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Transcriptional Profiling Reveals Coordinated Up-Regulation of Oxidative Metabolism Genes in Thyroid Oncocytic Tumors

Institut National de la Santé et de la Recherche Médicale, Equipe Mixte INSERM-Universitaire 0018, Laboratoire de Biochimie et Biologie Moléculaire (O.B., F.S., P.Ro., V.R., Y.M., P.Re.), Service d’Endocrinologie, Nutrition et Médecine Interne, Centre Hospitalier Universitaire (P.Ro., V.R.), Angers F-49033, France; Département d’Oncologie Moléculaire, Institut Paoli-Calmettes and Unité 119, Institut National de la Santé et de la Recherche Médicale (V.N., F.B., D.B.), Marseille F-13273, France; Laboratoire Technologies Avancées pour le Génome et la Clinique/Institut National de la Santé et de la Recherche Médicale, Equipe de Recherche et d’Innovation Technologique et Methodologique 206 (B.L., S.Gr., R.H.), Marseille F-13009, France; Laboratoire d’Anatomie Pathologique, Centre Hospitalier Recherche Universitaire (S.Gu.), Tours F-37044, France; and Laboratoire d’Anatomie Pathologique, Hôpital A. Paré (B.F.), Boulogne F-92104, France

Address all correspondence and requests for reprints to: Dr. Olivier Baris, Institut National de la Santé et de la Recherche Médicale, Equipe Mixte INSERM-Universitaire 0018, Laboratoire de Biochimie et de Biologie Moléculaire, Centre Hospitalier Universitaire, 4 rue Larrey, Angers F-49033, France. E-mail: olivier.baris{at}med.univ-angers.fr.

Oncocytomas are large cell tumors characterized by an abnormal proliferation of mitochondria. To investigate this phenomenon in thyroid oncocytomas, we determined gene expression profiles of 87 samples using microarrays of 6720 PCR products from cDNA clones. Samples included 29 thyroid oncocytomas and six papillary carcinomas, the remainder representing other thyroid pathologies or mitochondria-rich tumor samples, normal thyroid samples, and two thyroid cell lines. Hierarchical clustering and supervised analysis identified two specific oncocytic clusters and 163 distinctly regulated genes between oncocytoma and normal thyroid. Differential expression of five selected genes (APOD, BCL-2, COX, CTSB, and MAP2) was confirmed by immunohistochemistry. The two specific oncocytic clusters were rich in mitochondrial genes and revealed coordinated expression of nuclear and mitochondrial respiratory chain genes. We also observed the up-regulation of genes involved in mitochondrial biogenesis, such as nuclear respiratory factor 1 and the endothelial nitric oxide synthase. Several oxidative metabolism genes were overexpressed in oncocytomas, including those from the tricarboxylic acid cycle (MDH1) and cytosolic glycolysis (GAPD, ENO1, and GPI). On the contrary, the lactate dehydrogenase A gene, involved in anaerobic metabolism, was down-regulated. Our results suggest that, unlike a large number of solid tumors, thyroid oncocytomas produce energy through an aerobic pathway.

This work was supported by grants from the French Ministry of Research, Institut National de la Santé et de la Recherche Médicale, the Paoli-Calmettes Institute, the Anti-Cancer League of the Maine et Loire, the University Hospital of Angers (PHRC 01.10), and the University of Angers.

Abbreviations: DS, Discriminating score; EST, established sequence tag; mtDNA, mitochondrial DNA; NOS3, nitric oxide synthase; NRF-1, nuclear respiratory factor 1; PGC, peroxisome proliferator-activated receptor coactivator.

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