Molecular expression profiling shows overlapping pseudohypoxia phenotype and mitochondrial dysfunction in head and neck paragangliomas

The aim of the present study was to characterize the gene expression profiles of head and neck paraganglioma tumors (HN-PGL). Of the 22 cases investigated 10 carried germline SDHA/B/C/D/AF2 and TMEM127 mutations and 12 were non-carriers. Firstly, 14 HN-PGLs and 3 pools of 10 Jacobson’s nerves (JN) were analysed by gene expression Illumina Microarray Analysis. Ingenuity Pathway Analysis (IPA) revealed oxidative phosphorylation and mitochondrial dysfunction as top canonical pathways enriched in HN-PGLs compared to JN. Upstream regulator analysis highlighted activation of a hypoxia trascriptional program peculiar to the carotid body. RTqPCR confirmation and immunohistochemistry analysis of matched samples confirmed the most important hits modulated in HN-PGLs. An independent group of 8 consecutive HN-PGLs and 5 HN-PGL-derived cells were studied by western blot for protein expression of selected hits. This confirmed high protein expression of the most important modulated genes in HN-PGLs and in HN-PGL-derived cell cultures. Mitochondrial dysfunction studies, including complex I to V assembly and/or Seahorse technology, are under way in HN-PGLs and PGL-derived cells. Thus, pseudohypoxia phenotype and mitochondrial dysfunction appear to be constitutive features of HN-PGL. ACKNOWLEDGMENTS: Work supported by AIRC Grant IG 16932.