The present study aimed to characterize the molecular expression profiles of head and neck paragangliomas. Of the 22 cases investigated 10 carried germline class 3 to 5 sequence variants of the SDHA/B/C/D/AF2and TMEM127genes, 12 were non- carriers. Firstly, 14 HN-PGLs and 3 pools of 10 Jacobson’s nerves were analysed by gene expression microarray analysis.Pathway enrichment (IPA) revealed oxidative phosphorylation and mitochondrial dysfunction as top canonical pathways enriched in paragangliomas, with 13 and 15 upregulated genes respectively. These genes encoded proteins mainly localized in complex I of the mitochondrial electron transport chain. Upstream regulator analysis highlighted activation of a hypoxia transcriptional program peculiar to the carotid body. RNA expression and/or immunohistochemistry analysis of matched samples confirmed the most important hits modulated in paragangliomas (DLK1, NDUFA4L2, ADM, RGS4 and RGS5). High expression of the protein products of these genes was independently confirmed by immunofluorescence, immunohistochemistry and western blot in an another group of head and neck paragangliomas and in 2 out of 5 paraganglioma-derived cell cultures. In conclusion, DLK1, NDUFA4L2, ADM, RGS4 and RGS5 are expressed in both SDHx-related and unrelated paragangliomas. The EGF-like transmembrane protein DLK1 is a regulator of cell growth and differentiation widely expressed during the fetal period in the adrenal medulla and in the organ of Zuckerkandl (1). NDUFA4L2 links the pseudohypoxia phenotype to mitochondrial complex I dysfunction, whereas RGS4 and RGS5 are G-protein signaling regulators of vascular mural cells (2). Our data suggest that pseudohypoxia, mitochondrial dysfunction and aberrant vasculogenesis are constitutive features of paragangliomas. 1) El Faitwri T, Huber K. Gene Expr Patterns. 2018 Aug 23;30:49-54. doi: 10.1016/j.gep.2018.08.005. 2) Manzur M, Hamzah J, Ganss R. Cancer Res. 2009 Jan 15;69(2):396-9. doi: 10.1158/0008-5472.CAN-08-2842.
Molecular expression profiling shows pseudohypoxia phenotype, vasculogenesis and mitochondrial dysfunction in head and neck paragangliomas
D. L. Esposito
;F. Verginelli;M. R. Pantalone;S. Perconti;S. Valentinuzzi;M. Vacca;F. Napolitano;S. Vespa;G. M. Aceto;C. Moscatello;R. Lattanzio;C. T. Paties;M. Sanna;R. Mariani-Costantini
2018-01-01
Abstract
The present study aimed to characterize the molecular expression profiles of head and neck paragangliomas. Of the 22 cases investigated 10 carried germline class 3 to 5 sequence variants of the SDHA/B/C/D/AF2and TMEM127genes, 12 were non- carriers. Firstly, 14 HN-PGLs and 3 pools of 10 Jacobson’s nerves were analysed by gene expression microarray analysis.Pathway enrichment (IPA) revealed oxidative phosphorylation and mitochondrial dysfunction as top canonical pathways enriched in paragangliomas, with 13 and 15 upregulated genes respectively. These genes encoded proteins mainly localized in complex I of the mitochondrial electron transport chain. Upstream regulator analysis highlighted activation of a hypoxia transcriptional program peculiar to the carotid body. RNA expression and/or immunohistochemistry analysis of matched samples confirmed the most important hits modulated in paragangliomas (DLK1, NDUFA4L2, ADM, RGS4 and RGS5). High expression of the protein products of these genes was independently confirmed by immunofluorescence, immunohistochemistry and western blot in an another group of head and neck paragangliomas and in 2 out of 5 paraganglioma-derived cell cultures. In conclusion, DLK1, NDUFA4L2, ADM, RGS4 and RGS5 are expressed in both SDHx-related and unrelated paragangliomas. The EGF-like transmembrane protein DLK1 is a regulator of cell growth and differentiation widely expressed during the fetal period in the adrenal medulla and in the organ of Zuckerkandl (1). NDUFA4L2 links the pseudohypoxia phenotype to mitochondrial complex I dysfunction, whereas RGS4 and RGS5 are G-protein signaling regulators of vascular mural cells (2). Our data suggest that pseudohypoxia, mitochondrial dysfunction and aberrant vasculogenesis are constitutive features of paragangliomas. 1) El Faitwri T, Huber K. Gene Expr Patterns. 2018 Aug 23;30:49-54. doi: 10.1016/j.gep.2018.08.005. 2) Manzur M, Hamzah J, Ganss R. Cancer Res. 2009 Jan 15;69(2):396-9. doi: 10.1158/0008-5472.CAN-08-2842.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
