Quantitative expression profiling of G-protein-coupled receptors (GPCRs) in metastatic melanoma: the constitutively active orphan GPCR GPR18 as novel drug target.

Qin, Y; Verdegaal, E M E; Siderius, M; Bebelman, J P; Smit, M J; Leurs, R; Willemze, R; Tensen, C P; Osanto, S

Qin, Y; Verdegaal, E M E; Siderius, M; Bebelman, J P; Smit, M J; Leurs, R; Willemze, R; Tensen, C P; Osanto, S.

Afiliación

Qin Y; Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands.

Pigment Cell Melanoma Res ; 24(1): 207-18, 2011 Feb.

Article en En | MEDLINE | ID: mdl-20880198

RESUMEN

G-protein-coupled receptors (GPCRs) have been implicated in the tumorigenesis and metastasis of human cancers and are considered amongst the most desirable targets for drug development. Utilizing a robust quantitative PCR array, we quantified expression of 94 human GPCRs, including 75 orphan GPCRs and 19 chemokine receptors, and 36 chemokine ligands, in 40 melanoma metastases from different individuals and benign nevi. Inter-metastatic site comparison revealed that orphan GPR174 and CCL28 are statistically significantly overexpressed in subcutaneous metastases, while P2RY5 is overexpressed in brain metastases. Comparison between metastases (all three metastatic sites) and benign nevi revealed that 16 genes, including six orphan receptors (GPR18, GPR34, GPR119, GPR160, GPR183 and P2RY10) and chemokine receptors CCR5, CXCR4, and CXCR6, were statistically significantly differentially expressed. Subsequent functional experiments in yeast and melanoma cells indicate that GPR18, the most abundantly overexpressed orphan GPCR in all melanoma metastases, is constitutively active and inhibits apoptosis, indicating an important role for GPR18 in tumor cell survival. GPR18 and five other orphan GPCRs with yet unknown biological function may be considered potential novel anticancer targets in metastatic melanoma.

Asunto(s)

Antineoplásicos/farmacología; Perfilación de la Expresión Génica; Regulación Neoplásica de la Expresión Génica/efectos de los fármacos; Melanoma/genética; Receptores Acoplados a Proteínas G/genética; Adulto; Anciano; Análisis por Conglomerados; Femenino; Silenciador del Gen/efectos de los fármacos; Genes Relacionados con las Neoplasias/genética; Humanos; Masculino; Persona de Mediana Edad; Metástasis de la Neoplasia; Nevo/genética; ARN Interferente Pequeño/metabolismo; Receptores Acoplados a Proteínas G/metabolismo; Saccharomyces cerevisiae/efectos de los fármacos; Saccharomyces cerevisiae/metabolismo; Transfección

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulación Neoplásica de la Expresión Génica / Perfilación de la Expresión Génica / Receptores Acoplados a Proteínas G / Melanoma / Antineoplásicos Límite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Pigment Cell Melanoma Res Asunto de la revista: NEOPLASIAS Año: 2011 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido

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