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      GPR30, the Non-Classical Membrane G Protein Related Estrogen Receptor, Is Overexpressed in Human Seminoma and Promotes Seminoma Cell Proliferation

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          Abstract

          Background

          Testicular germ cell tumours are the most frequent cancer of young men with an increasing incidence all over the world. Pathogenesis and reasons of this increase remain unknown but epidemiological and clinical data have suggested that fetal exposure to environmental endocrine disruptors (EEDs) with estrogenic effects, could participate to testicular germ cell carcinogenesis. However, these EEDs (like bisphenol A) are often weak ligands for classical nuclear estrogen receptors. Several research groups recently showed that the non classical membrane G-protein coupled estrogen receptor (GPER/GPR30) mediates the effects of estrogens and several xenoestrogens through rapid non genomic activation of signal transduction pathways in various human estrogen dependent cancer cells (breast, ovary, endometrium). The aim of this study was to demonstrate that GPER was overexpressed in testicular tumours and was able to trigger JKT-1 seminoma cell proliferation.

          Results

          We report here for the first time a complete morphological and functional characterization of GPER in normal and malignant human testicular germ cells. In normal adult human testes, GPER was expressed by somatic (Sertoli cells) and germ cells (spermatogonia and spermatocytes). GPER was exclusively overexpressed in seminomas, the most frequent testicular germ cell cancer, localized at the cell membrane and triggered a proliferative effect on JKT-1 cells in vitro, which was completely abolished by G15 (a GPER selective antagonist) and by siRNA invalidation.

          Conclusion

          These results demonstrate that GPER is expressed by human normal adult testicular germ cells, specifically overexpressed in seminoma tumours and able to trigger seminoma cell proliferation in vitro. It should therefore be considered rather than classical ERs when xeno-estrogens or other endocrine disruptors are assessed in testicular germ cell cancers. It may also represent a prognosis marker and/or a therapeutic target for seminomas.

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          Most cited references 47

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          Epigenetics in cancer.

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            Cancer epigenomics: DNA methylomes and histone-modification maps.

            An altered pattern of epigenetic modifications is central to many common human diseases, including cancer. Many studies have explored the mosaic patterns of DNA methylation and histone modification in cancer cells on a gene-by-gene basis; among their results has been the seminal finding of transcriptional silencing of tumour-suppressor genes by CpG-island-promoter hypermethylation. However, recent technological advances are now allowing cancer epigenetics to be studied genome-wide - an approach that has already begun to provide both biological insight and new avenues for translational research. It is time to 'upgrade' cancer epigenetics research and put together an ambitious plan to tackle the many unanswered questions in this field using epigenomics approaches.
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              A transmembrane intracellular estrogen receptor mediates rapid cell signaling.

              The steroid hormone estrogen regulates many functionally unrelated processes in numerous tissues. Although it is traditionally thought to control transcriptional activation through the classical nuclear estrogen receptors, it also initiates many rapid nongenomic signaling events. We found that of all G protein-coupled receptors characterized to date, GPR30 is uniquely localized to the endoplasmic reticulum, where it specifically binds estrogen and fluorescent estrogen derivatives. Activating GPR30 by estrogen resulted in intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus. Thus, GPR30 represents an intracellular transmembrane estrogen receptor that may contribute to normal estrogen physiology as well as pathophysiology.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                4 April 2012
                : 7
                : 4
                Affiliations
                [1 ]Institut National de la Santé et de la Recherche Médicale (INSERM) UMR U1065/UNS, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe 5 « Environnement, Reproduction et Cancers Hormono-Dépendants », Nice, France
                [2 ]Université de Nice-Sophia Antipolis, Faculté de Médecine, Institut Signalisation et Pathologie (IFR 50), Nice, France
                [3 ]Centre Hospitalier Universitaire de Nice, Hôpital de l'Archet, Service d'Endocrinologie, Diabétologie et Médecine de la Reproduction, Nice, France
                [4 ]Centre Hospitalier Universitaire de Nice, Hôpital Pasteur, Laboratoire d'Anatomie et Cytologie Pathologiques, Nice, France
                [5 ]Centre Hospitalier Universitaire de Nice, Hôpital Pasteur, Service d'Urologie, Nice, France
                II Università di Napoli, Italy
                Author notes

                Conceived and designed the experiments: PF NC. Performed the experiments: NC AV AB BS. Analyzed the data: PF NC. Contributed reagents/materials/analysis tools: JFM DC. Wrote the paper: PF NC.

                Article
                PONE-D-11-21285
                10.1371/journal.pone.0034672
                3319601
                22496838
                Chevalier et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 9
                Categories
                Research Article
                Biology
                Biochemistry
                Proteins
                Intracellular Receptors
                Molecular Cell Biology
                Signal Transduction
                Signaling in Cellular Processes
                G-Protein Signaling
                Toxicology
                Toxic Agents
                Medicine
                Oncology
                Cancers and Neoplasms
                Gynecological Tumors
                Germ Cell Cancer
                Toxicology
                Toxic Agents
                Urology
                Testicular Cancer

                Uncategorized

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