Opposing effects of HIF1α and HIF2α on chromaffin cell phenotypic features and tumor cell proliferation: Insights from MYC-associated factor X
Corresponding Author
Nan Qin
Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
Correspondence to: Nan Qin, Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden 01307, Germany, Tel.: +49-351-458-4804, Fax: +49-351-458-7346, E-mail: [email protected]Search for more papers by this authorAguirre A. de Cubas
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain
Search for more papers by this authorRuben Garcia-Martin
Department of Clinical Pathobiochemistry, Technische Universität Dresden, Dresden, Germany
Search for more papers by this authorSusan Richter
Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
Search for more papers by this authorMirko Peitzsch
Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
Search for more papers by this authorMario Menschikowski
Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
Search for more papers by this authorJacques W.M. Lenders
Medical Clinic III, Technische Universität Dresden, Dresden, Germany
Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorHenri J. L. M. Timmers
Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorMassimo Mannelli
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
Search for more papers by this authorGiuseppe Opocher
Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology IRCCS, Padova, Italy
Department of Medicine, University of Padova, Padova, Italy
Search for more papers by this authorMatina Economopoulou
Department of Ophthalmology, Technische Universität Dresden, Dresden, Germany
Search for more papers by this authorGabriele Siegert
Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
Search for more papers by this authorTriantafyllos Chavakis
Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
Medical Clinic III, Technische Universität Dresden, Dresden, Germany
Department of Clinical Pathobiochemistry, Technische Universität Dresden, Dresden, Germany
Search for more papers by this authorKarel Pacak
Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Washington DC, Bethesda, MD
Search for more papers by this authorMercedes Robledo
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain
Search for more papers by this authorGraeme Eisenhofer
Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
Medical Clinic III, Technische Universität Dresden, Dresden, Germany
Search for more papers by this authorCorresponding Author
Nan Qin
Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
Correspondence to: Nan Qin, Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden 01307, Germany, Tel.: +49-351-458-4804, Fax: +49-351-458-7346, E-mail: [email protected]Search for more papers by this authorAguirre A. de Cubas
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain
Search for more papers by this authorRuben Garcia-Martin
Department of Clinical Pathobiochemistry, Technische Universität Dresden, Dresden, Germany
Search for more papers by this authorSusan Richter
Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
Search for more papers by this authorMirko Peitzsch
Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
Search for more papers by this authorMario Menschikowski
Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
Search for more papers by this authorJacques W.M. Lenders
Medical Clinic III, Technische Universität Dresden, Dresden, Germany
Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorHenri J. L. M. Timmers
Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorMassimo Mannelli
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
Search for more papers by this authorGiuseppe Opocher
Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology IRCCS, Padova, Italy
Department of Medicine, University of Padova, Padova, Italy
Search for more papers by this authorMatina Economopoulou
Department of Ophthalmology, Technische Universität Dresden, Dresden, Germany
Search for more papers by this authorGabriele Siegert
Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
Search for more papers by this authorTriantafyllos Chavakis
Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
Medical Clinic III, Technische Universität Dresden, Dresden, Germany
Department of Clinical Pathobiochemistry, Technische Universität Dresden, Dresden, Germany
Search for more papers by this authorKarel Pacak
Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Washington DC, Bethesda, MD
Search for more papers by this authorMercedes Robledo
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain
Search for more papers by this authorGraeme Eisenhofer
Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany
Medical Clinic III, Technische Universität Dresden, Dresden, Germany
Search for more papers by this authorAbstract
Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-producing chromaffin cell tumors with diverse phenotypic features reflecting mutations in numerous genes, including MYC-associated factor X (MAX). To explore whether phenotypic differences among PPGLs reflect a MAX-mediated mechanism and opposing influences of hypoxia-inducible factor (HIF)s HIF2α and HIF1α, we combined observational investigations in PPGLs and gene-manipulation studies in two pheochromocytoma cell lines. Among PPGLs from 140 patients, tumors due to MAX mutations were characterized by gene expression profiles and intermediate phenotypic features that distinguished these tumors from other PPGLs, all of which fell into two expression clusters: one cluster with low expression of HIF2α and mature phenotypic features and the other with high expression of HIF2α and immature phenotypic features due to mutations stabilizing HIFs. Max-mutated tumors distributed to a distinct subcluster of the former group. In cell lines lacking Max, re-expression of the gene resulted in maturation of phenotypic features and decreased cell cycle progression. In cell lines lacking Hif2α, overexpression of the gene led to immature phenotypic features, failure of dexamethasone to induce differentiation and increased proliferation. HIF1α had opposing actions to HIF2α in both cell lines, supporting evolving evidence of their differential actions on tumorigenic processes via a MYC/MAX-related pathway. Requirement of a fully functional MYC/MAX complex to facilitate differentiation explains the intermediate phenotypic features in tumors due to MAX mutations. Overexpression of HIF2α in chromaffin cell tumors due to mutations affecting HIF stabilization explains their proliferative features and why the tumors fail to differentiate even when exposed locally to adrenal steroids.
Abstract
What's new?
Chromaffin cell tumors can result from mutations in a number of different genes, and they show a variety of characteristics. In this study, the authors looked at patient samples to figure out how mutations in the Myc-associated factor X (MAX) gene influences gene expression patterns in the tumors. They also manipulated cell line models to see how the interactions of MAX, HIF1α, and HIF2α affect tumor characteristics. They found that tumors resulting from MAX mutations have a distinctive gene expression profile and phenotypic characteristics. HIF1α and HIF2α have opposing influences in the cell, they found, and the relative expression of these two can alter the characteristics of the tumor.
Supporting Information
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