Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain.
Oncogene. 2013 May 16;32(20):2534-42. doi: 10.1038/onc.2012.278. Epub 2012 Jul 2.
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.
G 蛋白偶联受体（GPCRs）控制着关键的生理过程，其功能障碍与包括癌症在内的各种人类疾病有关。孤儿 GPCR GPR55 十多年前被鉴定和克隆，但对其生理病理相关性知之甚少。最近的研究表明，GPR55 控制着人类癌细胞系在培养和异种移植中的行为。然而，由于缺乏对癌症临床相关模型中该受体功能影响的研究，评估该受体在体内恶性转化中的实际作用受到了阻碍。在这里，我们证明 GPR55 驱动小鼠皮肤肿瘤的发展。因此，与野生型同窝仔相比，GPR55 缺陷型小鼠对 DMBA/TPA 诱导的乳头瘤和癌形成的抵抗力更强。GPR55 发挥这种促肿瘤作用主要是通过赋予癌细胞增殖优势。此外，GPR55 增强了皮肤癌细胞在体内的无锚定生长、侵袭和致瘤性，表明它不仅促进了肿瘤的发展，而且促进了肿瘤的侵袭性。最后，我们观察到 GPR55 在人类皮肤肿瘤和其他人类鳞状细胞癌中上调，与相应的健康组织相比。总之，这些发现揭示了 GPR55 在皮肤肿瘤发展中的关键重要性，并表明该受体可作为鳞状细胞癌的新生物标志物和治疗靶点。
