry of Science and Innovation, respectively.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain

    E Pérez-Gómez, C Andradas, M Guzmán & C Sánchez

  2. Department of Animal Surgery and Medicine, School of Veterinary, Complutense University, Madrid, Spain

    J M Flores

  3. Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain

    M Quintanilla

  4. Division of Biomedicine, Molecular Oncology Unit, CIEMAT, Madrid, Spain

    J M Paramio

  5. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) and Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain

    M Guzmán

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  1. E Pérez-Gómez
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Correspondence to C Sánchez.

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Pérez-Gómez, E., Andradas, C., Flores, J. et al. The orphan receptor GPR55 drives skin carcinogenesis and is upregulated in human squamous cell carcinomas. Oncogene 32, 2534–2542 (2013). https://doi.org/10.1038/onc.2012.278

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  • DOI: https://doi.org/10.1038/onc.2012.278

Keywords

  • GPR55
  • G protein-coupled receptors
  • skin carcinogenesis
  • squamous cell carcinoma
  • cannabinoids

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