Regulation of epinephrine biosynthesis in HRAS-mutant paragangliomas

in Endocrine-Related Cancer
Authors:
Minghao Li Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany
Department of Urology, Xiangya Hospital, Central South University, Changsha, China

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Susan Richter Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

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Hermine Mohr Institute for Diabetes and Cancer, Helmholtz Centre Munich, Neuherberg, Germany

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Stephan Drukewitz Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany

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Isabel Poser Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

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Daniela Stanke Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

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Bruna Calsina Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

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Angel M Martinez-Montes Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

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Marcus Quinkler Endocrinology in Charlottenburg, Berlin, Germany

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Henri J L M Timmers Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

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Svenja Nölting Medizinische Klinik Und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany
Department of Endocrinology, Diabetology and Clinical Nutrition, Universitätsspital Zürich (USZ) and University of Zurich (UZH), Zurich, Switzerland

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Felix Beuschlein Medizinische Klinik Und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany
Department of Endocrinology, Diabetology and Clinical Nutrition, Universitätsspital Zürich (USZ) and University of Zurich (UZH), Zurich, Switzerland

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Hanna Remde Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital of Würzburg, Würzburg, Germany

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Giuseppe Opocher Department of Medicine, University of Padua, Padua, Italy

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Elena Rapizzi Department of Experimental and Clinical Medicine, University of Florence, Italy

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Karel Pacak Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States

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Christina Pamporaki Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany

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Mercedes Robledo Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

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Longfei Liu Department of Urology, Xiangya Hospital, Central South University, Changsha, China

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Jingjing Jiang Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China

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Stefan R Bornstein Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany

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Graeme Eisenhofer Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany

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Stephanie M J Fliedner University Cancer Center Schleswig-Holstein, University Medical Center Schleswig-Holsten, Lübeck, Germany

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Nicole Bechmann Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

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Correspondence should be addressed to N Bechmann: Nicole.bechmann@uniklinikum-dresden.de
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The biochemical phenotype of paragangliomas (PGLs) is highly dependent on the underlying genetic background and tumor location. PGLs at extra-adrenal locations usually do not express phenylethanolamine N-methyltransferase (PNMT), the enzyme required for epinephrine production, which was explained by the absence of glucocorticoids. PGLs with pathogenic variants (PVs) in Harvey rat sarcoma viral oncogene homolog (HRAS) can occur in or outside of the adrenal, but always synthesize epinephrine independently of the localization. Here, we characterize the signaling pathways through which PVs in HRAS influence PNMT expression. Catecholamines, cortisol, and transcriptional features of PGL tissues with known genetic background were analyzed. Genetically modified rat pheochromocytoma cells carrying PVs in Hras were generated and analyzed for regulation of Pnmt expression. Elevated epinephrine contents in PGLs with PVs in HRAS were accompanied by enrichment in mitogen-activated protein kinase (MAPK) signaling compared to PGLs with PVs in genes that activate hypoxia pathways. In vitro, Hras PVs increased Pnmt expression and epinephrine biosynthesis through increased phosphorylation of stimulatory protein 1 via MAPK signaling. Here, we provide a molecular mechanism that explains the PV-dependent epinephrine production of PGLs.

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