Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore; Department of Biology, San Diego State University, San Diego, CA, USA.
Biochim Biophys Acta Mol Cell Res. 2017 Jul;1864(7):1318-1327. doi: 10.1016/j.bbamcr.2017.05.001. Epub 2017 May 2.
Dysregulation of G protein-coupled receptors (GPCRs) is known to be involved in the pathogenesis of a variety of diseases, including cancer initiation and progression. Within this family, approximately 140 GPCRs have no known endogenous ligands and these "orphan" GPCRs remain poorly characterized. The orphan GPCR GPR19 was identified and cloned 2 decades ago, but relatively little is known about its physio-pathological relevance. We observed its expression to be elevated in breast cancers and therefore sought to investigate its potential role in breast cancer pathology. In this work, we show that overexpression of GPR19 drives mesenchymal-like breast cancer cells to adopt an epithelial-like phenotype, as demonstrated by the upregulation in E-cadherin expression and changes in functional behavior. We confirm a previous report that a peptide, adropin, is an endogenous ligand for GPR19. We further show that adropin-mediated activation of GPR19 activates the MAPK/ERK1/2 pathway, which is essential for the observed upregulation in E-cadherin and accompanying phenotypic changes. The recapitulation of epithelial characteristics at the secondary tumor sites is now understood to be an essential step in the colonization process. Taken together our work shows for the first time that GPR19 plays a potential role in metastasis by promoting the mesenchymal-epithelial transition (MET) through the ERK/MAPK pathway, thus facilitating colonization of metastatic breast tumor cells.
G 蛋白偶联受体（GPCRs）的失调已知与多种疾病的发病机制有关，包括癌症的起始和进展。在这个家族中，大约有 140 种 GPCR 没有已知的内源性配体，这些“孤儿”GPCR 仍然知之甚少。孤儿 GPCR GPR19 是在 20 年前被发现并克隆的，但对其生理病理相关性的了解相对较少。我们观察到它在乳腺癌中的表达升高，因此试图研究它在乳腺癌病理中的潜在作用。在这项工作中，我们表明 GPR19 的过表达促使间充质样乳腺癌细胞采用上皮样表型，这表现为 E-钙黏蛋白表达的上调和功能行为的变化。我们证实了之前的一份报告，即肽 adropin 是 GPR19 的内源性配体。我们进一步表明，adropin 介导的 GPR19 激活激活了 MAPK/ERK1/2 途径，这对于观察到的 E-钙黏蛋白上调和伴随的表型变化是必不可少的。在次级肿瘤部位重新获得上皮特征被认为是定植过程中的一个重要步骤。总之，我们的工作首次表明，GPR19 通过 ERK/MAPK 途径促进间质上皮转化（MET），从而促进转移性乳腺癌细胞的定植，在转移中发挥潜在作用。
